Cutis

What does your patient need to know at the first visit?

Most important is what you need to know before the first visit. As the prescribing physician, you must be familiar with the iPLEDGE program. Because of the complexity of the program, consider identifying a physician in your area to refer patients if you are not going to be a regular prescriber of the medication. 

If you are enrolled in iPLEDGE, let your patients (and/or their parents/guardians) know that there is a great deal of misinformation on the Internet. Reiterate that you and your staff are available to discuss their concerns. Also, give them reliable sources of information, such as the American Academy of Dermatology's patient information sheet as well as the Mayo Clinic's acne information. Drugs.com is another resource.

All patients—males, females who cannot become pregnant, and females of childbearing potential (FCBPs)—must be aware that this medication can cause birth defects if taken during pregnancy. They must be informed that the medication is not to be shared with anyone and that they should not give blood while taking this medication.

What treatment course do you recommend?

My evidence-based approach is a course of isotretinoin totaling a minimum of 150 mg per kilogram body weight. Do not give a more abbreviated course unless the patient has cleared early; even then I tend to complete 150 mg when possible. There is published evidence that pushing the course to a total of 220 mg per kilogram body weight results in a longer remission. 

Generally, I do few laboratory tests other than pretreatment lipid panels as well as 1 or 2 follow-up lipid panels at monthly intervals. To comply with the iPLEDGE program, FCBP patients must have a monthly pregnancy test, which is reported on the iPLEDGE website before the patient can be prescribed the drug and receive the drug from a pharmacist who is participating in the iPLEDGE program.

One of the defects of the iPLEDGE system is that although only a 30-day supply of pills can be prescribed, it is difficult to always bring a patient back in exactly 30 days; for example, we work on a 4-week cycle and 30 days brings us into the next week or uncommonly the weekend when we do not see patients. Our male patients or females not of childbearing potential are not affected, but for our FCBP patients, it means usually scheduling visits at 35-day intervals because the pregnancy tests must be performed at minimum 28-day intervals and the prescription cannot be written and the pregnancy test recorded until after at least 30 days. 

What are the side effects?

The common side effects are what you would expect from a medicine that is supposed to dry up the oil on your skin: dryness of the lips, mouth, and skin, as well as rashes due to the dryness. There also can be minor swelling of the eyelids or lips, nosebleeds, upset stomach, and thinning of the hair; dryness of the scalp may occur. I recommend using a little petroleum jelly inside the nostrils at night to counteract the dryness that leads to nosebleeds, and saline drops or gel for the eyes, especially for contact lens wearers.

Joint aches and pains have been reported, though I rarely see those effects in patients who are physically active such as those participating in competitive sports. Mood changes have been reported, including suicidal ideation.

What do you do if patients refuse treatment?

There is so much false information on the Internet about the dangers of isotretinoin, leaving some patients (and parents/guardians) too afraid to use it. I sympathize with this anxiety, but I do endeavor to point out that the birth defects occur only in women taking the drug while pregnant and have not been reported to occur after the drug is out of the patient's system. 

Similarly, I point out that almost all of the evidence-based studies failed to confirm any association between the use of isotretinoin and depression, teenage suicide, and subsequent inflammatory bowel disease. Nonetheless, I mention these issues and recommend that the parents/guardians observe the teenager; in the case of adult patients, they themselves must be sensitive to symptoms.

Suggested Readings

American Academy of Dermatology Association. Position statement on isotretinoin. https://www.aad.org/Forms/Policies/Uploads/PS/PS-Isotretinoin.pdf. Published December 9, 2000. Updated November 13, 2010. Accessed May 18, 2017.

Blasiak RC, Stamey CR, Burkhart CN, et al. High-dose isotretinoin treatment and the rate of retrial, relapse, and adverse effects in patients with acne vulgaris. JAMA Dermatol. 2013;149:1392-1398.

What does your patient need to know at the first visit?

Most important is what you need to know before the first visit. As the prescribing physician, you must be familiar with the iPLEDGE program. Because of the complexity of the program, consider identifying a physician in your area to refer patients if you are not going to be a regular prescriber of the medication. 

If you are enrolled in iPLEDGE, let your patients (and/or their parents/guardians) know that there is a great deal of misinformation on the Internet. Reiterate that you and your staff are available to discuss their concerns. Also, give them reliable sources of information, such as the American Academy of Dermatology's patient information sheet as well as the Mayo Clinic's acne information. Drugs.com is another resource.

All patients—males, females who cannot become pregnant, and females of childbearing potential (FCBPs)—must be aware that this medication can cause birth defects if taken during pregnancy. They must be informed that the medication is not to be shared with anyone and that they should not give blood while taking this medication.

What treatment course do you recommend?

My evidence-based approach is a course of isotretinoin totaling a minimum of 150 mg per kilogram body weight. Do not give a more abbreviated course unless the patient has cleared early; even then I tend to complete 150 mg when possible. There is published evidence that pushing the course to a total of 220 mg per kilogram body weight results in a longer remission. 

Generally, I do few laboratory tests other than pretreatment lipid panels as well as 1 or 2 follow-up lipid panels at monthly intervals. To comply with the iPLEDGE program, FCBP patients must have a monthly pregnancy test, which is reported on the iPLEDGE website before the patient can be prescribed the drug and receive the drug from a pharmacist who is participating in the iPLEDGE program.

One of the defects of the iPLEDGE system is that although only a 30-day supply of pills can be prescribed, it is difficult to always bring a patient back in exactly 30 days; for example, we work on a 4-week cycle and 30 days brings us into the next week or uncommonly the weekend when we do not see patients. Our male patients or females not of childbearing potential are not affected, but for our FCBP patients, it means usually scheduling visits at 35-day intervals because the pregnancy tests must be performed at minimum 28-day intervals and the prescription cannot be written and the pregnancy test recorded until after at least 30 days. 

What are the side effects?

The common side effects are what you would expect from a medicine that is supposed to dry up the oil on your skin: dryness of the lips, mouth, and skin, as well as rashes due to the dryness. There also can be minor swelling of the eyelids or lips, nosebleeds, upset stomach, and thinning of the hair; dryness of the scalp may occur. I recommend using a little petroleum jelly inside the nostrils at night to counteract the dryness that leads to nosebleeds, and saline drops or gel for the eyes, especially for contact lens wearers.

Joint aches and pains have been reported, though I rarely see those effects in patients who are physically active such as those participating in competitive sports. Mood changes have been reported, including suicidal ideation.

What do you do if patients refuse treatment?

There is so much false information on the Internet about the dangers of isotretinoin, leaving some patients (and parents/guardians) too afraid to use it. I sympathize with this anxiety, but I do endeavor to point out that the birth defects occur only in women taking the drug while pregnant and have not been reported to occur after the drug is out of the patient's system. 

Similarly, I point out that almost all of the evidence-based studies failed to confirm any association between the use of isotretinoin and depression, teenage suicide, and subsequent inflammatory bowel disease. Nonetheless, I mention these issues and recommend that the parents/guardians observe the teenager; in the case of adult patients, they themselves must be sensitive to symptoms.

Suggested Readings

American Academy of Dermatology Association. Position statement on isotretinoin. https://www.aad.org/Forms/Policies/Uploads/PS/PS-Isotretinoin.pdf. Published December 9, 2000. Updated November 13, 2010. Accessed May 18, 2017.

Blasiak RC, Stamey CR, Burkhart CN, et al. High-dose isotretinoin treatment and the rate of retrial, relapse, and adverse effects in patients with acne vulgaris. JAMA Dermatol. 2013;149:1392-1398.

What does your patient need to know at the first visit?

Most important is what you need to know before the first visit. As the prescribing physician, you must be familiar with the iPLEDGE program. Because of the complexity of the program, consider identifying a physician in your area to refer patients if you are not going to be a regular prescriber of the medication. 

If you are enrolled in iPLEDGE, let your patients (and/or their parents/guardians) know that there is a great deal of misinformation on the Internet. Reiterate that you and your staff are available to discuss their concerns. Also, give them reliable sources of information, such as the American Academy of Dermatology's patient information sheet as well as the Mayo Clinic's acne information. Drugs.com is another resource.

All patients—males, females who cannot become pregnant, and females of childbearing potential (FCBPs)—must be aware that this medication can cause birth defects if taken during pregnancy. They must be informed that the medication is not to be shared with anyone and that they should not give blood while taking this medication.

What treatment course do you recommend?

My evidence-based approach is a course of isotretinoin totaling a minimum of 150 mg per kilogram body weight. Do not give a more abbreviated course unless the patient has cleared early; even then I tend to complete 150 mg when possible. There is published evidence that pushing the course to a total of 220 mg per kilogram body weight results in a longer remission. 

Generally, I do few laboratory tests other than pretreatment lipid panels as well as 1 or 2 follow-up lipid panels at monthly intervals. To comply with the iPLEDGE program, FCBP patients must have a monthly pregnancy test, which is reported on the iPLEDGE website before the patient can be prescribed the drug and receive the drug from a pharmacist who is participating in the iPLEDGE program.

One of the defects of the iPLEDGE system is that although only a 30-day supply of pills can be prescribed, it is difficult to always bring a patient back in exactly 30 days; for example, we work on a 4-week cycle and 30 days brings us into the next week or uncommonly the weekend when we do not see patients. Our male patients or females not of childbearing potential are not affected, but for our FCBP patients, it means usually scheduling visits at 35-day intervals because the pregnancy tests must be performed at minimum 28-day intervals and the prescription cannot be written and the pregnancy test recorded until after at least 30 days. 

What are the side effects?

The common side effects are what you would expect from a medicine that is supposed to dry up the oil on your skin: dryness of the lips, mouth, and skin, as well as rashes due to the dryness. There also can be minor swelling of the eyelids or lips, nosebleeds, upset stomach, and thinning of the hair; dryness of the scalp may occur. I recommend using a little petroleum jelly inside the nostrils at night to counteract the dryness that leads to nosebleeds, and saline drops or gel for the eyes, especially for contact lens wearers.

Joint aches and pains have been reported, though I rarely see those effects in patients who are physically active such as those participating in competitive sports. Mood changes have been reported, including suicidal ideation.

What do you do if patients refuse treatment?

There is so much false information on the Internet about the dangers of isotretinoin, leaving some patients (and parents/guardians) too afraid to use it. I sympathize with this anxiety, but I do endeavor to point out that the birth defects occur only in women taking the drug while pregnant and have not been reported to occur after the drug is out of the patient's system. 

Similarly, I point out that almost all of the evidence-based studies failed to confirm any association between the use of isotretinoin and depression, teenage suicide, and subsequent inflammatory bowel disease. Nonetheless, I mention these issues and recommend that the parents/guardians observe the teenager; in the case of adult patients, they themselves must be sensitive to symptoms.

Suggested Readings

American Academy of Dermatology Association. Position statement on isotretinoin. https://www.aad.org/Forms/Policies/Uploads/PS/PS-Isotretinoin.pdf. Published December 9, 2000. Updated November 13, 2010. Accessed May 18, 2017.

Blasiak RC, Stamey CR, Burkhart CN, et al. High-dose isotretinoin treatment and the rate of retrial, relapse, and adverse effects in patients with acne vulgaris. JAMA Dermatol. 2013;149:1392-1398.

Reflectance confocal microscopy (RCM) imaging received Category I Current Procedural Terminology (CPT) codes by the Centers for Medicare & Medicaid Services in January 2016 and can now be submitted to insurance companies with reimbursement comparable to a skin biopsy or a global skin pathology service.¹ This fairly new technology is a US Food and Drug Administration–cleared noninvasive imaging modality that provides high-resolution in vivo cellular images of the skin. It has been shown to be efficacious in differentiating benign and malignant skin lesions, increasing diagnostic accuracy, and reducing the number of unnecessary skin biopsies that are performed. In addition to skin cancer diagnosis, RCM imaging also can help guide management of malignant lesions by detecting lateral margins prior to surgery as well as monitoring the lesion over time for treatment efficacy or recurrence. The potential impact of RCM imaging is tremendous, and reimbursement may lead to increased use in clinical practice to the benefit of our patients. Herein, we present a brief review of RCM imaging and reimbursement as well as the benefits and limitations of this new technology for dermatologists.

Reflectance Confocal Microscopy

In vivo RCM allows us to visualize the epidermis in real time on a cellular level down to the papillary dermis at a high resolution (×30) comparable to histologic examination. With optical sections 3- to 5-µm thick and a lateral resolution of 0.5 to 1.0 µm, RCM produces a stack of 500×500-µm² images up to a depth of approximately 200 µm.^2,3 At any chosen depth, these smaller images are stitched together with sophisticated software into a block, or mosaic, increasing the field of view to up to 8×8 mm². Imaging is performed in en face planes oriented parallel to the skin surface, similar to dermoscopy.

Current CPT Guidelines and Reimbursement

The CPT codes for RCM imaging provide reimbursement on a per-lesion basis and are similar to those used for skin biopsy and pathology (Table).¹ Codes 96931 through 96933 are used for imaging of a single lesion on a patient. The first code—96931—is used when image acquisition, interpretation, and report creation are carried out by a single clinician. The next 2 codes are used when one clinician acquires the image—96932—comparable to the technical component of a pathology code, while another reads it and creates the report—96933—similar to a dermatopathologist billing for the professional component of a pathology report. For patients presenting with multiple lesions, the next 3 codes—96934, 96935, and 96936—are used in conjunction with the applicable first code for each additional lesion with similar global, technical, and professional components. Because these codes are not in the radiology or pathology sections of CPT, a single code cannot be used with modifier -TC (technical component) and modifier -26, as they are in those sections.

The wide-probe VivaScope 1500 (Caliber I.D., Inc) currently is the only confocal device that can be reported with a CPT code and routinely reimbursed. The handheld VivaScope 3000 (Caliber I.D., Inc) can only view a small stack and does not have the ability to acquire a full mosaic image; it is not covered by these codes.

Images can be viewed as a stack captured at the same horizontal position but at sequential depths or as a mosaic, which has a larger field of view but is limited to a single plane. To appropriately assess a lesion, clinicians must obtain a mosaic that needs to be assessed at multiple layers for a diagnosis to be made because it is a cross-section view.

Diagnosis

Studies have demonstrated the usefulness of RCM imaging in the diagnosis of a wide range of skin diseases, including melanoma and nonmelanoma skin cancers, infectious diseases, and inflammatory and autoimmune conditions, as well as wound healing and skin aging. Reflectance confocal microscopy imaging is not limited to the skin; it can be used to evaluate the hair, nails, oral mucosa, and other organs.

According to several studies, RCM imaging notably increases the diagnostic accuracy and detection rate of skin cancers over clinical and dermoscopic examination alone and therefore can act as an aid in differentiating lesions that are benign versus those that are suspicious and should be biopsied.

Reflectance confocal microscopy has been shown to have a mean sensitivity of 94% (range, 92%–96%) and specificity of 83% (range, 81%–84%) for all types of skin cancer when used with dermoscopy.⁴ In particular, for melanocytic lesions that are ambiguous on dermoscopy, RCM used in addition to dermoscopy increases the mean sensitivity and specificity for melanoma diagnosis to 93% (range, 89%–96%) and 76% (range, 68%–83%), respectively.⁵ Although these reported sensitivities are comparable to dermoscopy, the specificity is superior, especially for detecting hypomelanotic and amelanotic melanomas, which often lack specific features on dermoscopy.^6-8

The combination of RCM with dermoscopy has reduced the number of unnecessary excisions of benign nevi by more than 50% when compared to dermoscopy alone.⁹ One study showed that the number needed to treat (ie, excise) a melanoma decreased from 14.6 with dermoscopy alone to 6.8 when guided by dermoscopy and RCM imaging.⁹ In a similar study, the number needed to treat dropped from 19.41 with dermoscopy alone to 6.25 with dermoscopy and RCM.¹⁰

These studies were not looking to evaluate RCM as a replacement test but rather as an add-on test to dermoscopy. Reflectance confocal microscopy imaging takes longer than dermoscopy for each lesion; therefore, RCM should only be used as an adjunctive tool to dermoscopy and not as an initial screening test. Consequentially, a dermatologist skilled in dermoscopy is essential in deciding which lesions would be appropriate for subsequent RCM imaging.

In Vivo Margin Mapping as an Adjunct to Surgery

Oftentimes, tumor margins are poorly defined and can be difficult to map clinically and dermoscopically. Studies have demonstrated the use of RCM in delineation of surgical margins prior to surgery or excisional biopsies.^11,12 Alternatively, when complete removal at biopsy would be impractical (eg, for extremely large lesions or lesions located in cosmetically sensitive areas such as the face), RCM can be used to pick the best site for an appropriate biopsy, which decreases the chance of sampling error due to skip lesions and increases histologic accuracy.

Nonsurgical Treatment Monitoring

One advantage of RCM over conventional histology is that RCM imaging leaves the tissue intact, allowing dynamic changes to be studied over time, which is useful for monitoring nonmelanoma skin cancers and lentigo maligna being treated with noninvasive therapeutic modalities.¹³ If not as a definitive treatment, RCM can act as an adjunct for surgery by monitoring reduction in lesion size prior to Mohs micrographic surgery, thereby decreasing the resulting surgical defect.¹⁴

Limitations

Imaging Depth
Although RCM is a revolutionary device in the field of dermatology, it has several limitations. With a maximal imaging depth of 350 µm, the imaging resolution decreases substantially with depth, limiting accurate interpretation to 200 µm. Reflectance confocal microscopy can only image the superficial portion of a lesion; therefore, deep tumor margins cannot be assessed. Hypertrophic or hyperkeratotic lesions, including lesions on the palms and soles, also are unable to be imaged with RCM. This limitation in depth penetration makes treatment monitoring impossible for invasive lesions that extend into the dermal layer.

Difficult-to-Reach Areas
Another limitation is the difficulty imaging areas such as the ocular canthi, nasal alae, or helices of the ear due to the wide probe size on the VivaScope 1500. The advent of the smaller handheld VivaScope 3000 device allows for improved imaging of concave services and difficult lesions at the risk of less accurate imaging, low field of view, and no reimbursement at present.

False-Positive Results
Although RCM has been shown to be helpful in reducing unnecessary biopsies, there still is the issue of false-positives on imaging. False-positives most commonly occur in nevi with severe atypia or when Langerhans cells are present that cannot always be differentiated from melanocytic cells.^3,15,16 One prospective study found 7 false-positive results from 63 sites using RCM for the diagnosis of lentigo malignas.¹⁶ False-negatives can occur in the presence of inflammatory infiltrates and scar tissue that can hide cellular morphology or in sampling errors due to skip lesions.^3,16

Time Efficiency
The time required for acquisition of RCM mosaics and stacks followed by reading and interpretation can be substantial depending on the size and complexity of the lesion, which is a major limitation for use of RCM in busy dermatology practices; therefore, RCM should be reserved for lesions selected to undergo biopsy that are clinically equivocal for malignancy prior to RCM examination.¹⁷ It would not be cost-effective or time effective to evaluate lesions that either clinically or dermoscopically have a high probability of malignancy; however, patients and physicians may opt for increased specificity at the expense of time, particularly when a lesion is located on a cosmetically sensitive area, as patients can avoid initial histologic biopsy and gain the cosmetic benefit of going straight to surgery versus obtaining an initial diagnostic biopsy.

Cost
Lastly, the high cost involved in purchasing an RCM device and the training involved to use and interpret RCM images currently limits RCM to large academic centers. Reimbursement may make more widespread use feasible. In any event, RCM imaging should be part of the curriculum for both dermatology and pathology trainees.

Future Directions

In vivo RCM is a noninvasive imaging modality that allows for real-time evaluation of the skin. Used in conjunction with dermoscopy, RCM can substantially improve diagnostic accuracy and reduce the number of unnecessary biopsies. Now that RCM has finally gained foundational CPT codes and insurance reimbursement, there may be a growing demand for clinicians to incorporate this technology into their clinical practice.

Reflectance confocal microscopy (RCM) imaging received Category I Current Procedural Terminology (CPT) codes by the Centers for Medicare & Medicaid Services in January 2016 and can now be submitted to insurance companies with reimbursement comparable to a skin biopsy or a global skin pathology service.¹ This fairly new technology is a US Food and Drug Administration–cleared noninvasive imaging modality that provides high-resolution in vivo cellular images of the skin. It has been shown to be efficacious in differentiating benign and malignant skin lesions, increasing diagnostic accuracy, and reducing the number of unnecessary skin biopsies that are performed. In addition to skin cancer diagnosis, RCM imaging also can help guide management of malignant lesions by detecting lateral margins prior to surgery as well as monitoring the lesion over time for treatment efficacy or recurrence. The potential impact of RCM imaging is tremendous, and reimbursement may lead to increased use in clinical practice to the benefit of our patients. Herein, we present a brief review of RCM imaging and reimbursement as well as the benefits and limitations of this new technology for dermatologists.

Reflectance Confocal Microscopy

In vivo RCM allows us to visualize the epidermis in real time on a cellular level down to the papillary dermis at a high resolution (×30) comparable to histologic examination. With optical sections 3- to 5-µm thick and a lateral resolution of 0.5 to 1.0 µm, RCM produces a stack of 500×500-µm² images up to a depth of approximately 200 µm.^2,3 At any chosen depth, these smaller images are stitched together with sophisticated software into a block, or mosaic, increasing the field of view to up to 8×8 mm². Imaging is performed in en face planes oriented parallel to the skin surface, similar to dermoscopy.

Current CPT Guidelines and Reimbursement

The CPT codes for RCM imaging provide reimbursement on a per-lesion basis and are similar to those used for skin biopsy and pathology (Table).¹ Codes 96931 through 96933 are used for imaging of a single lesion on a patient. The first code—96931—is used when image acquisition, interpretation, and report creation are carried out by a single clinician. The next 2 codes are used when one clinician acquires the image—96932—comparable to the technical component of a pathology code, while another reads it and creates the report—96933—similar to a dermatopathologist billing for the professional component of a pathology report. For patients presenting with multiple lesions, the next 3 codes—96934, 96935, and 96936—are used in conjunction with the applicable first code for each additional lesion with similar global, technical, and professional components. Because these codes are not in the radiology or pathology sections of CPT, a single code cannot be used with modifier -TC (technical component) and modifier -26, as they are in those sections.

The wide-probe VivaScope 1500 (Caliber I.D., Inc) currently is the only confocal device that can be reported with a CPT code and routinely reimbursed. The handheld VivaScope 3000 (Caliber I.D., Inc) can only view a small stack and does not have the ability to acquire a full mosaic image; it is not covered by these codes.

Images can be viewed as a stack captured at the same horizontal position but at sequential depths or as a mosaic, which has a larger field of view but is limited to a single plane. To appropriately assess a lesion, clinicians must obtain a mosaic that needs to be assessed at multiple layers for a diagnosis to be made because it is a cross-section view.

Diagnosis

Studies have demonstrated the usefulness of RCM imaging in the diagnosis of a wide range of skin diseases, including melanoma and nonmelanoma skin cancers, infectious diseases, and inflammatory and autoimmune conditions, as well as wound healing and skin aging. Reflectance confocal microscopy imaging is not limited to the skin; it can be used to evaluate the hair, nails, oral mucosa, and other organs.

According to several studies, RCM imaging notably increases the diagnostic accuracy and detection rate of skin cancers over clinical and dermoscopic examination alone and therefore can act as an aid in differentiating lesions that are benign versus those that are suspicious and should be biopsied.

Reflectance confocal microscopy has been shown to have a mean sensitivity of 94% (range, 92%–96%) and specificity of 83% (range, 81%–84%) for all types of skin cancer when used with dermoscopy.⁴ In particular, for melanocytic lesions that are ambiguous on dermoscopy, RCM used in addition to dermoscopy increases the mean sensitivity and specificity for melanoma diagnosis to 93% (range, 89%–96%) and 76% (range, 68%–83%), respectively.⁵ Although these reported sensitivities are comparable to dermoscopy, the specificity is superior, especially for detecting hypomelanotic and amelanotic melanomas, which often lack specific features on dermoscopy.^6-8

The combination of RCM with dermoscopy has reduced the number of unnecessary excisions of benign nevi by more than 50% when compared to dermoscopy alone.⁹ One study showed that the number needed to treat (ie, excise) a melanoma decreased from 14.6 with dermoscopy alone to 6.8 when guided by dermoscopy and RCM imaging.⁹ In a similar study, the number needed to treat dropped from 19.41 with dermoscopy alone to 6.25 with dermoscopy and RCM.¹⁰

These studies were not looking to evaluate RCM as a replacement test but rather as an add-on test to dermoscopy. Reflectance confocal microscopy imaging takes longer than dermoscopy for each lesion; therefore, RCM should only be used as an adjunctive tool to dermoscopy and not as an initial screening test. Consequentially, a dermatologist skilled in dermoscopy is essential in deciding which lesions would be appropriate for subsequent RCM imaging.

In Vivo Margin Mapping as an Adjunct to Surgery

Oftentimes, tumor margins are poorly defined and can be difficult to map clinically and dermoscopically. Studies have demonstrated the use of RCM in delineation of surgical margins prior to surgery or excisional biopsies.^11,12 Alternatively, when complete removal at biopsy would be impractical (eg, for extremely large lesions or lesions located in cosmetically sensitive areas such as the face), RCM can be used to pick the best site for an appropriate biopsy, which decreases the chance of sampling error due to skip lesions and increases histologic accuracy.

Nonsurgical Treatment Monitoring

One advantage of RCM over conventional histology is that RCM imaging leaves the tissue intact, allowing dynamic changes to be studied over time, which is useful for monitoring nonmelanoma skin cancers and lentigo maligna being treated with noninvasive therapeutic modalities.¹³ If not as a definitive treatment, RCM can act as an adjunct for surgery by monitoring reduction in lesion size prior to Mohs micrographic surgery, thereby decreasing the resulting surgical defect.¹⁴

Limitations

Imaging Depth
Although RCM is a revolutionary device in the field of dermatology, it has several limitations. With a maximal imaging depth of 350 µm, the imaging resolution decreases substantially with depth, limiting accurate interpretation to 200 µm. Reflectance confocal microscopy can only image the superficial portion of a lesion; therefore, deep tumor margins cannot be assessed. Hypertrophic or hyperkeratotic lesions, including lesions on the palms and soles, also are unable to be imaged with RCM. This limitation in depth penetration makes treatment monitoring impossible for invasive lesions that extend into the dermal layer.

Difficult-to-Reach Areas
Another limitation is the difficulty imaging areas such as the ocular canthi, nasal alae, or helices of the ear due to the wide probe size on the VivaScope 1500. The advent of the smaller handheld VivaScope 3000 device allows for improved imaging of concave services and difficult lesions at the risk of less accurate imaging, low field of view, and no reimbursement at present.

False-Positive Results
Although RCM has been shown to be helpful in reducing unnecessary biopsies, there still is the issue of false-positives on imaging. False-positives most commonly occur in nevi with severe atypia or when Langerhans cells are present that cannot always be differentiated from melanocytic cells.^3,15,16 One prospective study found 7 false-positive results from 63 sites using RCM for the diagnosis of lentigo malignas.¹⁶ False-negatives can occur in the presence of inflammatory infiltrates and scar tissue that can hide cellular morphology or in sampling errors due to skip lesions.^3,16

Time Efficiency
The time required for acquisition of RCM mosaics and stacks followed by reading and interpretation can be substantial depending on the size and complexity of the lesion, which is a major limitation for use of RCM in busy dermatology practices; therefore, RCM should be reserved for lesions selected to undergo biopsy that are clinically equivocal for malignancy prior to RCM examination.¹⁷ It would not be cost-effective or time effective to evaluate lesions that either clinically or dermoscopically have a high probability of malignancy; however, patients and physicians may opt for increased specificity at the expense of time, particularly when a lesion is located on a cosmetically sensitive area, as patients can avoid initial histologic biopsy and gain the cosmetic benefit of going straight to surgery versus obtaining an initial diagnostic biopsy.

Cost
Lastly, the high cost involved in purchasing an RCM device and the training involved to use and interpret RCM images currently limits RCM to large academic centers. Reimbursement may make more widespread use feasible. In any event, RCM imaging should be part of the curriculum for both dermatology and pathology trainees.

Future Directions

In vivo RCM is a noninvasive imaging modality that allows for real-time evaluation of the skin. Used in conjunction with dermoscopy, RCM can substantially improve diagnostic accuracy and reduce the number of unnecessary biopsies. Now that RCM has finally gained foundational CPT codes and insurance reimbursement, there may be a growing demand for clinicians to incorporate this technology into their clinical practice.

Reflectance confocal microscopy (RCM) imaging received Category I Current Procedural Terminology (CPT) codes by the Centers for Medicare & Medicaid Services in January 2016 and can now be submitted to insurance companies with reimbursement comparable to a skin biopsy or a global skin pathology service.¹ This fairly new technology is a US Food and Drug Administration–cleared noninvasive imaging modality that provides high-resolution in vivo cellular images of the skin. It has been shown to be efficacious in differentiating benign and malignant skin lesions, increasing diagnostic accuracy, and reducing the number of unnecessary skin biopsies that are performed. In addition to skin cancer diagnosis, RCM imaging also can help guide management of malignant lesions by detecting lateral margins prior to surgery as well as monitoring the lesion over time for treatment efficacy or recurrence. The potential impact of RCM imaging is tremendous, and reimbursement may lead to increased use in clinical practice to the benefit of our patients. Herein, we present a brief review of RCM imaging and reimbursement as well as the benefits and limitations of this new technology for dermatologists.

Reflectance Confocal Microscopy

In vivo RCM allows us to visualize the epidermis in real time on a cellular level down to the papillary dermis at a high resolution (×30) comparable to histologic examination. With optical sections 3- to 5-µm thick and a lateral resolution of 0.5 to 1.0 µm, RCM produces a stack of 500×500-µm² images up to a depth of approximately 200 µm.^2,3 At any chosen depth, these smaller images are stitched together with sophisticated software into a block, or mosaic, increasing the field of view to up to 8×8 mm². Imaging is performed in en face planes oriented parallel to the skin surface, similar to dermoscopy.

Current CPT Guidelines and Reimbursement

The CPT codes for RCM imaging provide reimbursement on a per-lesion basis and are similar to those used for skin biopsy and pathology (Table).¹ Codes 96931 through 96933 are used for imaging of a single lesion on a patient. The first code—96931—is used when image acquisition, interpretation, and report creation are carried out by a single clinician. The next 2 codes are used when one clinician acquires the image—96932—comparable to the technical component of a pathology code, while another reads it and creates the report—96933—similar to a dermatopathologist billing for the professional component of a pathology report. For patients presenting with multiple lesions, the next 3 codes—96934, 96935, and 96936—are used in conjunction with the applicable first code for each additional lesion with similar global, technical, and professional components. Because these codes are not in the radiology or pathology sections of CPT, a single code cannot be used with modifier -TC (technical component) and modifier -26, as they are in those sections.

The wide-probe VivaScope 1500 (Caliber I.D., Inc) currently is the only confocal device that can be reported with a CPT code and routinely reimbursed. The handheld VivaScope 3000 (Caliber I.D., Inc) can only view a small stack and does not have the ability to acquire a full mosaic image; it is not covered by these codes.

Images can be viewed as a stack captured at the same horizontal position but at sequential depths or as a mosaic, which has a larger field of view but is limited to a single plane. To appropriately assess a lesion, clinicians must obtain a mosaic that needs to be assessed at multiple layers for a diagnosis to be made because it is a cross-section view.

Diagnosis

Studies have demonstrated the usefulness of RCM imaging in the diagnosis of a wide range of skin diseases, including melanoma and nonmelanoma skin cancers, infectious diseases, and inflammatory and autoimmune conditions, as well as wound healing and skin aging. Reflectance confocal microscopy imaging is not limited to the skin; it can be used to evaluate the hair, nails, oral mucosa, and other organs.

According to several studies, RCM imaging notably increases the diagnostic accuracy and detection rate of skin cancers over clinical and dermoscopic examination alone and therefore can act as an aid in differentiating lesions that are benign versus those that are suspicious and should be biopsied.

Reflectance confocal microscopy has been shown to have a mean sensitivity of 94% (range, 92%–96%) and specificity of 83% (range, 81%–84%) for all types of skin cancer when used with dermoscopy.⁴ In particular, for melanocytic lesions that are ambiguous on dermoscopy, RCM used in addition to dermoscopy increases the mean sensitivity and specificity for melanoma diagnosis to 93% (range, 89%–96%) and 76% (range, 68%–83%), respectively.⁵ Although these reported sensitivities are comparable to dermoscopy, the specificity is superior, especially for detecting hypomelanotic and amelanotic melanomas, which often lack specific features on dermoscopy.^6-8

The combination of RCM with dermoscopy has reduced the number of unnecessary excisions of benign nevi by more than 50% when compared to dermoscopy alone.⁹ One study showed that the number needed to treat (ie, excise) a melanoma decreased from 14.6 with dermoscopy alone to 6.8 when guided by dermoscopy and RCM imaging.⁹ In a similar study, the number needed to treat dropped from 19.41 with dermoscopy alone to 6.25 with dermoscopy and RCM.¹⁰

These studies were not looking to evaluate RCM as a replacement test but rather as an add-on test to dermoscopy. Reflectance confocal microscopy imaging takes longer than dermoscopy for each lesion; therefore, RCM should only be used as an adjunctive tool to dermoscopy and not as an initial screening test. Consequentially, a dermatologist skilled in dermoscopy is essential in deciding which lesions would be appropriate for subsequent RCM imaging.

In Vivo Margin Mapping as an Adjunct to Surgery

Oftentimes, tumor margins are poorly defined and can be difficult to map clinically and dermoscopically. Studies have demonstrated the use of RCM in delineation of surgical margins prior to surgery or excisional biopsies.^11,12 Alternatively, when complete removal at biopsy would be impractical (eg, for extremely large lesions or lesions located in cosmetically sensitive areas such as the face), RCM can be used to pick the best site for an appropriate biopsy, which decreases the chance of sampling error due to skip lesions and increases histologic accuracy.

Nonsurgical Treatment Monitoring

One advantage of RCM over conventional histology is that RCM imaging leaves the tissue intact, allowing dynamic changes to be studied over time, which is useful for monitoring nonmelanoma skin cancers and lentigo maligna being treated with noninvasive therapeutic modalities.¹³ If not as a definitive treatment, RCM can act as an adjunct for surgery by monitoring reduction in lesion size prior to Mohs micrographic surgery, thereby decreasing the resulting surgical defect.¹⁴

Limitations

Imaging Depth
Although RCM is a revolutionary device in the field of dermatology, it has several limitations. With a maximal imaging depth of 350 µm, the imaging resolution decreases substantially with depth, limiting accurate interpretation to 200 µm. Reflectance confocal microscopy can only image the superficial portion of a lesion; therefore, deep tumor margins cannot be assessed. Hypertrophic or hyperkeratotic lesions, including lesions on the palms and soles, also are unable to be imaged with RCM. This limitation in depth penetration makes treatment monitoring impossible for invasive lesions that extend into the dermal layer.

Difficult-to-Reach Areas
Another limitation is the difficulty imaging areas such as the ocular canthi, nasal alae, or helices of the ear due to the wide probe size on the VivaScope 1500. The advent of the smaller handheld VivaScope 3000 device allows for improved imaging of concave services and difficult lesions at the risk of less accurate imaging, low field of view, and no reimbursement at present.

False-Positive Results
Although RCM has been shown to be helpful in reducing unnecessary biopsies, there still is the issue of false-positives on imaging. False-positives most commonly occur in nevi with severe atypia or when Langerhans cells are present that cannot always be differentiated from melanocytic cells.^3,15,16 One prospective study found 7 false-positive results from 63 sites using RCM for the diagnosis of lentigo malignas.¹⁶ False-negatives can occur in the presence of inflammatory infiltrates and scar tissue that can hide cellular morphology or in sampling errors due to skip lesions.^3,16

Time Efficiency
The time required for acquisition of RCM mosaics and stacks followed by reading and interpretation can be substantial depending on the size and complexity of the lesion, which is a major limitation for use of RCM in busy dermatology practices; therefore, RCM should be reserved for lesions selected to undergo biopsy that are clinically equivocal for malignancy prior to RCM examination.¹⁷ It would not be cost-effective or time effective to evaluate lesions that either clinically or dermoscopically have a high probability of malignancy; however, patients and physicians may opt for increased specificity at the expense of time, particularly when a lesion is located on a cosmetically sensitive area, as patients can avoid initial histologic biopsy and gain the cosmetic benefit of going straight to surgery versus obtaining an initial diagnostic biopsy.

Cost
Lastly, the high cost involved in purchasing an RCM device and the training involved to use and interpret RCM images currently limits RCM to large academic centers. Reimbursement may make more widespread use feasible. In any event, RCM imaging should be part of the curriculum for both dermatology and pathology trainees.

Future Directions

In vivo RCM is a noninvasive imaging modality that allows for real-time evaluation of the skin. Used in conjunction with dermoscopy, RCM can substantially improve diagnostic accuracy and reduce the number of unnecessary biopsies. Now that RCM has finally gained foundational CPT codes and insurance reimbursement, there may be a growing demand for clinicians to incorporate this technology into their clinical practice.

Muckle-Wells syndrome (MWS) was first described in 1962 and is part of a broad category of hereditary periodic fever syndromes that include the autoinflammatory syndromes and the cryopyrin-associated periodic syndromes (CAPSs). Unlike autoimmune diseases, autoinflammatory syndromes are not associated with antigen-specific T-cell responses or high titers of autoantibodies but are related to disorders of the innate immune system. Basal cell nevus syndrome (BCNS), or Gorlin syndrome, is a rare genodermatosis inherited in an autosomal-dominant fashion that is characterized by a broad range of anomalies. Most notable is the early and strong predisposition to develop several to hundreds of basal cell carcinomas (BCCs). Classic clinical features of MWS and a thorough history and physical examination can assist in the diagnosis of this rare entity.

Case Report

A 35-year-old woman with a history of BCNS, which had been diagnosed at 24 years of age based on the presence of more than 2 BCCs and a family history of BCNS in her mother, presented with intermittent pruritic urticaria on the chest and back, episodic fevers, associated joint pain and swelling that worsened several hours after exercise, headache, conjunctivitis, blurred vision, and severe debilitating fatigue that had been present since childhood. The symptoms had progressively worsened with age and symptom-free intervals became shorter. She was diagnosed by her rheumatologist with biopsy-proven MWS and a positive NLRP3 (NLR family pyrin domain containing 3) gene mutation at 29 years of age. She was treated unsuccessfully with prednisone and antihistamines and entered a trial with anakinra. She showed improvement for 2 weeks but developed severe swelling and erythema at the injection sites at week 3, along with large leathery patches on the legs and difficulty ambulating.

The patient subsequently underwent excision of her BCCs and reported each site became erythematous, edematous, warm, and painful 6 hours after excision, which lasted for hours to days (Figures 1–3). After the first excision on the right forearm, she was seen in the emergency department, started on intravenous antibiotics and prednisone, and kept overnight in the hospital. She was discharged the following day and the edema in the right forearm subsided over several days. Bacterial culture and laboratory evaluation for infection were negative after the first excision on the right forearm. Because of the symptoms she experienced following this excision, she was referred to the plastic surgery department for excision followed by postoperative monitoring in the hospital. The patient continued to undergo excisions for BCCs and developed more severe symptoms including erythema, edema, warmth, and tenderness at the surrounding sites. Once again, the excision sites were cultured and laboratory work to rule out infection was ordered with a negative result. After several excisions and subsequent clinical findings, the patients’ symptoms were deemed consistent with MWS and not a result of infectious etiology. A diagnosis of MWS and BCNS with exacerbation of MWS with surgical procedures was made.

The patient has continued therapy with rilonacept for MWS, which is managed by her rheumatologist. She has tolerated rilonacept without adverse effects and has experienced a reduction in symptoms that has enhanced her quality of life and allows for further treatment of her BCNS. Her dermatologist (J.W.L.) has been treating her BCCs with vismodegib, but treatment has been sporadic due to muscle cramping after 7 days of therapy. She reported subjective improvement to her dermatologist and has tried alternating 7 days on and 7 days off vismodegib. The muscle cramping still has limited her treatment with this regimen, and she is currently on a trial of 3 days on, 4 days off per week.

Comment

Classification and Clinical Presentation
The hereditary periodic fever syndromes include the autoinflammatory syndromes and the CAPSs. The autoinflammatory syndromes include familial Mediterranean fever, hyperimmunoglobulinemia D with periodic fever syndrome, and tumor necrosis factor receptor–associated periodic syndrome. The CAPSs are similar but distinct and include familial cold autoinflammatory syndrome, neonatal-onset multisystem inflammatory disease (also known as chronic infantile neurologic cutaneous and articular syndrome, or cutaneous articular syndrome) and MWS.^1,2

Cryopyrin-associated periodic syndromes are rare inherited diseases that result from mutations in the NLRP3 gene. There is a gain-of-function mutation on the NLRP3 gene located on the long arm of chromosome 1 at position 44, which codes for cryopyrin. An NLRP3 gene mutation causes cryopyrin to become hyperactive, leading to the formation of an inflammasome, which is a group of cryopyrin molecules. Inflammasomes, along with other proteins, activate caspase 1 to produce excess IL-1β, leading to persistent inflammatory symptoms.³ IL-1β is one of the key mediators of the body’s response to microbial invasion, inflammation, immunologic reactions, and tissue injury. It affects a large range of cells and organs. Although IL-1β production is critical for the control of pathogenic infections, excessive cytokine production is harmful to the host and can even be fatal.^3,4

Cryopyrin-associated periodic syndromes encompass a disease continuum. The 3 distinct entities share many overlapping features as well as unique and distinguishing characteristics. Familial cold autoinflammatory syndrome is the mildest phenotype and is inherited in an autosomal-dominant fashion. It is characterized by a chronic urticarial eruption that starts early in infancy or childhood. The distribution of the cutaneous eruption is widespread and favors the arms and legs over the face and trunk. A low-grade fever often is seen along with musculoskeletal concerns of arthralgia and pain. Other commonly reported symptoms include conjunctivitis, myalgia, fatigue, and headache. Neurologic symptoms can include headaches. Symptoms usually begin 1 to 2 hours after cold exposure and last less than 24 hours.^5-8

Neonatal-onset multisystem inflammatory disease is the most severe phenotype and occurs sporadically. Continuous symptoms and flares are characteristic and the length of the flare can vary from minutes to days. The cutaneous eruption favors the face, trunk, arms, and legs, and varies in intensity, beginning in infancy or childhood. Fever may be intermittent, mild, or absent. Rheumatologic manifestations include arthralgia and swelling, with approximately one-third of patients experiencing severe disabling arthropathy that causes gross joint deformity. Ocular findings include conjunctivitis, uveitis, papilledema, and even blindness. Neurologic sequelae include headaches, sensorineural hearing loss, and aseptic meningitis. Amyloidosis has been seen as a late complication.^5,8

Muckle-Wells syndrome is a rare hereditary inflammatory disorder. It has no ethnic predisposition and is mostly inherited in an autosomal-dominant fashion. Classically, the condition is characterized by recurrent urticaria beginning at birth with intermittent episodic fever and malaise. The eruption has a predilection for the face, trunk, arms, and legs, which is similar to neonatal-onset multisystem inflammatory disease. Associated myalgia and arthralgia are common as well as ocular findings of conjunctivitis and episcleritis. Neurologic manifestations include headache and progressive sensorineural hearing loss in 60% to 70% of patients.⁶ Abdominal pain may be seen along with rare serositis in MWS but is rare in the other CAPSs. Amyloidosis caused by chronic inflammation is the most serious complication of MWS and is seen in approximately one-third of patients, manifesting as proteinuria followed by renal impairment. Symptoms of MWS may occur daily but vary individually, are broad in intensity and duration, and can last 1 to 2 days before resolving spontaneously. The symptoms can result from metabolic stressors including cold, stress, and exercise, as well as microbial pathogens. Leukocytosis and increased acute-phase reactants are observed during episodes of inflammation.^4,6,8

Histopathology
Mild phenotypic variability exists between individuals, and many of the symptoms overlap in CAPSs. Although CAPSs display several distinguishing clinical characteristics, interestingly they share the same histopathological features regardless of the syndrome. The typical histopathological finding is a dermal neutrophilic infiltrate that tends to be perivascular and also may be perieccrine. Vasodilation and dermal edema also may be seen. These histopathological findings contrast with the typical lymphocytic and eosinophilic infiltrate seen in classic urticaria. Similar histopathologic findings have been seen in other neutrophilic urticarial dermatoses such as Schnitzler syndrome.^4,6

Differential
The differential diagnoses for CAPSs include Schnitzler syndrome, cold urticaria, systemic-onset juvenile idiopathic arthritis/adult-onset Still disease, and deficiency in IL-1ra. It is important to consider these differential diagnoses for management and treatment options.

Management
The discovery of the NLRP3 gene mutation as well as an understanding of IL-1 biology has led to targeted therapy for these syndromes. Cryopyrin-associated periodic syndromes are mediated by IL-1β with an in vivo rate 5 times higher than in healthy patients.⁴ The blockade of IL-1β results in complete resolution of symptoms.

In the last several years, anakinra, rilonacept, and canakinumab have shown efficacy in targeting IL-1β as receptor antagonists. Anakinra is a short-acting recombinant IL-1ra with a half-life of 4 to 6 hours. This short half-life requires daily injections and the most common adverse events included injection-site reaction and upper respiratory tract infection.^2,4 Rilonacept is a dimeric fusion protein that contains binding regions for the type 1 receptor and the IL-1 receptor accessory protein and is fused to the fragment, crystallizable (Fc) portion of human IgG1. Rilonacept is long acting with a circulating half-life of 8.6 days and offers patients ease of dosing with weekly subcutaneous injections. Rilonacept generally is well tolerated, with the most frequent adverse effects being injection-site reaction, upper respiratory tract infection, headache, arthralgia, and diarrhea.^2,7

The newest of the treatments for patients with CAPS is canakinumab. It is a fully human IL-1β monoclonal antibody that is specific for IL-1β and not other members of the IL-1 family. It has a mean half-life of 26 days and is dosed subcutaneously once every 8 weeks. The most common adverse effects include nasopharyngitis, rhinitis, nausea, diarrhea, and vertigo.⁴ In one study, most patients did not report injection-site reactions.⁷ Studies also are underway on VX-765, a caspace-1 targeted therapy that acts upstream in the IL-1β pathway. Treatment with anakinra, rilonacept, and canakinumab generally offers rapid and sustained remission in the majority of MWS patients and helps prevent the development of systemic amyloidosis and lessens the potential for end organ damage.^2,7

MWS and BCNS
Our patient had an unusual presentation of MWS complicated by BCNS, another rare autosomal-dominant inherited genodermatosis. In an extensive review of PubMed articles indexed for MEDLINE using the search terms Muckle-Wells syndrome and basal cell nevus syndrome, no association was identified between MWS and BCNS. Basal cell nevus syndrome is linked to PTCH1 (patched 1) gene mutation with an incidence of 1:150,000 in the United States and Europe and is characterized by a broad range of anomalies including skeletal abnormalities, ectopic calcification, odontogenic keratocysts, facial dysmorphism with macrocephaly, palmoplantar pits, and numerous tumors. Most notable is the early and strong predisposition to develop several to hundreds of BCCs.⁹

Conclusion

Muckle-Wells syndrome may go undiagnosed for many years or may be misdiagnosed as refractory urticaria, as in our patient. It is important to include periodic fever syndromes in the differential diagnosis of refractory urticaria with episodic fever to diagnose these cases of MWS earlier.

Muckle-Wells syndrome (MWS) was first described in 1962 and is part of a broad category of hereditary periodic fever syndromes that include the autoinflammatory syndromes and the cryopyrin-associated periodic syndromes (CAPSs). Unlike autoimmune diseases, autoinflammatory syndromes are not associated with antigen-specific T-cell responses or high titers of autoantibodies but are related to disorders of the innate immune system. Basal cell nevus syndrome (BCNS), or Gorlin syndrome, is a rare genodermatosis inherited in an autosomal-dominant fashion that is characterized by a broad range of anomalies. Most notable is the early and strong predisposition to develop several to hundreds of basal cell carcinomas (BCCs). Classic clinical features of MWS and a thorough history and physical examination can assist in the diagnosis of this rare entity.

Case Report

A 35-year-old woman with a history of BCNS, which had been diagnosed at 24 years of age based on the presence of more than 2 BCCs and a family history of BCNS in her mother, presented with intermittent pruritic urticaria on the chest and back, episodic fevers, associated joint pain and swelling that worsened several hours after exercise, headache, conjunctivitis, blurred vision, and severe debilitating fatigue that had been present since childhood. The symptoms had progressively worsened with age and symptom-free intervals became shorter. She was diagnosed by her rheumatologist with biopsy-proven MWS and a positive NLRP3 (NLR family pyrin domain containing 3) gene mutation at 29 years of age. She was treated unsuccessfully with prednisone and antihistamines and entered a trial with anakinra. She showed improvement for 2 weeks but developed severe swelling and erythema at the injection sites at week 3, along with large leathery patches on the legs and difficulty ambulating.

The patient subsequently underwent excision of her BCCs and reported each site became erythematous, edematous, warm, and painful 6 hours after excision, which lasted for hours to days (Figures 1–3). After the first excision on the right forearm, she was seen in the emergency department, started on intravenous antibiotics and prednisone, and kept overnight in the hospital. She was discharged the following day and the edema in the right forearm subsided over several days. Bacterial culture and laboratory evaluation for infection were negative after the first excision on the right forearm. Because of the symptoms she experienced following this excision, she was referred to the plastic surgery department for excision followed by postoperative monitoring in the hospital. The patient continued to undergo excisions for BCCs and developed more severe symptoms including erythema, edema, warmth, and tenderness at the surrounding sites. Once again, the excision sites were cultured and laboratory work to rule out infection was ordered with a negative result. After several excisions and subsequent clinical findings, the patients’ symptoms were deemed consistent with MWS and not a result of infectious etiology. A diagnosis of MWS and BCNS with exacerbation of MWS with surgical procedures was made.

The patient has continued therapy with rilonacept for MWS, which is managed by her rheumatologist. She has tolerated rilonacept without adverse effects and has experienced a reduction in symptoms that has enhanced her quality of life and allows for further treatment of her BCNS. Her dermatologist (J.W.L.) has been treating her BCCs with vismodegib, but treatment has been sporadic due to muscle cramping after 7 days of therapy. She reported subjective improvement to her dermatologist and has tried alternating 7 days on and 7 days off vismodegib. The muscle cramping still has limited her treatment with this regimen, and she is currently on a trial of 3 days on, 4 days off per week.

Comment

Classification and Clinical Presentation
The hereditary periodic fever syndromes include the autoinflammatory syndromes and the CAPSs. The autoinflammatory syndromes include familial Mediterranean fever, hyperimmunoglobulinemia D with periodic fever syndrome, and tumor necrosis factor receptor–associated periodic syndrome. The CAPSs are similar but distinct and include familial cold autoinflammatory syndrome, neonatal-onset multisystem inflammatory disease (also known as chronic infantile neurologic cutaneous and articular syndrome, or cutaneous articular syndrome) and MWS.^1,2

Cryopyrin-associated periodic syndromes are rare inherited diseases that result from mutations in the NLRP3 gene. There is a gain-of-function mutation on the NLRP3 gene located on the long arm of chromosome 1 at position 44, which codes for cryopyrin. An NLRP3 gene mutation causes cryopyrin to become hyperactive, leading to the formation of an inflammasome, which is a group of cryopyrin molecules. Inflammasomes, along with other proteins, activate caspase 1 to produce excess IL-1β, leading to persistent inflammatory symptoms.³ IL-1β is one of the key mediators of the body’s response to microbial invasion, inflammation, immunologic reactions, and tissue injury. It affects a large range of cells and organs. Although IL-1β production is critical for the control of pathogenic infections, excessive cytokine production is harmful to the host and can even be fatal.^3,4

Cryopyrin-associated periodic syndromes encompass a disease continuum. The 3 distinct entities share many overlapping features as well as unique and distinguishing characteristics. Familial cold autoinflammatory syndrome is the mildest phenotype and is inherited in an autosomal-dominant fashion. It is characterized by a chronic urticarial eruption that starts early in infancy or childhood. The distribution of the cutaneous eruption is widespread and favors the arms and legs over the face and trunk. A low-grade fever often is seen along with musculoskeletal concerns of arthralgia and pain. Other commonly reported symptoms include conjunctivitis, myalgia, fatigue, and headache. Neurologic symptoms can include headaches. Symptoms usually begin 1 to 2 hours after cold exposure and last less than 24 hours.^5-8

Neonatal-onset multisystem inflammatory disease is the most severe phenotype and occurs sporadically. Continuous symptoms and flares are characteristic and the length of the flare can vary from minutes to days. The cutaneous eruption favors the face, trunk, arms, and legs, and varies in intensity, beginning in infancy or childhood. Fever may be intermittent, mild, or absent. Rheumatologic manifestations include arthralgia and swelling, with approximately one-third of patients experiencing severe disabling arthropathy that causes gross joint deformity. Ocular findings include conjunctivitis, uveitis, papilledema, and even blindness. Neurologic sequelae include headaches, sensorineural hearing loss, and aseptic meningitis. Amyloidosis has been seen as a late complication.^5,8

Muckle-Wells syndrome is a rare hereditary inflammatory disorder. It has no ethnic predisposition and is mostly inherited in an autosomal-dominant fashion. Classically, the condition is characterized by recurrent urticaria beginning at birth with intermittent episodic fever and malaise. The eruption has a predilection for the face, trunk, arms, and legs, which is similar to neonatal-onset multisystem inflammatory disease. Associated myalgia and arthralgia are common as well as ocular findings of conjunctivitis and episcleritis. Neurologic manifestations include headache and progressive sensorineural hearing loss in 60% to 70% of patients.⁶ Abdominal pain may be seen along with rare serositis in MWS but is rare in the other CAPSs. Amyloidosis caused by chronic inflammation is the most serious complication of MWS and is seen in approximately one-third of patients, manifesting as proteinuria followed by renal impairment. Symptoms of MWS may occur daily but vary individually, are broad in intensity and duration, and can last 1 to 2 days before resolving spontaneously. The symptoms can result from metabolic stressors including cold, stress, and exercise, as well as microbial pathogens. Leukocytosis and increased acute-phase reactants are observed during episodes of inflammation.^4,6,8

Histopathology
Mild phenotypic variability exists between individuals, and many of the symptoms overlap in CAPSs. Although CAPSs display several distinguishing clinical characteristics, interestingly they share the same histopathological features regardless of the syndrome. The typical histopathological finding is a dermal neutrophilic infiltrate that tends to be perivascular and also may be perieccrine. Vasodilation and dermal edema also may be seen. These histopathological findings contrast with the typical lymphocytic and eosinophilic infiltrate seen in classic urticaria. Similar histopathologic findings have been seen in other neutrophilic urticarial dermatoses such as Schnitzler syndrome.^4,6

Differential
The differential diagnoses for CAPSs include Schnitzler syndrome, cold urticaria, systemic-onset juvenile idiopathic arthritis/adult-onset Still disease, and deficiency in IL-1ra. It is important to consider these differential diagnoses for management and treatment options.

Management
The discovery of the NLRP3 gene mutation as well as an understanding of IL-1 biology has led to targeted therapy for these syndromes. Cryopyrin-associated periodic syndromes are mediated by IL-1β with an in vivo rate 5 times higher than in healthy patients.⁴ The blockade of IL-1β results in complete resolution of symptoms.

In the last several years, anakinra, rilonacept, and canakinumab have shown efficacy in targeting IL-1β as receptor antagonists. Anakinra is a short-acting recombinant IL-1ra with a half-life of 4 to 6 hours. This short half-life requires daily injections and the most common adverse events included injection-site reaction and upper respiratory tract infection.^2,4 Rilonacept is a dimeric fusion protein that contains binding regions for the type 1 receptor and the IL-1 receptor accessory protein and is fused to the fragment, crystallizable (Fc) portion of human IgG1. Rilonacept is long acting with a circulating half-life of 8.6 days and offers patients ease of dosing with weekly subcutaneous injections. Rilonacept generally is well tolerated, with the most frequent adverse effects being injection-site reaction, upper respiratory tract infection, headache, arthralgia, and diarrhea.^2,7

The newest of the treatments for patients with CAPS is canakinumab. It is a fully human IL-1β monoclonal antibody that is specific for IL-1β and not other members of the IL-1 family. It has a mean half-life of 26 days and is dosed subcutaneously once every 8 weeks. The most common adverse effects include nasopharyngitis, rhinitis, nausea, diarrhea, and vertigo.⁴ In one study, most patients did not report injection-site reactions.⁷ Studies also are underway on VX-765, a caspace-1 targeted therapy that acts upstream in the IL-1β pathway. Treatment with anakinra, rilonacept, and canakinumab generally offers rapid and sustained remission in the majority of MWS patients and helps prevent the development of systemic amyloidosis and lessens the potential for end organ damage.^2,7

MWS and BCNS
Our patient had an unusual presentation of MWS complicated by BCNS, another rare autosomal-dominant inherited genodermatosis. In an extensive review of PubMed articles indexed for MEDLINE using the search terms Muckle-Wells syndrome and basal cell nevus syndrome, no association was identified between MWS and BCNS. Basal cell nevus syndrome is linked to PTCH1 (patched 1) gene mutation with an incidence of 1:150,000 in the United States and Europe and is characterized by a broad range of anomalies including skeletal abnormalities, ectopic calcification, odontogenic keratocysts, facial dysmorphism with macrocephaly, palmoplantar pits, and numerous tumors. Most notable is the early and strong predisposition to develop several to hundreds of BCCs.⁹

Conclusion

Muckle-Wells syndrome may go undiagnosed for many years or may be misdiagnosed as refractory urticaria, as in our patient. It is important to include periodic fever syndromes in the differential diagnosis of refractory urticaria with episodic fever to diagnose these cases of MWS earlier.

Muckle-Wells syndrome (MWS) was first described in 1962 and is part of a broad category of hereditary periodic fever syndromes that include the autoinflammatory syndromes and the cryopyrin-associated periodic syndromes (CAPSs). Unlike autoimmune diseases, autoinflammatory syndromes are not associated with antigen-specific T-cell responses or high titers of autoantibodies but are related to disorders of the innate immune system. Basal cell nevus syndrome (BCNS), or Gorlin syndrome, is a rare genodermatosis inherited in an autosomal-dominant fashion that is characterized by a broad range of anomalies. Most notable is the early and strong predisposition to develop several to hundreds of basal cell carcinomas (BCCs). Classic clinical features of MWS and a thorough history and physical examination can assist in the diagnosis of this rare entity.

Case Report

A 35-year-old woman with a history of BCNS, which had been diagnosed at 24 years of age based on the presence of more than 2 BCCs and a family history of BCNS in her mother, presented with intermittent pruritic urticaria on the chest and back, episodic fevers, associated joint pain and swelling that worsened several hours after exercise, headache, conjunctivitis, blurred vision, and severe debilitating fatigue that had been present since childhood. The symptoms had progressively worsened with age and symptom-free intervals became shorter. She was diagnosed by her rheumatologist with biopsy-proven MWS and a positive NLRP3 (NLR family pyrin domain containing 3) gene mutation at 29 years of age. She was treated unsuccessfully with prednisone and antihistamines and entered a trial with anakinra. She showed improvement for 2 weeks but developed severe swelling and erythema at the injection sites at week 3, along with large leathery patches on the legs and difficulty ambulating.

The patient subsequently underwent excision of her BCCs and reported each site became erythematous, edematous, warm, and painful 6 hours after excision, which lasted for hours to days (Figures 1–3). After the first excision on the right forearm, she was seen in the emergency department, started on intravenous antibiotics and prednisone, and kept overnight in the hospital. She was discharged the following day and the edema in the right forearm subsided over several days. Bacterial culture and laboratory evaluation for infection were negative after the first excision on the right forearm. Because of the symptoms she experienced following this excision, she was referred to the plastic surgery department for excision followed by postoperative monitoring in the hospital. The patient continued to undergo excisions for BCCs and developed more severe symptoms including erythema, edema, warmth, and tenderness at the surrounding sites. Once again, the excision sites were cultured and laboratory work to rule out infection was ordered with a negative result. After several excisions and subsequent clinical findings, the patients’ symptoms were deemed consistent with MWS and not a result of infectious etiology. A diagnosis of MWS and BCNS with exacerbation of MWS with surgical procedures was made.

The patient has continued therapy with rilonacept for MWS, which is managed by her rheumatologist. She has tolerated rilonacept without adverse effects and has experienced a reduction in symptoms that has enhanced her quality of life and allows for further treatment of her BCNS. Her dermatologist (J.W.L.) has been treating her BCCs with vismodegib, but treatment has been sporadic due to muscle cramping after 7 days of therapy. She reported subjective improvement to her dermatologist and has tried alternating 7 days on and 7 days off vismodegib. The muscle cramping still has limited her treatment with this regimen, and she is currently on a trial of 3 days on, 4 days off per week.

Comment

Classification and Clinical Presentation
The hereditary periodic fever syndromes include the autoinflammatory syndromes and the CAPSs. The autoinflammatory syndromes include familial Mediterranean fever, hyperimmunoglobulinemia D with periodic fever syndrome, and tumor necrosis factor receptor–associated periodic syndrome. The CAPSs are similar but distinct and include familial cold autoinflammatory syndrome, neonatal-onset multisystem inflammatory disease (also known as chronic infantile neurologic cutaneous and articular syndrome, or cutaneous articular syndrome) and MWS.^1,2

Cryopyrin-associated periodic syndromes are rare inherited diseases that result from mutations in the NLRP3 gene. There is a gain-of-function mutation on the NLRP3 gene located on the long arm of chromosome 1 at position 44, which codes for cryopyrin. An NLRP3 gene mutation causes cryopyrin to become hyperactive, leading to the formation of an inflammasome, which is a group of cryopyrin molecules. Inflammasomes, along with other proteins, activate caspase 1 to produce excess IL-1β, leading to persistent inflammatory symptoms.³ IL-1β is one of the key mediators of the body’s response to microbial invasion, inflammation, immunologic reactions, and tissue injury. It affects a large range of cells and organs. Although IL-1β production is critical for the control of pathogenic infections, excessive cytokine production is harmful to the host and can even be fatal.^3,4

Cryopyrin-associated periodic syndromes encompass a disease continuum. The 3 distinct entities share many overlapping features as well as unique and distinguishing characteristics. Familial cold autoinflammatory syndrome is the mildest phenotype and is inherited in an autosomal-dominant fashion. It is characterized by a chronic urticarial eruption that starts early in infancy or childhood. The distribution of the cutaneous eruption is widespread and favors the arms and legs over the face and trunk. A low-grade fever often is seen along with musculoskeletal concerns of arthralgia and pain. Other commonly reported symptoms include conjunctivitis, myalgia, fatigue, and headache. Neurologic symptoms can include headaches. Symptoms usually begin 1 to 2 hours after cold exposure and last less than 24 hours.^5-8

Neonatal-onset multisystem inflammatory disease is the most severe phenotype and occurs sporadically. Continuous symptoms and flares are characteristic and the length of the flare can vary from minutes to days. The cutaneous eruption favors the face, trunk, arms, and legs, and varies in intensity, beginning in infancy or childhood. Fever may be intermittent, mild, or absent. Rheumatologic manifestations include arthralgia and swelling, with approximately one-third of patients experiencing severe disabling arthropathy that causes gross joint deformity. Ocular findings include conjunctivitis, uveitis, papilledema, and even blindness. Neurologic sequelae include headaches, sensorineural hearing loss, and aseptic meningitis. Amyloidosis has been seen as a late complication.^5,8

Muckle-Wells syndrome is a rare hereditary inflammatory disorder. It has no ethnic predisposition and is mostly inherited in an autosomal-dominant fashion. Classically, the condition is characterized by recurrent urticaria beginning at birth with intermittent episodic fever and malaise. The eruption has a predilection for the face, trunk, arms, and legs, which is similar to neonatal-onset multisystem inflammatory disease. Associated myalgia and arthralgia are common as well as ocular findings of conjunctivitis and episcleritis. Neurologic manifestations include headache and progressive sensorineural hearing loss in 60% to 70% of patients.⁶ Abdominal pain may be seen along with rare serositis in MWS but is rare in the other CAPSs. Amyloidosis caused by chronic inflammation is the most serious complication of MWS and is seen in approximately one-third of patients, manifesting as proteinuria followed by renal impairment. Symptoms of MWS may occur daily but vary individually, are broad in intensity and duration, and can last 1 to 2 days before resolving spontaneously. The symptoms can result from metabolic stressors including cold, stress, and exercise, as well as microbial pathogens. Leukocytosis and increased acute-phase reactants are observed during episodes of inflammation.^4,6,8

Histopathology
Mild phenotypic variability exists between individuals, and many of the symptoms overlap in CAPSs. Although CAPSs display several distinguishing clinical characteristics, interestingly they share the same histopathological features regardless of the syndrome. The typical histopathological finding is a dermal neutrophilic infiltrate that tends to be perivascular and also may be perieccrine. Vasodilation and dermal edema also may be seen. These histopathological findings contrast with the typical lymphocytic and eosinophilic infiltrate seen in classic urticaria. Similar histopathologic findings have been seen in other neutrophilic urticarial dermatoses such as Schnitzler syndrome.^4,6

Differential
The differential diagnoses for CAPSs include Schnitzler syndrome, cold urticaria, systemic-onset juvenile idiopathic arthritis/adult-onset Still disease, and deficiency in IL-1ra. It is important to consider these differential diagnoses for management and treatment options.

Management
The discovery of the NLRP3 gene mutation as well as an understanding of IL-1 biology has led to targeted therapy for these syndromes. Cryopyrin-associated periodic syndromes are mediated by IL-1β with an in vivo rate 5 times higher than in healthy patients.⁴ The blockade of IL-1β results in complete resolution of symptoms.

In the last several years, anakinra, rilonacept, and canakinumab have shown efficacy in targeting IL-1β as receptor antagonists. Anakinra is a short-acting recombinant IL-1ra with a half-life of 4 to 6 hours. This short half-life requires daily injections and the most common adverse events included injection-site reaction and upper respiratory tract infection.^2,4 Rilonacept is a dimeric fusion protein that contains binding regions for the type 1 receptor and the IL-1 receptor accessory protein and is fused to the fragment, crystallizable (Fc) portion of human IgG1. Rilonacept is long acting with a circulating half-life of 8.6 days and offers patients ease of dosing with weekly subcutaneous injections. Rilonacept generally is well tolerated, with the most frequent adverse effects being injection-site reaction, upper respiratory tract infection, headache, arthralgia, and diarrhea.^2,7

The newest of the treatments for patients with CAPS is canakinumab. It is a fully human IL-1β monoclonal antibody that is specific for IL-1β and not other members of the IL-1 family. It has a mean half-life of 26 days and is dosed subcutaneously once every 8 weeks. The most common adverse effects include nasopharyngitis, rhinitis, nausea, diarrhea, and vertigo.⁴ In one study, most patients did not report injection-site reactions.⁷ Studies also are underway on VX-765, a caspace-1 targeted therapy that acts upstream in the IL-1β pathway. Treatment with anakinra, rilonacept, and canakinumab generally offers rapid and sustained remission in the majority of MWS patients and helps prevent the development of systemic amyloidosis and lessens the potential for end organ damage.^2,7

MWS and BCNS
Our patient had an unusual presentation of MWS complicated by BCNS, another rare autosomal-dominant inherited genodermatosis. In an extensive review of PubMed articles indexed for MEDLINE using the search terms Muckle-Wells syndrome and basal cell nevus syndrome, no association was identified between MWS and BCNS. Basal cell nevus syndrome is linked to PTCH1 (patched 1) gene mutation with an incidence of 1:150,000 in the United States and Europe and is characterized by a broad range of anomalies including skeletal abnormalities, ectopic calcification, odontogenic keratocysts, facial dysmorphism with macrocephaly, palmoplantar pits, and numerous tumors. Most notable is the early and strong predisposition to develop several to hundreds of BCCs.⁹

Conclusion

Muckle-Wells syndrome may go undiagnosed for many years or may be misdiagnosed as refractory urticaria, as in our patient. It is important to include periodic fever syndromes in the differential diagnosis of refractory urticaria with episodic fever to diagnose these cases of MWS earlier.

Dermatologic surgeons are susceptible to work-related ailments given the nature of their working posture, the most common of which are pain and stiffness in the neck, shoulders, and lower back, as well as headaches.^1,2 Awkward posture and positioning, for the sake of getting a better view of the task at hand, puts the surgeon in ergonomically disagreeable positions. Because the prime working years for a dermatologic surgeon tend to coincide with the age of presbyopia onset, magnification may help reduce and thwart musculoskeletal problems and eye strain. Indeed, a multitude of surgical specialties and dentists use intraoperative magnification.³ Knowledge and use of available magnification options can be a key addition to the dermatologic surgeon’s armamentarium. We discuss the need for magnification and review magnification devices that are readily available to the dermatologic surgeon. Table 1 presents a summary of all magnification options discussed.

Need for Magnification

Presbyopia is a condition of aging in which one loses the ability to accommodate and focus at near distances. The estimated prevalence of presbyopia in North America is 83%, typically with onset by 45 years of age.⁴ Individuals with presbyopia often hold objects farther away from their eyes to bring them into focus, causing eye strain, headaches, and musculoskeletal injury.

Use of intraoperative magnification allows for enhanced visualization of fine anatomic details and precise suture placement for the surgeon with or without presbyopia. Higher magnification produces a larger image; however, it also reduces field of view and depth of field (ie, the amount of depth that stays in focus without repositioning). The resolution and quality of the image are dependent on the optical properties of the lens system. The ideal optic system is surgeon dependent and involves a combination of magnification level that will not result in dramatic loss of view and depth of field, while maintaining crispness and quality of image.

Intraoperative magnification yields ergonomic benefits by promoting a safer neck flexion angle by increasing the working distance to a more ideal position (Figure). In doing so, it improves posture and minimizes eye and musculoskeletal strain secondary to awkward positioning and presbyopia.^1,5 Stationary working position and neck flexion and rotation with precise and repetitive tasks are risk factors for strain and injuries that dermatologic surgeons often encounter.¹ Magnification devices are tools that the dermatologic surgeon can utilize for a more ergonomically sound practice. Indeed, magnification has been shown to improve posture in the dental literature, a specialty with similar occupational risk factors to dermatologic surgery.^6-8 Ergonomic practice reduces occupational injuries and improves work quality and productivity, thereby having a favorable effect on both the patient and the physician.

Improved Outcomes With Magnification

There are many examples of improved surgical quality and outcomes with magnification in other specialties. Hart and Hall⁵ illustrated the advantage of magnification in laceration repairs in the emergency department. In one study, increased magnification resulted in a substantial decrease in positive surgical margin rates in open radical retropubic prostatectomy.⁹ Schoeffl et al¹⁰ demonstrated that the microsurgical success of fine surgical procedures was directly related to optical magnification strength when comparing the unaided eye, surgical loupes, and the operating microscope. The dental literature also has numerous examples of magnification producing improved quality dentistry.^11-13 Although magnification is not a novel concept to dermatologic surgery, little has been written about its use in the dermatologic surgery literature.

Magnification Options

One-Piece Bifocal Magnifying Safety Glasses
Bifocal magnifying safety glasses are polycarbonate safety glasses made with lenses in which the lower half is a magnifying lens. They are available in +1.5, +2.0, +2.5, and +3.0 diopter strengths. The total magnification power is calculated as follows: (diopter/4) + 1. The glasses are lightweight, easy to wear, inexpensive, and protect the eyes; however, they provide minimal magnification and do not compensate for differences in vision between both eyes.

Magnification Visor
The magnification visor is a headband visor with magnification lenses. It comes in various levels of magnification ranging from ×1.5 to ×3.5. It can be worn over prescription or safety glasses, may be pivoted out of the way when not in use, and is inexpensive. Conversely, it may be bulky to wear, cannot be customized, and does not offer the best resolution.

Magnification Clips
Magnification clips are hard-coated magnifying lens plates that fasten to eyeglass frames and range in level of magnification from ×1.5 to ×3.5. They can be pivoted out of the viewing angle, are lightweight, and are inexpensive; however, positioning may be difficult for ideal working distance and viewing angle.

Magnifier With Frame/Headband
The magnifier with frame is similar to magnification clips, but the magnification lens plate comes with a frame. It can be used with or without glasses and comes in magnification levels of ×1.5 to ×3.5. It is light, inexpensive, and may be pivoted out of sight, but similar to magnification clips, positioning for the right viewing angle and working distance may be difficult.

The magnifier with headband is essentially the same as the magnifier with frame. The only difference is the magnification plate is attached to a headband as opposed to a frame. It has similar benefits and limitations as the magnifier with frame.

Magnification Stand
The magnification stand comes as a large magnification lens with a flexible arm attached to a stand. It is a basic magnification tool and does not need to be worn; however, the stand is not easily portable and may be cumbersome to use.

Surgical Loupes
Surgical loupes are a robust magnification choice and the mainstay in magnification for the dermatologic surgeon. Loupes have proven to have comparable results in some procedures to the powerful operating surgical microscope.^14-17 Factors to consider with loupes include brand, design, lens, magnification, resolution, optimal working distance, field depth, and declination angle.¹⁸

The 2 surgical loupe designs—flip-up loupes and through-the-lens loupes—differ in the mounting of the optic lenses on safety glasses. Flip-up loupes have the optics mounted to the bridge of the frame, whereas through-the-lens loupes are fixed in the lenses.

There are 3 different optical systems for surgical loupe magnification: simple, compound, and prismatic. Simple lenses consist of one pair of positive meniscus lenses similar to reading glasses. Compound lenses are made of 2 magnification lenses. Prismatic lenses magnify using a prism that folds and lengthens the light path.^19,20

Loupes range in magnification level from ×2.5 to ×4.5. Compared to other magnification modalities, they can be customized and offer better resolution with quality magnification. Additionally, loupes can be fitted with a light source; however, they are expensive and surgeons need time to get used to the increased magnification as well as wearing the loupes.

There are advantages and disadvantages to the different loupe designs (Table 2). Flip-up loupes are more versatile, allowing for use on various safety glasses. They can be flipped out of view, and the declination angle may be altered; however, flip-up loupes have a narrower field of view and are heavier and bulkier than through-the-lens loupes. Through-the-lens loupes are lighter and have a larger field of view, as the optics are closer to the eye. They are customized to the declination angle and working distance of the surgeon. Conversely, through-the-lens loupes are more expensive and cannot be adjusted or moved from the line of vision.

Operating Surgical Microscope
The operating surgical microscope is not practical in the dermatologic surgeon’s practice. It is expensive and provides unnecessarily powerful magnification for dermatologic surgery. This tool usually is used in the operating room for suturing nerves and vessels with sutures sized 8-0 and smaller. Most skin procedures require size 6-0 and larger sutures.

Dermoscope
Dermoscopy, also known as epiluminescence microscopy, is a technique utilizing a handheld device made up of polarized light and a ×10 magnifying lens to evaluate skin lesions. In skilled hands, dermoscopy allows for the examination of characteristic patterns and morphologic features of skin lesions to enhance the clinician’s diagnostic accuracy.²¹ It may aid the dermatologic surgeon in identifying the surgical margins of difficult-to-define skin cancers. It is small and mobile; however, it has minimal benefit to the dermatologic surgeon during surgery because it is handheld and has a small field of view.

Conclusion

Good ergonomic practices facilitate a healthier and prolonged career for the dermatologic surgeon. When used properly, magnification devices can be a beneficial adjunct to the dermatologic surgeon by promoting better posture, preventing eyestrain, and providing enhanced visualization of the operating field and instruments. Use of magnification devices has been demonstrated to improve patient outcomes in other specialties. There are opportunities for further research specific to magnification improving dermatologic surgery outcomes given the high level of precision and accuracy needed for Mohs micrographic surgery, wound reconstruction, nail surgery, and hair transplantation.

Dermatologic surgeons are susceptible to work-related ailments given the nature of their working posture, the most common of which are pain and stiffness in the neck, shoulders, and lower back, as well as headaches.^1,2 Awkward posture and positioning, for the sake of getting a better view of the task at hand, puts the surgeon in ergonomically disagreeable positions. Because the prime working years for a dermatologic surgeon tend to coincide with the age of presbyopia onset, magnification may help reduce and thwart musculoskeletal problems and eye strain. Indeed, a multitude of surgical specialties and dentists use intraoperative magnification.³ Knowledge and use of available magnification options can be a key addition to the dermatologic surgeon’s armamentarium. We discuss the need for magnification and review magnification devices that are readily available to the dermatologic surgeon. Table 1 presents a summary of all magnification options discussed.

Need for Magnification

Presbyopia is a condition of aging in which one loses the ability to accommodate and focus at near distances. The estimated prevalence of presbyopia in North America is 83%, typically with onset by 45 years of age.⁴ Individuals with presbyopia often hold objects farther away from their eyes to bring them into focus, causing eye strain, headaches, and musculoskeletal injury.

Use of intraoperative magnification allows for enhanced visualization of fine anatomic details and precise suture placement for the surgeon with or without presbyopia. Higher magnification produces a larger image; however, it also reduces field of view and depth of field (ie, the amount of depth that stays in focus without repositioning). The resolution and quality of the image are dependent on the optical properties of the lens system. The ideal optic system is surgeon dependent and involves a combination of magnification level that will not result in dramatic loss of view and depth of field, while maintaining crispness and quality of image.

Intraoperative magnification yields ergonomic benefits by promoting a safer neck flexion angle by increasing the working distance to a more ideal position (Figure). In doing so, it improves posture and minimizes eye and musculoskeletal strain secondary to awkward positioning and presbyopia.^1,5 Stationary working position and neck flexion and rotation with precise and repetitive tasks are risk factors for strain and injuries that dermatologic surgeons often encounter.¹ Magnification devices are tools that the dermatologic surgeon can utilize for a more ergonomically sound practice. Indeed, magnification has been shown to improve posture in the dental literature, a specialty with similar occupational risk factors to dermatologic surgery.^6-8 Ergonomic practice reduces occupational injuries and improves work quality and productivity, thereby having a favorable effect on both the patient and the physician.

Improved Outcomes With Magnification

There are many examples of improved surgical quality and outcomes with magnification in other specialties. Hart and Hall⁵ illustrated the advantage of magnification in laceration repairs in the emergency department. In one study, increased magnification resulted in a substantial decrease in positive surgical margin rates in open radical retropubic prostatectomy.⁹ Schoeffl et al¹⁰ demonstrated that the microsurgical success of fine surgical procedures was directly related to optical magnification strength when comparing the unaided eye, surgical loupes, and the operating microscope. The dental literature also has numerous examples of magnification producing improved quality dentistry.^11-13 Although magnification is not a novel concept to dermatologic surgery, little has been written about its use in the dermatologic surgery literature.

Magnification Options

One-Piece Bifocal Magnifying Safety Glasses
Bifocal magnifying safety glasses are polycarbonate safety glasses made with lenses in which the lower half is a magnifying lens. They are available in +1.5, +2.0, +2.5, and +3.0 diopter strengths. The total magnification power is calculated as follows: (diopter/4) + 1. The glasses are lightweight, easy to wear, inexpensive, and protect the eyes; however, they provide minimal magnification and do not compensate for differences in vision between both eyes.

Magnification Visor
The magnification visor is a headband visor with magnification lenses. It comes in various levels of magnification ranging from ×1.5 to ×3.5. It can be worn over prescription or safety glasses, may be pivoted out of the way when not in use, and is inexpensive. Conversely, it may be bulky to wear, cannot be customized, and does not offer the best resolution.

Magnification Clips
Magnification clips are hard-coated magnifying lens plates that fasten to eyeglass frames and range in level of magnification from ×1.5 to ×3.5. They can be pivoted out of the viewing angle, are lightweight, and are inexpensive; however, positioning may be difficult for ideal working distance and viewing angle.

Magnifier With Frame/Headband
The magnifier with frame is similar to magnification clips, but the magnification lens plate comes with a frame. It can be used with or without glasses and comes in magnification levels of ×1.5 to ×3.5. It is light, inexpensive, and may be pivoted out of sight, but similar to magnification clips, positioning for the right viewing angle and working distance may be difficult.

The magnifier with headband is essentially the same as the magnifier with frame. The only difference is the magnification plate is attached to a headband as opposed to a frame. It has similar benefits and limitations as the magnifier with frame.

Magnification Stand
The magnification stand comes as a large magnification lens with a flexible arm attached to a stand. It is a basic magnification tool and does not need to be worn; however, the stand is not easily portable and may be cumbersome to use.

Surgical Loupes
Surgical loupes are a robust magnification choice and the mainstay in magnification for the dermatologic surgeon. Loupes have proven to have comparable results in some procedures to the powerful operating surgical microscope.^14-17 Factors to consider with loupes include brand, design, lens, magnification, resolution, optimal working distance, field depth, and declination angle.¹⁸

The 2 surgical loupe designs—flip-up loupes and through-the-lens loupes—differ in the mounting of the optic lenses on safety glasses. Flip-up loupes have the optics mounted to the bridge of the frame, whereas through-the-lens loupes are fixed in the lenses.

There are 3 different optical systems for surgical loupe magnification: simple, compound, and prismatic. Simple lenses consist of one pair of positive meniscus lenses similar to reading glasses. Compound lenses are made of 2 magnification lenses. Prismatic lenses magnify using a prism that folds and lengthens the light path.^19,20

Loupes range in magnification level from ×2.5 to ×4.5. Compared to other magnification modalities, they can be customized and offer better resolution with quality magnification. Additionally, loupes can be fitted with a light source; however, they are expensive and surgeons need time to get used to the increased magnification as well as wearing the loupes.

There are advantages and disadvantages to the different loupe designs (Table 2). Flip-up loupes are more versatile, allowing for use on various safety glasses. They can be flipped out of view, and the declination angle may be altered; however, flip-up loupes have a narrower field of view and are heavier and bulkier than through-the-lens loupes. Through-the-lens loupes are lighter and have a larger field of view, as the optics are closer to the eye. They are customized to the declination angle and working distance of the surgeon. Conversely, through-the-lens loupes are more expensive and cannot be adjusted or moved from the line of vision.

Operating Surgical Microscope
The operating surgical microscope is not practical in the dermatologic surgeon’s practice. It is expensive and provides unnecessarily powerful magnification for dermatologic surgery. This tool usually is used in the operating room for suturing nerves and vessels with sutures sized 8-0 and smaller. Most skin procedures require size 6-0 and larger sutures.

Dermoscope
Dermoscopy, also known as epiluminescence microscopy, is a technique utilizing a handheld device made up of polarized light and a ×10 magnifying lens to evaluate skin lesions. In skilled hands, dermoscopy allows for the examination of characteristic patterns and morphologic features of skin lesions to enhance the clinician’s diagnostic accuracy.²¹ It may aid the dermatologic surgeon in identifying the surgical margins of difficult-to-define skin cancers. It is small and mobile; however, it has minimal benefit to the dermatologic surgeon during surgery because it is handheld and has a small field of view.

Conclusion

Good ergonomic practices facilitate a healthier and prolonged career for the dermatologic surgeon. When used properly, magnification devices can be a beneficial adjunct to the dermatologic surgeon by promoting better posture, preventing eyestrain, and providing enhanced visualization of the operating field and instruments. Use of magnification devices has been demonstrated to improve patient outcomes in other specialties. There are opportunities for further research specific to magnification improving dermatologic surgery outcomes given the high level of precision and accuracy needed for Mohs micrographic surgery, wound reconstruction, nail surgery, and hair transplantation.

Dermatologic surgeons are susceptible to work-related ailments given the nature of their working posture, the most common of which are pain and stiffness in the neck, shoulders, and lower back, as well as headaches.^1,2 Awkward posture and positioning, for the sake of getting a better view of the task at hand, puts the surgeon in ergonomically disagreeable positions. Because the prime working years for a dermatologic surgeon tend to coincide with the age of presbyopia onset, magnification may help reduce and thwart musculoskeletal problems and eye strain. Indeed, a multitude of surgical specialties and dentists use intraoperative magnification.³ Knowledge and use of available magnification options can be a key addition to the dermatologic surgeon’s armamentarium. We discuss the need for magnification and review magnification devices that are readily available to the dermatologic surgeon. Table 1 presents a summary of all magnification options discussed.

Need for Magnification

Presbyopia is a condition of aging in which one loses the ability to accommodate and focus at near distances. The estimated prevalence of presbyopia in North America is 83%, typically with onset by 45 years of age.⁴ Individuals with presbyopia often hold objects farther away from their eyes to bring them into focus, causing eye strain, headaches, and musculoskeletal injury.

Use of intraoperative magnification allows for enhanced visualization of fine anatomic details and precise suture placement for the surgeon with or without presbyopia. Higher magnification produces a larger image; however, it also reduces field of view and depth of field (ie, the amount of depth that stays in focus without repositioning). The resolution and quality of the image are dependent on the optical properties of the lens system. The ideal optic system is surgeon dependent and involves a combination of magnification level that will not result in dramatic loss of view and depth of field, while maintaining crispness and quality of image.

Intraoperative magnification yields ergonomic benefits by promoting a safer neck flexion angle by increasing the working distance to a more ideal position (Figure). In doing so, it improves posture and minimizes eye and musculoskeletal strain secondary to awkward positioning and presbyopia.^1,5 Stationary working position and neck flexion and rotation with precise and repetitive tasks are risk factors for strain and injuries that dermatologic surgeons often encounter.¹ Magnification devices are tools that the dermatologic surgeon can utilize for a more ergonomically sound practice. Indeed, magnification has been shown to improve posture in the dental literature, a specialty with similar occupational risk factors to dermatologic surgery.^6-8 Ergonomic practice reduces occupational injuries and improves work quality and productivity, thereby having a favorable effect on both the patient and the physician.

Improved Outcomes With Magnification

There are many examples of improved surgical quality and outcomes with magnification in other specialties. Hart and Hall⁵ illustrated the advantage of magnification in laceration repairs in the emergency department. In one study, increased magnification resulted in a substantial decrease in positive surgical margin rates in open radical retropubic prostatectomy.⁹ Schoeffl et al¹⁰ demonstrated that the microsurgical success of fine surgical procedures was directly related to optical magnification strength when comparing the unaided eye, surgical loupes, and the operating microscope. The dental literature also has numerous examples of magnification producing improved quality dentistry.^11-13 Although magnification is not a novel concept to dermatologic surgery, little has been written about its use in the dermatologic surgery literature.

Magnification Options

One-Piece Bifocal Magnifying Safety Glasses
Bifocal magnifying safety glasses are polycarbonate safety glasses made with lenses in which the lower half is a magnifying lens. They are available in +1.5, +2.0, +2.5, and +3.0 diopter strengths. The total magnification power is calculated as follows: (diopter/4) + 1. The glasses are lightweight, easy to wear, inexpensive, and protect the eyes; however, they provide minimal magnification and do not compensate for differences in vision between both eyes.

Magnification Visor
The magnification visor is a headband visor with magnification lenses. It comes in various levels of magnification ranging from ×1.5 to ×3.5. It can be worn over prescription or safety glasses, may be pivoted out of the way when not in use, and is inexpensive. Conversely, it may be bulky to wear, cannot be customized, and does not offer the best resolution.

Magnification Clips
Magnification clips are hard-coated magnifying lens plates that fasten to eyeglass frames and range in level of magnification from ×1.5 to ×3.5. They can be pivoted out of the viewing angle, are lightweight, and are inexpensive; however, positioning may be difficult for ideal working distance and viewing angle.

Magnifier With Frame/Headband
The magnifier with frame is similar to magnification clips, but the magnification lens plate comes with a frame. It can be used with or without glasses and comes in magnification levels of ×1.5 to ×3.5. It is light, inexpensive, and may be pivoted out of sight, but similar to magnification clips, positioning for the right viewing angle and working distance may be difficult.

The magnifier with headband is essentially the same as the magnifier with frame. The only difference is the magnification plate is attached to a headband as opposed to a frame. It has similar benefits and limitations as the magnifier with frame.

Magnification Stand
The magnification stand comes as a large magnification lens with a flexible arm attached to a stand. It is a basic magnification tool and does not need to be worn; however, the stand is not easily portable and may be cumbersome to use.

Surgical Loupes
Surgical loupes are a robust magnification choice and the mainstay in magnification for the dermatologic surgeon. Loupes have proven to have comparable results in some procedures to the powerful operating surgical microscope.^14-17 Factors to consider with loupes include brand, design, lens, magnification, resolution, optimal working distance, field depth, and declination angle.¹⁸

The 2 surgical loupe designs—flip-up loupes and through-the-lens loupes—differ in the mounting of the optic lenses on safety glasses. Flip-up loupes have the optics mounted to the bridge of the frame, whereas through-the-lens loupes are fixed in the lenses.

There are 3 different optical systems for surgical loupe magnification: simple, compound, and prismatic. Simple lenses consist of one pair of positive meniscus lenses similar to reading glasses. Compound lenses are made of 2 magnification lenses. Prismatic lenses magnify using a prism that folds and lengthens the light path.^19,20

Loupes range in magnification level from ×2.5 to ×4.5. Compared to other magnification modalities, they can be customized and offer better resolution with quality magnification. Additionally, loupes can be fitted with a light source; however, they are expensive and surgeons need time to get used to the increased magnification as well as wearing the loupes.

There are advantages and disadvantages to the different loupe designs (Table 2). Flip-up loupes are more versatile, allowing for use on various safety glasses. They can be flipped out of view, and the declination angle may be altered; however, flip-up loupes have a narrower field of view and are heavier and bulkier than through-the-lens loupes. Through-the-lens loupes are lighter and have a larger field of view, as the optics are closer to the eye. They are customized to the declination angle and working distance of the surgeon. Conversely, through-the-lens loupes are more expensive and cannot be adjusted or moved from the line of vision.

Operating Surgical Microscope
The operating surgical microscope is not practical in the dermatologic surgeon’s practice. It is expensive and provides unnecessarily powerful magnification for dermatologic surgery. This tool usually is used in the operating room for suturing nerves and vessels with sutures sized 8-0 and smaller. Most skin procedures require size 6-0 and larger sutures.

Dermoscope
Dermoscopy, also known as epiluminescence microscopy, is a technique utilizing a handheld device made up of polarized light and a ×10 magnifying lens to evaluate skin lesions. In skilled hands, dermoscopy allows for the examination of characteristic patterns and morphologic features of skin lesions to enhance the clinician’s diagnostic accuracy.²¹ It may aid the dermatologic surgeon in identifying the surgical margins of difficult-to-define skin cancers. It is small and mobile; however, it has minimal benefit to the dermatologic surgeon during surgery because it is handheld and has a small field of view.

Conclusion

Good ergonomic practices facilitate a healthier and prolonged career for the dermatologic surgeon. When used properly, magnification devices can be a beneficial adjunct to the dermatologic surgeon by promoting better posture, preventing eyestrain, and providing enhanced visualization of the operating field and instruments. Use of magnification devices has been demonstrated to improve patient outcomes in other specialties. There are opportunities for further research specific to magnification improving dermatologic surgery outcomes given the high level of precision and accuracy needed for Mohs micrographic surgery, wound reconstruction, nail surgery, and hair transplantation.

Maintenance of Certification (MOC) was adopted by the 24 certifying boards constituting the American Board of Medical Specialties (ABMS) in 2000. The American Board of Dermatology (ABD) granted its first time-limited certificates in 1991 with the first cohort of diplomates entering MOC in 2006. The rationale for MOC centered on 2 propositions: First, continuing medical education (CME) alone was insufficient to assure the public that physicians were remaining up-to-date with an expanding knowledge base and offered little opportunity to engage in meaningful self-assessment and practice improvement. Second, parties external to the medical profession were focusing increased attention on physician error and quality assurance in medical practice. Maintenance of Certification, therefore, provided a mechanism of physician self-regulation in meeting public scrutiny.^1,2

The basic framework of MOC remains unchanged since its inception, though notable effort has been expended in simplifying the tools available. All MOC components offered directly by ABD including the MOC examination are covered by the $150 annual fee.

Professional Standing

Diplomates attest to the status of all state medical licenses and level of clinical activity. All licenses must be unrestricted. “Clinically active” is defined as any patient care delivered within the prior 12 months. Having a restricted license or being clinically inactive does not automatically trigger loss of certification but does result in an ABD review.

Self-assessment

Diplomates complete 300 credits (1 question=1 credit) over 10 years and complete, or attest to prior completion of, a foundational course in patient safety. Self-assessment questions are widely available from various sources, including the Question of the Week offered by the American Academy of Dermatology, Clinicopathologic Correlation and CME-designated articles offered by JAMA Dermatology, and Photo Challenges and Dermatopathology Diagnosis quizzes offered by Cutis. The ABD recognizes patient safety education satisfied as part of medical school and residency as well as various other venues. Online courses offering CME and MOC credit also are available. Credit is accrued whether the item is answered correctly or not.

Cognitive Expertise

Dermatologists take a general dermatology module and choose one subspecialty module composed of questions directed to the clinical practitioner. The general module consists of 100 image items, most of which ask for a diagnosis. The list of entities potentially included on the assessment is made available in advance for self-study. The subspecialty module consists of 50 questions targeting the specific content area selected: medical dermatology, surgical dermatology, pediatric dermatology, and dermatopathology. The actual questions also are made available in advance for self-study. Board-certified pediatric dermatologists and dermatopathologists are offered a second 50-question set of items in their specialty to allow maintenance of the second certificate. Venues include Pearson VUE testing centers and at-home or in-office tests by remote proctoring.

The ABD is considering participation in the longitudinal assessment program developed by the ABMS. If adopted, it will offer questions distributed over a many-year span in small packets, on mobile devices, and on personal computers. Diplomates will have the ability to select content and pace, including opt-out periods as life events dictate. A minimum number of correctly answered items over time will form the basis for summative assessment.

Practice Improvement

A critical element of MOC, practice improvement affords the physician the opportunity to study how patients receive care in a wide range of settings. Beginning in 2015, the ABD developed focused practice improvement modules, now totaling 21, with many more coming in the future. The free modules are offered on an online platform (https://secure.dataharborsolutions.com/ABDermOrg/Default.aspx) and target narrow content areas. The broad range of offerings allows diplomates to choose an area of specific interest. The participant is asked to read an overview and rationale for the module, consider reading selected references that provide the evidence base, and perform 5 chart abstractions consisting of yes or no answers to no more than 5 questions narrowly focused on the chosen topic. If a first round shows no room for improvement, the participant is finished. If a deficiency is identified, the diplomate can reflect on and implement any necessary changes in process of care and pursue a second round. These modules have been very well received, with typical diplomates’ comments expressing appreciation for the ease of use and relevance to practice. Unedited and unselected reviews can be found online (https://www.abderm.org/diplomates/fulfilling-moc-requirements/resource-vendor-list/practice-improvement/american-board-of-dermatology-focused-pi-modules-free.aspx).

Future Direction

The ABD continuously communicates with diplomates about changes and new opportunities in its MOC program with a goal of maximizing value and minimizing cost in terms of dollars and time.³ The directors of the ABD continue to seek feedback about the MOC program and are committed to further refinements to achieve this goal. A critical feature of the redesigned website (http://www.abderm.org/) allows diplomates to submit and read anonymous reviews of all tools available to fulfill MOC requirements. This thoughtful diplomate feedback informs MOC developmental efforts.

All directors and executive staff of the ABD, regardless of certificate status, pay the annual fee and participate in MOC. Active participation in MOC is made public on the ABMS website. This acknowledgment is an assurance to patients that the physician’s professional standing is sound, that the physician periodically self-assesses what he/she knows, that this knowledge meets psychometrically valid standards set by dermatologists, and that physicians explore the quality of care delivered in specific practice settings. It’s the right thing to do!

Maintenance of Certification (MOC) was adopted by the 24 certifying boards constituting the American Board of Medical Specialties (ABMS) in 2000. The American Board of Dermatology (ABD) granted its first time-limited certificates in 1991 with the first cohort of diplomates entering MOC in 2006. The rationale for MOC centered on 2 propositions: First, continuing medical education (CME) alone was insufficient to assure the public that physicians were remaining up-to-date with an expanding knowledge base and offered little opportunity to engage in meaningful self-assessment and practice improvement. Second, parties external to the medical profession were focusing increased attention on physician error and quality assurance in medical practice. Maintenance of Certification, therefore, provided a mechanism of physician self-regulation in meeting public scrutiny.^1,2

The basic framework of MOC remains unchanged since its inception, though notable effort has been expended in simplifying the tools available. All MOC components offered directly by ABD including the MOC examination are covered by the $150 annual fee.

Professional Standing

Diplomates attest to the status of all state medical licenses and level of clinical activity. All licenses must be unrestricted. “Clinically active” is defined as any patient care delivered within the prior 12 months. Having a restricted license or being clinically inactive does not automatically trigger loss of certification but does result in an ABD review.

Self-assessment

Diplomates complete 300 credits (1 question=1 credit) over 10 years and complete, or attest to prior completion of, a foundational course in patient safety. Self-assessment questions are widely available from various sources, including the Question of the Week offered by the American Academy of Dermatology, Clinicopathologic Correlation and CME-designated articles offered by JAMA Dermatology, and Photo Challenges and Dermatopathology Diagnosis quizzes offered by Cutis. The ABD recognizes patient safety education satisfied as part of medical school and residency as well as various other venues. Online courses offering CME and MOC credit also are available. Credit is accrued whether the item is answered correctly or not.

Cognitive Expertise

Dermatologists take a general dermatology module and choose one subspecialty module composed of questions directed to the clinical practitioner. The general module consists of 100 image items, most of which ask for a diagnosis. The list of entities potentially included on the assessment is made available in advance for self-study. The subspecialty module consists of 50 questions targeting the specific content area selected: medical dermatology, surgical dermatology, pediatric dermatology, and dermatopathology. The actual questions also are made available in advance for self-study. Board-certified pediatric dermatologists and dermatopathologists are offered a second 50-question set of items in their specialty to allow maintenance of the second certificate. Venues include Pearson VUE testing centers and at-home or in-office tests by remote proctoring.

The ABD is considering participation in the longitudinal assessment program developed by the ABMS. If adopted, it will offer questions distributed over a many-year span in small packets, on mobile devices, and on personal computers. Diplomates will have the ability to select content and pace, including opt-out periods as life events dictate. A minimum number of correctly answered items over time will form the basis for summative assessment.

Practice Improvement

A critical element of MOC, practice improvement affords the physician the opportunity to study how patients receive care in a wide range of settings. Beginning in 2015, the ABD developed focused practice improvement modules, now totaling 21, with many more coming in the future. The free modules are offered on an online platform (https://secure.dataharborsolutions.com/ABDermOrg/Default.aspx) and target narrow content areas. The broad range of offerings allows diplomates to choose an area of specific interest. The participant is asked to read an overview and rationale for the module, consider reading selected references that provide the evidence base, and perform 5 chart abstractions consisting of yes or no answers to no more than 5 questions narrowly focused on the chosen topic. If a first round shows no room for improvement, the participant is finished. If a deficiency is identified, the diplomate can reflect on and implement any necessary changes in process of care and pursue a second round. These modules have been very well received, with typical diplomates’ comments expressing appreciation for the ease of use and relevance to practice. Unedited and unselected reviews can be found online (https://www.abderm.org/diplomates/fulfilling-moc-requirements/resource-vendor-list/practice-improvement/american-board-of-dermatology-focused-pi-modules-free.aspx).

Future Direction

The ABD continuously communicates with diplomates about changes and new opportunities in its MOC program with a goal of maximizing value and minimizing cost in terms of dollars and time.³ The directors of the ABD continue to seek feedback about the MOC program and are committed to further refinements to achieve this goal. A critical feature of the redesigned website (http://www.abderm.org/) allows diplomates to submit and read anonymous reviews of all tools available to fulfill MOC requirements. This thoughtful diplomate feedback informs MOC developmental efforts.

All directors and executive staff of the ABD, regardless of certificate status, pay the annual fee and participate in MOC. Active participation in MOC is made public on the ABMS website. This acknowledgment is an assurance to patients that the physician’s professional standing is sound, that the physician periodically self-assesses what he/she knows, that this knowledge meets psychometrically valid standards set by dermatologists, and that physicians explore the quality of care delivered in specific practice settings. It’s the right thing to do!

Maintenance of Certification (MOC) was adopted by the 24 certifying boards constituting the American Board of Medical Specialties (ABMS) in 2000. The American Board of Dermatology (ABD) granted its first time-limited certificates in 1991 with the first cohort of diplomates entering MOC in 2006. The rationale for MOC centered on 2 propositions: First, continuing medical education (CME) alone was insufficient to assure the public that physicians were remaining up-to-date with an expanding knowledge base and offered little opportunity to engage in meaningful self-assessment and practice improvement. Second, parties external to the medical profession were focusing increased attention on physician error and quality assurance in medical practice. Maintenance of Certification, therefore, provided a mechanism of physician self-regulation in meeting public scrutiny.^1,2

The basic framework of MOC remains unchanged since its inception, though notable effort has been expended in simplifying the tools available. All MOC components offered directly by ABD including the MOC examination are covered by the $150 annual fee.

Professional Standing

Diplomates attest to the status of all state medical licenses and level of clinical activity. All licenses must be unrestricted. “Clinically active” is defined as any patient care delivered within the prior 12 months. Having a restricted license or being clinically inactive does not automatically trigger loss of certification but does result in an ABD review.

Self-assessment

Diplomates complete 300 credits (1 question=1 credit) over 10 years and complete, or attest to prior completion of, a foundational course in patient safety. Self-assessment questions are widely available from various sources, including the Question of the Week offered by the American Academy of Dermatology, Clinicopathologic Correlation and CME-designated articles offered by JAMA Dermatology, and Photo Challenges and Dermatopathology Diagnosis quizzes offered by Cutis. The ABD recognizes patient safety education satisfied as part of medical school and residency as well as various other venues. Online courses offering CME and MOC credit also are available. Credit is accrued whether the item is answered correctly or not.

Cognitive Expertise

Dermatologists take a general dermatology module and choose one subspecialty module composed of questions directed to the clinical practitioner. The general module consists of 100 image items, most of which ask for a diagnosis. The list of entities potentially included on the assessment is made available in advance for self-study. The subspecialty module consists of 50 questions targeting the specific content area selected: medical dermatology, surgical dermatology, pediatric dermatology, and dermatopathology. The actual questions also are made available in advance for self-study. Board-certified pediatric dermatologists and dermatopathologists are offered a second 50-question set of items in their specialty to allow maintenance of the second certificate. Venues include Pearson VUE testing centers and at-home or in-office tests by remote proctoring.

The ABD is considering participation in the longitudinal assessment program developed by the ABMS. If adopted, it will offer questions distributed over a many-year span in small packets, on mobile devices, and on personal computers. Diplomates will have the ability to select content and pace, including opt-out periods as life events dictate. A minimum number of correctly answered items over time will form the basis for summative assessment.

Practice Improvement

A critical element of MOC, practice improvement affords the physician the opportunity to study how patients receive care in a wide range of settings. Beginning in 2015, the ABD developed focused practice improvement modules, now totaling 21, with many more coming in the future. The free modules are offered on an online platform (https://secure.dataharborsolutions.com/ABDermOrg/Default.aspx) and target narrow content areas. The broad range of offerings allows diplomates to choose an area of specific interest. The participant is asked to read an overview and rationale for the module, consider reading selected references that provide the evidence base, and perform 5 chart abstractions consisting of yes or no answers to no more than 5 questions narrowly focused on the chosen topic. If a first round shows no room for improvement, the participant is finished. If a deficiency is identified, the diplomate can reflect on and implement any necessary changes in process of care and pursue a second round. These modules have been very well received, with typical diplomates’ comments expressing appreciation for the ease of use and relevance to practice. Unedited and unselected reviews can be found online (https://www.abderm.org/diplomates/fulfilling-moc-requirements/resource-vendor-list/practice-improvement/american-board-of-dermatology-focused-pi-modules-free.aspx).

Future Direction

The ABD continuously communicates with diplomates about changes and new opportunities in its MOC program with a goal of maximizing value and minimizing cost in terms of dollars and time.³ The directors of the ABD continue to seek feedback about the MOC program and are committed to further refinements to achieve this goal. A critical feature of the redesigned website (http://www.abderm.org/) allows diplomates to submit and read anonymous reviews of all tools available to fulfill MOC requirements. This thoughtful diplomate feedback informs MOC developmental efforts.

All directors and executive staff of the ABD, regardless of certificate status, pay the annual fee and participate in MOC. Active participation in MOC is made public on the ABMS website. This acknowledgment is an assurance to patients that the physician’s professional standing is sound, that the physician periodically self-assesses what he/she knows, that this knowledge meets psychometrically valid standards set by dermatologists, and that physicians explore the quality of care delivered in specific practice settings. It’s the right thing to do!

Currently, there is no widely accepted tool for assessing the severity of psoriasis in the clinical setting.^1-5 Moreover, there is still a need for a simple assessment tool to assist in evaluating a patient’s response to therapy in clinical practice.⁶

The body surface area (BSA) is a familiar and widely used measurement by clinicians. It is easily calculated by the rule of nines or with the patient’s open palm and thumb approximating 1% of the BSA.⁷ Body surface area is an uncomplicated concept for patients to understand and interpret. It also promotes patient empowerment and self-care by allowing patients to monitor short-term and long-term response to therapy.

The National Psoriasis Foundation Medical Board published treatment targets for plaque psoriasis. One of the conclusions states, “The acceptable response at 3 months postinitiation was either BSA 3% or less or BSA improvement 75% or more from baseline.”⁸

We propose a new nomenclature that a 75% improvement in BSA be recognized as BSA75, a 90% improvement in BSA as BSA90, and a 100% improvement in BSA as BSA100. These classifications would be analogous to corresponding improvements in the following psoriasis area and severity index (PASI) scores: PASI 75, PASI 90, PASI 100.⁹ A loss of BSA goals/milestones (ie, BSA75) could encourage and facilitate physician-patient conversations and further direct modifications to disease management and treatment therapy.

A potential drawback to the implementation of this novel categorization system is that other notable aspects of psoriasis would not be assessed, such as erythema, induration, or scale; subjective measurements; patient quality of life; patient symptoms; areas of involvement (eg, palms, soles of feet); and disease course. Nevertheless, the BSA75, BSA90, and BSA100 classifications can serve as practical, objective, and straightforward tools to monitor disease progression and treatment response in psoriasis patients, which may potentially promote improved patient outcomes in clinical practice.

Currently, there is no widely accepted tool for assessing the severity of psoriasis in the clinical setting.^1-5 Moreover, there is still a need for a simple assessment tool to assist in evaluating a patient’s response to therapy in clinical practice.⁶

The body surface area (BSA) is a familiar and widely used measurement by clinicians. It is easily calculated by the rule of nines or with the patient’s open palm and thumb approximating 1% of the BSA.⁷ Body surface area is an uncomplicated concept for patients to understand and interpret. It also promotes patient empowerment and self-care by allowing patients to monitor short-term and long-term response to therapy.

The National Psoriasis Foundation Medical Board published treatment targets for plaque psoriasis. One of the conclusions states, “The acceptable response at 3 months postinitiation was either BSA 3% or less or BSA improvement 75% or more from baseline.”⁸

We propose a new nomenclature that a 75% improvement in BSA be recognized as BSA75, a 90% improvement in BSA as BSA90, and a 100% improvement in BSA as BSA100. These classifications would be analogous to corresponding improvements in the following psoriasis area and severity index (PASI) scores: PASI 75, PASI 90, PASI 100.⁹ A loss of BSA goals/milestones (ie, BSA75) could encourage and facilitate physician-patient conversations and further direct modifications to disease management and treatment therapy.

A potential drawback to the implementation of this novel categorization system is that other notable aspects of psoriasis would not be assessed, such as erythema, induration, or scale; subjective measurements; patient quality of life; patient symptoms; areas of involvement (eg, palms, soles of feet); and disease course. Nevertheless, the BSA75, BSA90, and BSA100 classifications can serve as practical, objective, and straightforward tools to monitor disease progression and treatment response in psoriasis patients, which may potentially promote improved patient outcomes in clinical practice.

Currently, there is no widely accepted tool for assessing the severity of psoriasis in the clinical setting.^1-5 Moreover, there is still a need for a simple assessment tool to assist in evaluating a patient’s response to therapy in clinical practice.⁶

The body surface area (BSA) is a familiar and widely used measurement by clinicians. It is easily calculated by the rule of nines or with the patient’s open palm and thumb approximating 1% of the BSA.⁷ Body surface area is an uncomplicated concept for patients to understand and interpret. It also promotes patient empowerment and self-care by allowing patients to monitor short-term and long-term response to therapy.

The National Psoriasis Foundation Medical Board published treatment targets for plaque psoriasis. One of the conclusions states, “The acceptable response at 3 months postinitiation was either BSA 3% or less or BSA improvement 75% or more from baseline.”⁸

We propose a new nomenclature that a 75% improvement in BSA be recognized as BSA75, a 90% improvement in BSA as BSA90, and a 100% improvement in BSA as BSA100. These classifications would be analogous to corresponding improvements in the following psoriasis area and severity index (PASI) scores: PASI 75, PASI 90, PASI 100.⁹ A loss of BSA goals/milestones (ie, BSA75) could encourage and facilitate physician-patient conversations and further direct modifications to disease management and treatment therapy.

A potential drawback to the implementation of this novel categorization system is that other notable aspects of psoriasis would not be assessed, such as erythema, induration, or scale; subjective measurements; patient quality of life; patient symptoms; areas of involvement (eg, palms, soles of feet); and disease course. Nevertheless, the BSA75, BSA90, and BSA100 classifications can serve as practical, objective, and straightforward tools to monitor disease progression and treatment response in psoriasis patients, which may potentially promote improved patient outcomes in clinical practice.

To improve patient care and outcomes, leading dermatologists offered their recommendations on face scrubs. Consideration must be given to:

• Crystal Peel Microdermabrasion Exfoliating Face Crème
  Formulary for Physicians, Inc
  
  “This product is a highly effective facial scrub for patients with thick skin. Its exfoliating ingredient is corundum, another name for aluminum oxide, the crystal used by most microabrasion machines.”— Mark G. Rubin, MD, Beverly Hills, California
  
   
• Facial Fuel Energizing Scrub
  Kiehl’s
  
  Recommended by Gary Goldenberg, MD, New York, New York
  
   
• Olay Regenerist Regenerating Cream Cleanser
  Procter & Gamble
  
  “Oxygenated beads in the creamy formula help to gently exfoliate the skin without overdrying and stripping the skin’s outer layer, leaving the skin soft and fresh.”—Jeannette Graf, MD, New York, New York
  
   
• PRESCRIBEDsolutions: Starting Up/Face, Surface Improvement
  Biopelle, Inc
  
  “I use Starting Up/Face as my daily cleanser, as it contains salicylic acid and helps improve the overall texture plus minimize bumps from shaving, and Surface Improvement about every other day on my face in the shower.”—Joel L. Cohen, MD, Greenwood Village, Colorado
  
   
• St. Ives Apricot Blemish Control Scrub
  Unilever
  
  “It exfoliates and has salicylic acid. After exfoliating, I recommend allowing it to sit on the skin for 5 minutes before washing off.”—Anthony M. Rossi, MD, New York, New York

Cutis invites readers to send us their recommendations. Athlete’s foot treatments, cleansing devices, and redness-reducing products will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on face scrubs. Consideration must be given to:

• Crystal Peel Microdermabrasion Exfoliating Face Crème
  Formulary for Physicians, Inc
  
  “This product is a highly effective facial scrub for patients with thick skin. Its exfoliating ingredient is corundum, another name for aluminum oxide, the crystal used by most microabrasion machines.”— Mark G. Rubin, MD, Beverly Hills, California
  
   
• Facial Fuel Energizing Scrub
  Kiehl’s
  
  Recommended by Gary Goldenberg, MD, New York, New York
  
   
• Olay Regenerist Regenerating Cream Cleanser
  Procter & Gamble
  
  “Oxygenated beads in the creamy formula help to gently exfoliate the skin without overdrying and stripping the skin’s outer layer, leaving the skin soft and fresh.”—Jeannette Graf, MD, New York, New York
  
   
• PRESCRIBEDsolutions: Starting Up/Face, Surface Improvement
  Biopelle, Inc
  
  “I use Starting Up/Face as my daily cleanser, as it contains salicylic acid and helps improve the overall texture plus minimize bumps from shaving, and Surface Improvement about every other day on my face in the shower.”—Joel L. Cohen, MD, Greenwood Village, Colorado
  
   
• St. Ives Apricot Blemish Control Scrub
  Unilever
  
  “It exfoliates and has salicylic acid. After exfoliating, I recommend allowing it to sit on the skin for 5 minutes before washing off.”—Anthony M. Rossi, MD, New York, New York

Cutis invites readers to send us their recommendations. Athlete’s foot treatments, cleansing devices, and redness-reducing products will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on face scrubs. Consideration must be given to:

• Crystal Peel Microdermabrasion Exfoliating Face Crème
  Formulary for Physicians, Inc
  
  “This product is a highly effective facial scrub for patients with thick skin. Its exfoliating ingredient is corundum, another name for aluminum oxide, the crystal used by most microabrasion machines.”— Mark G. Rubin, MD, Beverly Hills, California
  
   
• Facial Fuel Energizing Scrub
  Kiehl’s
  
  Recommended by Gary Goldenberg, MD, New York, New York
  
   
• Olay Regenerist Regenerating Cream Cleanser
  Procter & Gamble
  
  “Oxygenated beads in the creamy formula help to gently exfoliate the skin without overdrying and stripping the skin’s outer layer, leaving the skin soft and fresh.”—Jeannette Graf, MD, New York, New York
  
   
• PRESCRIBEDsolutions: Starting Up/Face, Surface Improvement
  Biopelle, Inc
  
  “I use Starting Up/Face as my daily cleanser, as it contains salicylic acid and helps improve the overall texture plus minimize bumps from shaving, and Surface Improvement about every other day on my face in the shower.”—Joel L. Cohen, MD, Greenwood Village, Colorado
  
   
• St. Ives Apricot Blemish Control Scrub
  Unilever
  
  “It exfoliates and has salicylic acid. After exfoliating, I recommend allowing it to sit on the skin for 5 minutes before washing off.”—Anthony M. Rossi, MD, New York, New York

Cutis invites readers to send us their recommendations. Athlete’s foot treatments, cleansing devices, and redness-reducing products will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

Systemic mastocytosis is a heterogeneous disorder of stem cell origin defined by abnormal hyperplasia and accumulation of mast cells (MCs) in one or more tissues.^1,2 The most commonly affected tissues are the bone marrow, gastrointestinal tract, and skin. Based on a number of major and minor criteria defined by the World Health Organization (WHO), the mastocytoses are subdivided into 7 variants that range from isolated cutaneous involvement to widespread systemic disease.^1-4 The most frequently diagnosed subtype is indolent systemic mastocytosis (ISM), a chronic disorder characterized by diffuse cutaneous macules and papules as well as bone marrow involvement in the form of multifocal dense infiltrates of MCs that frequently are phenotypically positive for c-KIT and tryptase. Serum tryptase levels are nearly invariably elevated in patients with this condition.^1,2

Symptoms of ISM are determined by the intermittent release of histamine and leukotrienes from hyperproliferating MCs as well as IL-6 and eosinophil chemotactic factors. As the burden of MC secretory products increases, patients experience worsening pruritus, flushing, palpitations, vomiting, and anaphylaxis in severe instances.^1,2,5 The mainstay of treatment of this condition involves symptom control through the inhibition of MC mediators.¹ The majority of patients respond well to antihistamines, antileukotriene agents, and oral corticosteroids during severe episodes of MC degranulation.^1,2,5

Unfortunately, some patients are unable to achieve adequate symptom control through the use of mediator-targeting treatments alone. In these cases, physicians often are faced with the following treatment dilemma: Either attempt to use therapies such as interferon alfa, which is cytoreductive to MCs, or 2-chlorodeoxyadenosine to reduce the overall MC burden, or turn to newer nonimmunosuppressive second-line options. We present the case of a patient with chronic ISM with progressive cutaneous lesions and poorly controlled pruritus that was previously managed with topical corticosteroids and antihistamines who responded favorably to treatment with narrowband UVB (NB-UVB) phototherapy.

Case Report

A 57-year-old woman presented with a 10-year history of widespread red-brown macules and papules on the trunk and upper and lower extremities. The lesions were intermittently pruritic, a symptom that was exacerbated on sun and heat exposure. A skin biopsy performed by an outside dermatologist 9 years prior confirmed the presence of mastocytosis. The patient was originally treated with triamcinolone cream and oral antihistamines, which controlled her symptoms successfully for nearly a decade.

At the current presentation, the patient reported increasingly severe pruritus and lesional spread to the neck and face of 15 months’ duration. She denied any symptoms of flushing, diarrhea, syncopal episodes, or lightheadedness. Physical examination revealed a well-appearing middle-aged woman with multiple 3- to 8-mm, red-brown, blanchable macules and papules with areas coalescing into plaques that primarily involved the legs (Figure 1A); arms; back; and to a lesser extent the abdomen, neck, and face. There was no palpable lymphadenopathy.

Laboratory results revealed a complete blood cell count and basic metabolic profile within reference range; however, the serum tryptase level was elevated at 65 ng/mL (reference range, <11.4 ng/mL). A positron emission tomography–computed tomography scan was negative, as well as a c-KIT mutation analysis. A review of the skin biopsy from 9 years prior demonstrated slight acanthosis with dermal proliferation of mononuclear cells (Figure 2A), some of which had abundant cytoplasm and oval-shaped nuclei. There were few eosinophils and marked dermal telangiectasias. Giemsa stain revealed increased numbers of MCs in the upper dermis (Figure 2B). A bone marrow biopsy performed 9 years later showed multifocal lesions composed of MCs with associated lymphoid aggregates without notable myelodyspoiesis (or myeloproliferative neoplasm). These features were all consistent with WHO criteria for ISM. Based on the most current clinical, laboratory, and histopathologic findings, the patient was diagnosed with category IB ISM.

The patient’s symptoms had remained stable for 9 years with a regimen of triamcinolone cream 0.1% twice daily, doxepin cream 5% daily as needed, and oral fexofenadine 180 mg once daily. The patient continues to use topical steroids and oral antihistamines. Due to inadequate symptom control, breakthrough pruritus, and the development of new skin lesions on the head and neck, she was started on NB-UVB treatment 2 months after presentation. The patient’s symptoms and the extent of cutaneous maculopapular lesions improved after 20 light treatments (Figure 1B), with even more dramatic results after 40 cycles of therapy (Figure 1C). Overall, the lower legs have proved most recalcitrant to this treatment modality. She is currently continuing to receive NB-UVB treatment twice weekly.

Comment

Systemic mastocytosis is a heterogeneous disorder characterized by the proliferation and accumulation of atypical MCs in tissues, principally in the bone marrow and skin, though involvement of the gastrointestinal tract, liver, spleen, and lymphatic system also have been reported.^1,2,6 The WHO classification of mastocytosis divides this condition into 7 subtypes.⁴ Indolent systemic mastocytosis is the most common variant.^2,6 The etiology of ISM is not fully understood, but there is evidence suggesting that an activating mutation of KIT proto-oncogene receptor tyrosine kinase, KIT (usually D816V), present in the MCs of nearly 80% of patients with ISM may be involved.^1,3-5,7 Patients occasionally present with predominantly cutaneous findings but typically seek medical attention due to the recurrent systemic symptoms of the disease (eg, pruritus, flushing, syncope, palpitations, headache, dyspepsia, vomiting, diarrhea), which are related to the release of MC mediators.^1,2

The management of ISM is complex and based primarily on symptom reduction without alteration of disease course.^1,2,5,7 Patients should avoid symptom triggers such as heat, humidity, emotional and physical stress, alcohol, and certain medications (ie, aspirin, opioids, radiocontrast agents).⁷ Patients are initially treated with histamine H1- and H2-receptor antagonists to alleviate MC mediator release symptoms.^1,2,8 Although H1 blockers are most effective in mitigating cutaneous symptoms and limiting pruritus, H2 blockers are used to control gastric hypersecretion and dyspepsia.² Proton pump inhibitors are useful in patients with peptic ulcer disease who are unresponsive to H2-receptor antagonist therapy.^2,7 Cromolyn sodium and ketotifen fumarate are MC stabilizers that help prevent degranulation, which is helpful in relieving most major ISM symptoms. Leukotriene antagonists, such as zafirlukast, montelukast sodium, or zileuton, also may be employed to target the proinflammatory and pruritogenic leukotrienes, also products of the MC protein.^2,7 Imatinib mesylate and masitinib mesylate, both tyrosine kinase inhibitors, have been shown to improve symptoms and reduce MC mediator levels in ISM; however, most patients harbor the resistant KIT D816V mutation, which limits the utility of this medication.Patients with sensitive KIT mutations or those who have the wild-type KIT D816 mutation may be more appropriate candidates for imatinib or masitinib therapy, which can ameliorate symptoms of flushing, pruritus, and depression.^7-10 Treatment with omalizumab, a humanized murine anti-IgE monoclonal antibody, can be effective in treating recurrent, treatment-refractory anaphylaxis in ISM patients.^5,7

Symptoms unresponsive to these therapies can be effectively treated with a short course of oral corticosteroids,^6,7 while MC cytoreductive therapies such as interferon alfa or 2-chlorodeoxyadenosine (cladribine/2-CdA) are reserved for refractory cases.^2,7 Alternative therapies such as NB-UVB² or psoralen plus UVA phototherapy¹¹ also have demonstrated success in treating ISM symptoms. In the past, NB-UVB has shown efficacy in controlling pruriginous conditions ranging from chronic urticaria^12,13 to atopic dermatitis¹⁴ to psoriasis.¹⁵ This evidence has spurred studies to evaluate if NB-UVB has a role in the management of uncontrolled cases of cutaneous and ISM.^2,13,16,17 To date, the evidence has been promising. The majority of patients treated with this regimen report subjective reduction in pruritus in addition to clinical cutaneous disease burden.^2,11 Also, laboratory analysis demonstrates decreased levels of tryptase in patients utilizing NB-UVB phototherapy.² Thus far, the use of NB-UVB phototherapy in the treatment of pruriginous disorders such as ISM has not been associated with any severe side effects such as increased rates of anaphylaxis, though some research has suggested that this therapy may lower the threshold for patients to develop symptomatic dermographism.¹² Overall, patients treated with NB-UVB phototherapy report improved quality of life related to more effective symptom control.¹⁶

Although ISM is currently considered an incurable chronic condition,⁶ this case illustrates that symptomatic management is possible, even in cases of long-standing, severe disease. Patients should still be encouraged to avoid triggering factors and be vigilant in preventing potential anaphylaxis. However, NB-UVB phototherapy provides a supplemental or alternative treatment choice when other therapies have failed. We hope that the success of NB-UVB demonstrated in this case provides further evidence that this light-based therapy is a valuable treatment option in mastocytosis patients with unremitting or poorly controlled symptoms.

Systemic mastocytosis is a heterogeneous disorder of stem cell origin defined by abnormal hyperplasia and accumulation of mast cells (MCs) in one or more tissues.^1,2 The most commonly affected tissues are the bone marrow, gastrointestinal tract, and skin. Based on a number of major and minor criteria defined by the World Health Organization (WHO), the mastocytoses are subdivided into 7 variants that range from isolated cutaneous involvement to widespread systemic disease.^1-4 The most frequently diagnosed subtype is indolent systemic mastocytosis (ISM), a chronic disorder characterized by diffuse cutaneous macules and papules as well as bone marrow involvement in the form of multifocal dense infiltrates of MCs that frequently are phenotypically positive for c-KIT and tryptase. Serum tryptase levels are nearly invariably elevated in patients with this condition.^1,2

Symptoms of ISM are determined by the intermittent release of histamine and leukotrienes from hyperproliferating MCs as well as IL-6 and eosinophil chemotactic factors. As the burden of MC secretory products increases, patients experience worsening pruritus, flushing, palpitations, vomiting, and anaphylaxis in severe instances.^1,2,5 The mainstay of treatment of this condition involves symptom control through the inhibition of MC mediators.¹ The majority of patients respond well to antihistamines, antileukotriene agents, and oral corticosteroids during severe episodes of MC degranulation.^1,2,5

Unfortunately, some patients are unable to achieve adequate symptom control through the use of mediator-targeting treatments alone. In these cases, physicians often are faced with the following treatment dilemma: Either attempt to use therapies such as interferon alfa, which is cytoreductive to MCs, or 2-chlorodeoxyadenosine to reduce the overall MC burden, or turn to newer nonimmunosuppressive second-line options. We present the case of a patient with chronic ISM with progressive cutaneous lesions and poorly controlled pruritus that was previously managed with topical corticosteroids and antihistamines who responded favorably to treatment with narrowband UVB (NB-UVB) phototherapy.

Case Report

A 57-year-old woman presented with a 10-year history of widespread red-brown macules and papules on the trunk and upper and lower extremities. The lesions were intermittently pruritic, a symptom that was exacerbated on sun and heat exposure. A skin biopsy performed by an outside dermatologist 9 years prior confirmed the presence of mastocytosis. The patient was originally treated with triamcinolone cream and oral antihistamines, which controlled her symptoms successfully for nearly a decade.

At the current presentation, the patient reported increasingly severe pruritus and lesional spread to the neck and face of 15 months’ duration. She denied any symptoms of flushing, diarrhea, syncopal episodes, or lightheadedness. Physical examination revealed a well-appearing middle-aged woman with multiple 3- to 8-mm, red-brown, blanchable macules and papules with areas coalescing into plaques that primarily involved the legs (Figure 1A); arms; back; and to a lesser extent the abdomen, neck, and face. There was no palpable lymphadenopathy.

Laboratory results revealed a complete blood cell count and basic metabolic profile within reference range; however, the serum tryptase level was elevated at 65 ng/mL (reference range, <11.4 ng/mL). A positron emission tomography–computed tomography scan was negative, as well as a c-KIT mutation analysis. A review of the skin biopsy from 9 years prior demonstrated slight acanthosis with dermal proliferation of mononuclear cells (Figure 2A), some of which had abundant cytoplasm and oval-shaped nuclei. There were few eosinophils and marked dermal telangiectasias. Giemsa stain revealed increased numbers of MCs in the upper dermis (Figure 2B). A bone marrow biopsy performed 9 years later showed multifocal lesions composed of MCs with associated lymphoid aggregates without notable myelodyspoiesis (or myeloproliferative neoplasm). These features were all consistent with WHO criteria for ISM. Based on the most current clinical, laboratory, and histopathologic findings, the patient was diagnosed with category IB ISM.

The patient’s symptoms had remained stable for 9 years with a regimen of triamcinolone cream 0.1% twice daily, doxepin cream 5% daily as needed, and oral fexofenadine 180 mg once daily. The patient continues to use topical steroids and oral antihistamines. Due to inadequate symptom control, breakthrough pruritus, and the development of new skin lesions on the head and neck, she was started on NB-UVB treatment 2 months after presentation. The patient’s symptoms and the extent of cutaneous maculopapular lesions improved after 20 light treatments (Figure 1B), with even more dramatic results after 40 cycles of therapy (Figure 1C). Overall, the lower legs have proved most recalcitrant to this treatment modality. She is currently continuing to receive NB-UVB treatment twice weekly.

Comment

Systemic mastocytosis is a heterogeneous disorder characterized by the proliferation and accumulation of atypical MCs in tissues, principally in the bone marrow and skin, though involvement of the gastrointestinal tract, liver, spleen, and lymphatic system also have been reported.^1,2,6 The WHO classification of mastocytosis divides this condition into 7 subtypes.⁴ Indolent systemic mastocytosis is the most common variant.^2,6 The etiology of ISM is not fully understood, but there is evidence suggesting that an activating mutation of KIT proto-oncogene receptor tyrosine kinase, KIT (usually D816V), present in the MCs of nearly 80% of patients with ISM may be involved.^1,3-5,7 Patients occasionally present with predominantly cutaneous findings but typically seek medical attention due to the recurrent systemic symptoms of the disease (eg, pruritus, flushing, syncope, palpitations, headache, dyspepsia, vomiting, diarrhea), which are related to the release of MC mediators.^1,2

The management of ISM is complex and based primarily on symptom reduction without alteration of disease course.^1,2,5,7 Patients should avoid symptom triggers such as heat, humidity, emotional and physical stress, alcohol, and certain medications (ie, aspirin, opioids, radiocontrast agents).⁷ Patients are initially treated with histamine H1- and H2-receptor antagonists to alleviate MC mediator release symptoms.^1,2,8 Although H1 blockers are most effective in mitigating cutaneous symptoms and limiting pruritus, H2 blockers are used to control gastric hypersecretion and dyspepsia.² Proton pump inhibitors are useful in patients with peptic ulcer disease who are unresponsive to H2-receptor antagonist therapy.^2,7 Cromolyn sodium and ketotifen fumarate are MC stabilizers that help prevent degranulation, which is helpful in relieving most major ISM symptoms. Leukotriene antagonists, such as zafirlukast, montelukast sodium, or zileuton, also may be employed to target the proinflammatory and pruritogenic leukotrienes, also products of the MC protein.^2,7 Imatinib mesylate and masitinib mesylate, both tyrosine kinase inhibitors, have been shown to improve symptoms and reduce MC mediator levels in ISM; however, most patients harbor the resistant KIT D816V mutation, which limits the utility of this medication.Patients with sensitive KIT mutations or those who have the wild-type KIT D816 mutation may be more appropriate candidates for imatinib or masitinib therapy, which can ameliorate symptoms of flushing, pruritus, and depression.^7-10 Treatment with omalizumab, a humanized murine anti-IgE monoclonal antibody, can be effective in treating recurrent, treatment-refractory anaphylaxis in ISM patients.^5,7

Symptoms unresponsive to these therapies can be effectively treated with a short course of oral corticosteroids,^6,7 while MC cytoreductive therapies such as interferon alfa or 2-chlorodeoxyadenosine (cladribine/2-CdA) are reserved for refractory cases.^2,7 Alternative therapies such as NB-UVB² or psoralen plus UVA phototherapy¹¹ also have demonstrated success in treating ISM symptoms. In the past, NB-UVB has shown efficacy in controlling pruriginous conditions ranging from chronic urticaria^12,13 to atopic dermatitis¹⁴ to psoriasis.¹⁵ This evidence has spurred studies to evaluate if NB-UVB has a role in the management of uncontrolled cases of cutaneous and ISM.^2,13,16,17 To date, the evidence has been promising. The majority of patients treated with this regimen report subjective reduction in pruritus in addition to clinical cutaneous disease burden.^2,11 Also, laboratory analysis demonstrates decreased levels of tryptase in patients utilizing NB-UVB phototherapy.² Thus far, the use of NB-UVB phototherapy in the treatment of pruriginous disorders such as ISM has not been associated with any severe side effects such as increased rates of anaphylaxis, though some research has suggested that this therapy may lower the threshold for patients to develop symptomatic dermographism.¹² Overall, patients treated with NB-UVB phototherapy report improved quality of life related to more effective symptom control.¹⁶

Although ISM is currently considered an incurable chronic condition,⁶ this case illustrates that symptomatic management is possible, even in cases of long-standing, severe disease. Patients should still be encouraged to avoid triggering factors and be vigilant in preventing potential anaphylaxis. However, NB-UVB phototherapy provides a supplemental or alternative treatment choice when other therapies have failed. We hope that the success of NB-UVB demonstrated in this case provides further evidence that this light-based therapy is a valuable treatment option in mastocytosis patients with unremitting or poorly controlled symptoms.

Systemic mastocytosis is a heterogeneous disorder of stem cell origin defined by abnormal hyperplasia and accumulation of mast cells (MCs) in one or more tissues.^1,2 The most commonly affected tissues are the bone marrow, gastrointestinal tract, and skin. Based on a number of major and minor criteria defined by the World Health Organization (WHO), the mastocytoses are subdivided into 7 variants that range from isolated cutaneous involvement to widespread systemic disease.^1-4 The most frequently diagnosed subtype is indolent systemic mastocytosis (ISM), a chronic disorder characterized by diffuse cutaneous macules and papules as well as bone marrow involvement in the form of multifocal dense infiltrates of MCs that frequently are phenotypically positive for c-KIT and tryptase. Serum tryptase levels are nearly invariably elevated in patients with this condition.^1,2

Symptoms of ISM are determined by the intermittent release of histamine and leukotrienes from hyperproliferating MCs as well as IL-6 and eosinophil chemotactic factors. As the burden of MC secretory products increases, patients experience worsening pruritus, flushing, palpitations, vomiting, and anaphylaxis in severe instances.^1,2,5 The mainstay of treatment of this condition involves symptom control through the inhibition of MC mediators.¹ The majority of patients respond well to antihistamines, antileukotriene agents, and oral corticosteroids during severe episodes of MC degranulation.^1,2,5

Unfortunately, some patients are unable to achieve adequate symptom control through the use of mediator-targeting treatments alone. In these cases, physicians often are faced with the following treatment dilemma: Either attempt to use therapies such as interferon alfa, which is cytoreductive to MCs, or 2-chlorodeoxyadenosine to reduce the overall MC burden, or turn to newer nonimmunosuppressive second-line options. We present the case of a patient with chronic ISM with progressive cutaneous lesions and poorly controlled pruritus that was previously managed with topical corticosteroids and antihistamines who responded favorably to treatment with narrowband UVB (NB-UVB) phototherapy.

Case Report

A 57-year-old woman presented with a 10-year history of widespread red-brown macules and papules on the trunk and upper and lower extremities. The lesions were intermittently pruritic, a symptom that was exacerbated on sun and heat exposure. A skin biopsy performed by an outside dermatologist 9 years prior confirmed the presence of mastocytosis. The patient was originally treated with triamcinolone cream and oral antihistamines, which controlled her symptoms successfully for nearly a decade.

At the current presentation, the patient reported increasingly severe pruritus and lesional spread to the neck and face of 15 months’ duration. She denied any symptoms of flushing, diarrhea, syncopal episodes, or lightheadedness. Physical examination revealed a well-appearing middle-aged woman with multiple 3- to 8-mm, red-brown, blanchable macules and papules with areas coalescing into plaques that primarily involved the legs (Figure 1A); arms; back; and to a lesser extent the abdomen, neck, and face. There was no palpable lymphadenopathy.

Laboratory results revealed a complete blood cell count and basic metabolic profile within reference range; however, the serum tryptase level was elevated at 65 ng/mL (reference range, <11.4 ng/mL). A positron emission tomography–computed tomography scan was negative, as well as a c-KIT mutation analysis. A review of the skin biopsy from 9 years prior demonstrated slight acanthosis with dermal proliferation of mononuclear cells (Figure 2A), some of which had abundant cytoplasm and oval-shaped nuclei. There were few eosinophils and marked dermal telangiectasias. Giemsa stain revealed increased numbers of MCs in the upper dermis (Figure 2B). A bone marrow biopsy performed 9 years later showed multifocal lesions composed of MCs with associated lymphoid aggregates without notable myelodyspoiesis (or myeloproliferative neoplasm). These features were all consistent with WHO criteria for ISM. Based on the most current clinical, laboratory, and histopathologic findings, the patient was diagnosed with category IB ISM.

The patient’s symptoms had remained stable for 9 years with a regimen of triamcinolone cream 0.1% twice daily, doxepin cream 5% daily as needed, and oral fexofenadine 180 mg once daily. The patient continues to use topical steroids and oral antihistamines. Due to inadequate symptom control, breakthrough pruritus, and the development of new skin lesions on the head and neck, she was started on NB-UVB treatment 2 months after presentation. The patient’s symptoms and the extent of cutaneous maculopapular lesions improved after 20 light treatments (Figure 1B), with even more dramatic results after 40 cycles of therapy (Figure 1C). Overall, the lower legs have proved most recalcitrant to this treatment modality. She is currently continuing to receive NB-UVB treatment twice weekly.

Comment

Systemic mastocytosis is a heterogeneous disorder characterized by the proliferation and accumulation of atypical MCs in tissues, principally in the bone marrow and skin, though involvement of the gastrointestinal tract, liver, spleen, and lymphatic system also have been reported.^1,2,6 The WHO classification of mastocytosis divides this condition into 7 subtypes.⁴ Indolent systemic mastocytosis is the most common variant.^2,6 The etiology of ISM is not fully understood, but there is evidence suggesting that an activating mutation of KIT proto-oncogene receptor tyrosine kinase, KIT (usually D816V), present in the MCs of nearly 80% of patients with ISM may be involved.^1,3-5,7 Patients occasionally present with predominantly cutaneous findings but typically seek medical attention due to the recurrent systemic symptoms of the disease (eg, pruritus, flushing, syncope, palpitations, headache, dyspepsia, vomiting, diarrhea), which are related to the release of MC mediators.^1,2

The management of ISM is complex and based primarily on symptom reduction without alteration of disease course.^1,2,5,7 Patients should avoid symptom triggers such as heat, humidity, emotional and physical stress, alcohol, and certain medications (ie, aspirin, opioids, radiocontrast agents).⁷ Patients are initially treated with histamine H1- and H2-receptor antagonists to alleviate MC mediator release symptoms.^1,2,8 Although H1 blockers are most effective in mitigating cutaneous symptoms and limiting pruritus, H2 blockers are used to control gastric hypersecretion and dyspepsia.² Proton pump inhibitors are useful in patients with peptic ulcer disease who are unresponsive to H2-receptor antagonist therapy.^2,7 Cromolyn sodium and ketotifen fumarate are MC stabilizers that help prevent degranulation, which is helpful in relieving most major ISM symptoms. Leukotriene antagonists, such as zafirlukast, montelukast sodium, or zileuton, also may be employed to target the proinflammatory and pruritogenic leukotrienes, also products of the MC protein.^2,7 Imatinib mesylate and masitinib mesylate, both tyrosine kinase inhibitors, have been shown to improve symptoms and reduce MC mediator levels in ISM; however, most patients harbor the resistant KIT D816V mutation, which limits the utility of this medication.Patients with sensitive KIT mutations or those who have the wild-type KIT D816 mutation may be more appropriate candidates for imatinib or masitinib therapy, which can ameliorate symptoms of flushing, pruritus, and depression.^7-10 Treatment with omalizumab, a humanized murine anti-IgE monoclonal antibody, can be effective in treating recurrent, treatment-refractory anaphylaxis in ISM patients.^5,7

Symptoms unresponsive to these therapies can be effectively treated with a short course of oral corticosteroids,^6,7 while MC cytoreductive therapies such as interferon alfa or 2-chlorodeoxyadenosine (cladribine/2-CdA) are reserved for refractory cases.^2,7 Alternative therapies such as NB-UVB² or psoralen plus UVA phototherapy¹¹ also have demonstrated success in treating ISM symptoms. In the past, NB-UVB has shown efficacy in controlling pruriginous conditions ranging from chronic urticaria^12,13 to atopic dermatitis¹⁴ to psoriasis.¹⁵ This evidence has spurred studies to evaluate if NB-UVB has a role in the management of uncontrolled cases of cutaneous and ISM.^2,13,16,17 To date, the evidence has been promising. The majority of patients treated with this regimen report subjective reduction in pruritus in addition to clinical cutaneous disease burden.^2,11 Also, laboratory analysis demonstrates decreased levels of tryptase in patients utilizing NB-UVB phototherapy.² Thus far, the use of NB-UVB phototherapy in the treatment of pruriginous disorders such as ISM has not been associated with any severe side effects such as increased rates of anaphylaxis, though some research has suggested that this therapy may lower the threshold for patients to develop symptomatic dermographism.¹² Overall, patients treated with NB-UVB phototherapy report improved quality of life related to more effective symptom control.¹⁶

Although ISM is currently considered an incurable chronic condition,⁶ this case illustrates that symptomatic management is possible, even in cases of long-standing, severe disease. Patients should still be encouraged to avoid triggering factors and be vigilant in preventing potential anaphylaxis. However, NB-UVB phototherapy provides a supplemental or alternative treatment choice when other therapies have failed. We hope that the success of NB-UVB demonstrated in this case provides further evidence that this light-based therapy is a valuable treatment option in mastocytosis patients with unremitting or poorly controlled symptoms.

Hydralazine-induced antineutrophil cytoplasmic antibody (ANCA)–positive vasculitis is a complex entity characterized by a distinctive clinical presentation comprising acral hemorrhagic vesiculopustules and necrotic ulcerations, at times with severe mucosal involvement. Although it is an established entity, a PubMed search of articles indexed for MEDLINE using the terms hydralazine vasculitis, ANCA positive vasculitis, and hydralazine associated vasculitis revealed a limited number of cases reported in the dermatologic literature (Table 1).^1-6 We report a rare case of hydralazine-induced vasculitis associated with airway compromise and severe gastrointestinal tract bleeding.

RELATED ARTICLE: Sweet Syndrome Associated With Hydralazine-Induced Lupus Erythematosus

Case Report

A 71-year-old woman with a history of end-stage renal disease treated with hemodialysis, as well as hypertension, diabetes mellitus, and ischemic cardiomyopathy, presented to our emergency department with odynophagia, muscle weakness, shortness of breath, and a distinctive mucocutaneous eruption on the left eyelid, lips, and tongue of 2 days’ duration. Physical examination revealed an ill-appearing, afebrile, dyspneic woman with swelling of the left upper eyelid, conjunctival injection, ulcerations on the lips and tongue, and tense hemorrhagic vesicles, as well as vesiculopustules on the elbows, palms, fingers, lower legs, and toes (Figure 1). Given her dyspnea, flexible laryngoscopy was performed and revealed ulceration and edema involving the epiglottis, aryepiglottic folds, and arytenoids. The patient was intubated for airway protection and started on intravenous dexamethasone.

An extensive diagnostic workup commenced. Bacterial, viral, and fungal cultures of blood, skin tissue, and respiratory secretions, as well as human immunodeficiency virus screening, were all negative. Specifically, a tissue culture was performed on skin from the left thigh, viral culture and direct fluorescent antibody were performed on a vesicle on the right knee for herpes simplex virus and herpes zoster, and a superficial wound culture was taken from the left arm, all showing no growth. The patient’s home medications were reviewed and revealed she was currently taking hydralazine (100 mg 3 times daily), which was started approximately 2 years prior. Laboratory results revealed a positive antinuclear antibody titer of 1:320 (diffuse pattern), positive antihistone antibody, and positive ANCA with cytoplasmic and perinuclear accentuation (Table 2). Enzyme-linked immunosorbent assays showed IgG antibodies to myeloperoxidase (MPO) and proteinase 3 (Table 2). Skin biopsies from the right lower leg and right upper arm were compatible with necrotizing leukocytoclastic vasculitis characterized by mural and luminal fibrin deposition involving capillaries and venules of the superficial and deep dermis (Figure 2). The vessel walls were infiltrated by neutrophils with concomitant leukocytoclasia. Vessels in the mid dermis were occluded by cellular fibrin thrombi. Foci of neutrophilic interface dermatitis with subepidermal bulla formation were observed. Infectious stains were negative. On direct immunofluorescence, striking homogeneous mantles of staining of IgG were present within the cutaneous vasculature.

Because the infectious workup was negative and there was no other known instigating factor of vasculitis, concern for a drug-induced process prompted thorough review of the patient’s home medications and discontinuation of hydralazine. A diagnosis of hydralazine-associated cutaneous vasculitis was made when laboratory workup confirmed no underlying infectious process or rheumatologic condition and the medication known to cause her symptoms was on her medication list. The dexamethasone dose was increased, leading to rapid improvement of her mucocutaneous findings; however, on initiation of a steroid taper, she developed substantial gastrointestinal tract bleeding. An esophageal biopsy revealed a neutrophil-rich necrotizing process that essentially mirrored the cutaneous biopsy consistent with vasculitic involvement of the gastrointestinal tract. Steroids were again increased with resolution in gastrointestinal tract bleeding.

Comment

Our case highlights a distinct clinical presentation of hydralazine-induced ANCA-positive cutaneous vasculitis associated with severe involvement of the aerodigestive tract with gastrointestinal tract bleeding and airway compromise requiring intubation. Although discontinuation of hydralazine and in certain cases the addition of immunosuppressive agents may be adequate for resolution of symptoms, some cases progress despite treatment, leading to skin grafting, amputation, and death.^3,4 Therefore, early recognition of hydralazine-induced cutaneous vasculitis and discontinuation of hydralazine are of paramount importance.

Reporting hydralazine-induced vasculitis is valuable because of its unique cutaneous, extracutaneous, and serologic findings. In our case, the cutaneous vasculitis presented clinically with acral hemorrhagic vesiculopustules and necrotic ulcerations resembling septic emboli, as opposed to classic lesions of palpable purpura typical of drug-induced leukocytoclastic vasculitis. Similar cutaneous findings have been described in other cases of hydralazine-induced vasculitis, indicating that this pattern of acral pseudoembolic vesiculopustules with necrosis and ulceration is characteristic of this entity.^1,3,6 In addition, involvement of the oral cavity, larynx, and gastrointestinal tract have been reported in cases of hydralazine-induced vasculitis, indicating mucosal involvement is an important feature of this disease.^3,6 Although involvement of the oral mucosa, larynx, and acral sites appears to be characteristic, the exact basis for this site localization remains elusive. A precedent has been established for a similar pattern of intraoral and laryngeal involvement in other ANCA-positive vasculitic syndromes, most notably Wegener granulomatosis.⁷ Similarly, there are certain occlusive vasculitic syndromes that show acral localization including chronic septic vasculitis and vasculitis of collagen vascular disease.

Serologic trends can aid in diagnosing hydralazine-induced vasculitis. In theory, the nonspecific cutaneous findings, often in association with joint pain and positive antinuclear antibodies, may lead clinicians to the misdiagnosis of a connective tissue disease, such as systemic lupus erythematosus (SLE). However, unlike SLE, hydralazine-induced vasculitis is associated with positive ANCAs, while antibodies against double-stranded DNA, a highly specific antibody for SLE, are uncommon.^8,9 Our patient had both positive perinuclear ANCA with cytoplasmic ANCA as well as a positive antihistone antibodies, a combination highly suggestive of a drug-induced process.

Despite the often acute presentation of hydralazine-induced ANCA-positive vasculitis, afflicted patients have characteristically been on the drug for a long period of time. Our patient is exemplary of most reported cases, as the time from initiation of hydralazine to onset of vasculitis was 2 years.⁴

The mechanism by which hydralazine causes this reaction is still a matter of debate. It seems clear that there are certain at-risk populations, such as slow acetylators and patients with an underlying hypercoagulable state. There are several theories by which hydralazine induces autoantibody formation. The first involves hydralazine metabolization by MPO released from activated neutrophils to form reactive intermediate metabolites. Such metabolites can be cytotoxic and may cause abnormal degradation of chromatin in susceptible individuals, leading to an autoimmune response against histone-DNA complexes. Alternatively, hydralazine may act as a hapten and bind to MPO, inducing an immune response against the hydralazine-MPO complex, with resultant formation of anti-MPO antibodies in susceptible individuals.¹⁰

Conclusion

Hydralazine-induced ANCA-positive vasculitis is a syndromic complex characterized by a distinctive clinical presentation comprising acral hemorrhagic vesiculopustules and necrotic ulcerations, at times with severe mucosal involvement along with a characteristic ANCA-positive serologic profile. Drug withdrawal is the cornerstone of therapy, and depending on the severity of symptoms, additional immunosuppressive treatment such as corticosteroids may be necessary. Older age of onset, female gender, and underlying autoimmune diatheses likely define important risk factors. With more recognition and reporting of this disease, further trends in both clinical and serological presentation will emerge.

Hydralazine-induced antineutrophil cytoplasmic antibody (ANCA)–positive vasculitis is a complex entity characterized by a distinctive clinical presentation comprising acral hemorrhagic vesiculopustules and necrotic ulcerations, at times with severe mucosal involvement. Although it is an established entity, a PubMed search of articles indexed for MEDLINE using the terms hydralazine vasculitis, ANCA positive vasculitis, and hydralazine associated vasculitis revealed a limited number of cases reported in the dermatologic literature (Table 1).^1-6 We report a rare case of hydralazine-induced vasculitis associated with airway compromise and severe gastrointestinal tract bleeding.

RELATED ARTICLE: Sweet Syndrome Associated With Hydralazine-Induced Lupus Erythematosus

Case Report

A 71-year-old woman with a history of end-stage renal disease treated with hemodialysis, as well as hypertension, diabetes mellitus, and ischemic cardiomyopathy, presented to our emergency department with odynophagia, muscle weakness, shortness of breath, and a distinctive mucocutaneous eruption on the left eyelid, lips, and tongue of 2 days’ duration. Physical examination revealed an ill-appearing, afebrile, dyspneic woman with swelling of the left upper eyelid, conjunctival injection, ulcerations on the lips and tongue, and tense hemorrhagic vesicles, as well as vesiculopustules on the elbows, palms, fingers, lower legs, and toes (Figure 1). Given her dyspnea, flexible laryngoscopy was performed and revealed ulceration and edema involving the epiglottis, aryepiglottic folds, and arytenoids. The patient was intubated for airway protection and started on intravenous dexamethasone.

An extensive diagnostic workup commenced. Bacterial, viral, and fungal cultures of blood, skin tissue, and respiratory secretions, as well as human immunodeficiency virus screening, were all negative. Specifically, a tissue culture was performed on skin from the left thigh, viral culture and direct fluorescent antibody were performed on a vesicle on the right knee for herpes simplex virus and herpes zoster, and a superficial wound culture was taken from the left arm, all showing no growth. The patient’s home medications were reviewed and revealed she was currently taking hydralazine (100 mg 3 times daily), which was started approximately 2 years prior. Laboratory results revealed a positive antinuclear antibody titer of 1:320 (diffuse pattern), positive antihistone antibody, and positive ANCA with cytoplasmic and perinuclear accentuation (Table 2). Enzyme-linked immunosorbent assays showed IgG antibodies to myeloperoxidase (MPO) and proteinase 3 (Table 2). Skin biopsies from the right lower leg and right upper arm were compatible with necrotizing leukocytoclastic vasculitis characterized by mural and luminal fibrin deposition involving capillaries and venules of the superficial and deep dermis (Figure 2). The vessel walls were infiltrated by neutrophils with concomitant leukocytoclasia. Vessels in the mid dermis were occluded by cellular fibrin thrombi. Foci of neutrophilic interface dermatitis with subepidermal bulla formation were observed. Infectious stains were negative. On direct immunofluorescence, striking homogeneous mantles of staining of IgG were present within the cutaneous vasculature.

Because the infectious workup was negative and there was no other known instigating factor of vasculitis, concern for a drug-induced process prompted thorough review of the patient’s home medications and discontinuation of hydralazine. A diagnosis of hydralazine-associated cutaneous vasculitis was made when laboratory workup confirmed no underlying infectious process or rheumatologic condition and the medication known to cause her symptoms was on her medication list. The dexamethasone dose was increased, leading to rapid improvement of her mucocutaneous findings; however, on initiation of a steroid taper, she developed substantial gastrointestinal tract bleeding. An esophageal biopsy revealed a neutrophil-rich necrotizing process that essentially mirrored the cutaneous biopsy consistent with vasculitic involvement of the gastrointestinal tract. Steroids were again increased with resolution in gastrointestinal tract bleeding.

Comment

Our case highlights a distinct clinical presentation of hydralazine-induced ANCA-positive cutaneous vasculitis associated with severe involvement of the aerodigestive tract with gastrointestinal tract bleeding and airway compromise requiring intubation. Although discontinuation of hydralazine and in certain cases the addition of immunosuppressive agents may be adequate for resolution of symptoms, some cases progress despite treatment, leading to skin grafting, amputation, and death.^3,4 Therefore, early recognition of hydralazine-induced cutaneous vasculitis and discontinuation of hydralazine are of paramount importance.

Reporting hydralazine-induced vasculitis is valuable because of its unique cutaneous, extracutaneous, and serologic findings. In our case, the cutaneous vasculitis presented clinically with acral hemorrhagic vesiculopustules and necrotic ulcerations resembling septic emboli, as opposed to classic lesions of palpable purpura typical of drug-induced leukocytoclastic vasculitis. Similar cutaneous findings have been described in other cases of hydralazine-induced vasculitis, indicating that this pattern of acral pseudoembolic vesiculopustules with necrosis and ulceration is characteristic of this entity.^1,3,6 In addition, involvement of the oral cavity, larynx, and gastrointestinal tract have been reported in cases of hydralazine-induced vasculitis, indicating mucosal involvement is an important feature of this disease.^3,6 Although involvement of the oral mucosa, larynx, and acral sites appears to be characteristic, the exact basis for this site localization remains elusive. A precedent has been established for a similar pattern of intraoral and laryngeal involvement in other ANCA-positive vasculitic syndromes, most notably Wegener granulomatosis.⁷ Similarly, there are certain occlusive vasculitic syndromes that show acral localization including chronic septic vasculitis and vasculitis of collagen vascular disease.

Serologic trends can aid in diagnosing hydralazine-induced vasculitis. In theory, the nonspecific cutaneous findings, often in association with joint pain and positive antinuclear antibodies, may lead clinicians to the misdiagnosis of a connective tissue disease, such as systemic lupus erythematosus (SLE). However, unlike SLE, hydralazine-induced vasculitis is associated with positive ANCAs, while antibodies against double-stranded DNA, a highly specific antibody for SLE, are uncommon.^8,9 Our patient had both positive perinuclear ANCA with cytoplasmic ANCA as well as a positive antihistone antibodies, a combination highly suggestive of a drug-induced process.

Despite the often acute presentation of hydralazine-induced ANCA-positive vasculitis, afflicted patients have characteristically been on the drug for a long period of time. Our patient is exemplary of most reported cases, as the time from initiation of hydralazine to onset of vasculitis was 2 years.⁴

The mechanism by which hydralazine causes this reaction is still a matter of debate. It seems clear that there are certain at-risk populations, such as slow acetylators and patients with an underlying hypercoagulable state. There are several theories by which hydralazine induces autoantibody formation. The first involves hydralazine metabolization by MPO released from activated neutrophils to form reactive intermediate metabolites. Such metabolites can be cytotoxic and may cause abnormal degradation of chromatin in susceptible individuals, leading to an autoimmune response against histone-DNA complexes. Alternatively, hydralazine may act as a hapten and bind to MPO, inducing an immune response against the hydralazine-MPO complex, with resultant formation of anti-MPO antibodies in susceptible individuals.¹⁰

Conclusion

Hydralazine-induced ANCA-positive vasculitis is a syndromic complex characterized by a distinctive clinical presentation comprising acral hemorrhagic vesiculopustules and necrotic ulcerations, at times with severe mucosal involvement along with a characteristic ANCA-positive serologic profile. Drug withdrawal is the cornerstone of therapy, and depending on the severity of symptoms, additional immunosuppressive treatment such as corticosteroids may be necessary. Older age of onset, female gender, and underlying autoimmune diatheses likely define important risk factors. With more recognition and reporting of this disease, further trends in both clinical and serological presentation will emerge.

Hydralazine-induced antineutrophil cytoplasmic antibody (ANCA)–positive vasculitis is a complex entity characterized by a distinctive clinical presentation comprising acral hemorrhagic vesiculopustules and necrotic ulcerations, at times with severe mucosal involvement. Although it is an established entity, a PubMed search of articles indexed for MEDLINE using the terms hydralazine vasculitis, ANCA positive vasculitis, and hydralazine associated vasculitis revealed a limited number of cases reported in the dermatologic literature (Table 1).^1-6 We report a rare case of hydralazine-induced vasculitis associated with airway compromise and severe gastrointestinal tract bleeding.

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Case Report

A 71-year-old woman with a history of end-stage renal disease treated with hemodialysis, as well as hypertension, diabetes mellitus, and ischemic cardiomyopathy, presented to our emergency department with odynophagia, muscle weakness, shortness of breath, and a distinctive mucocutaneous eruption on the left eyelid, lips, and tongue of 2 days’ duration. Physical examination revealed an ill-appearing, afebrile, dyspneic woman with swelling of the left upper eyelid, conjunctival injection, ulcerations on the lips and tongue, and tense hemorrhagic vesicles, as well as vesiculopustules on the elbows, palms, fingers, lower legs, and toes (Figure 1). Given her dyspnea, flexible laryngoscopy was performed and revealed ulceration and edema involving the epiglottis, aryepiglottic folds, and arytenoids. The patient was intubated for airway protection and started on intravenous dexamethasone.

An extensive diagnostic workup commenced. Bacterial, viral, and fungal cultures of blood, skin tissue, and respiratory secretions, as well as human immunodeficiency virus screening, were all negative. Specifically, a tissue culture was performed on skin from the left thigh, viral culture and direct fluorescent antibody were performed on a vesicle on the right knee for herpes simplex virus and herpes zoster, and a superficial wound culture was taken from the left arm, all showing no growth. The patient’s home medications were reviewed and revealed she was currently taking hydralazine (100 mg 3 times daily), which was started approximately 2 years prior. Laboratory results revealed a positive antinuclear antibody titer of 1:320 (diffuse pattern), positive antihistone antibody, and positive ANCA with cytoplasmic and perinuclear accentuation (Table 2). Enzyme-linked immunosorbent assays showed IgG antibodies to myeloperoxidase (MPO) and proteinase 3 (Table 2). Skin biopsies from the right lower leg and right upper arm were compatible with necrotizing leukocytoclastic vasculitis characterized by mural and luminal fibrin deposition involving capillaries and venules of the superficial and deep dermis (Figure 2). The vessel walls were infiltrated by neutrophils with concomitant leukocytoclasia. Vessels in the mid dermis were occluded by cellular fibrin thrombi. Foci of neutrophilic interface dermatitis with subepidermal bulla formation were observed. Infectious stains were negative. On direct immunofluorescence, striking homogeneous mantles of staining of IgG were present within the cutaneous vasculature.

Because the infectious workup was negative and there was no other known instigating factor of vasculitis, concern for a drug-induced process prompted thorough review of the patient’s home medications and discontinuation of hydralazine. A diagnosis of hydralazine-associated cutaneous vasculitis was made when laboratory workup confirmed no underlying infectious process or rheumatologic condition and the medication known to cause her symptoms was on her medication list. The dexamethasone dose was increased, leading to rapid improvement of her mucocutaneous findings; however, on initiation of a steroid taper, she developed substantial gastrointestinal tract bleeding. An esophageal biopsy revealed a neutrophil-rich necrotizing process that essentially mirrored the cutaneous biopsy consistent with vasculitic involvement of the gastrointestinal tract. Steroids were again increased with resolution in gastrointestinal tract bleeding.

Comment

Our case highlights a distinct clinical presentation of hydralazine-induced ANCA-positive cutaneous vasculitis associated with severe involvement of the aerodigestive tract with gastrointestinal tract bleeding and airway compromise requiring intubation. Although discontinuation of hydralazine and in certain cases the addition of immunosuppressive agents may be adequate for resolution of symptoms, some cases progress despite treatment, leading to skin grafting, amputation, and death.^3,4 Therefore, early recognition of hydralazine-induced cutaneous vasculitis and discontinuation of hydralazine are of paramount importance.

Reporting hydralazine-induced vasculitis is valuable because of its unique cutaneous, extracutaneous, and serologic findings. In our case, the cutaneous vasculitis presented clinically with acral hemorrhagic vesiculopustules and necrotic ulcerations resembling septic emboli, as opposed to classic lesions of palpable purpura typical of drug-induced leukocytoclastic vasculitis. Similar cutaneous findings have been described in other cases of hydralazine-induced vasculitis, indicating that this pattern of acral pseudoembolic vesiculopustules with necrosis and ulceration is characteristic of this entity.^1,3,6 In addition, involvement of the oral cavity, larynx, and gastrointestinal tract have been reported in cases of hydralazine-induced vasculitis, indicating mucosal involvement is an important feature of this disease.^3,6 Although involvement of the oral mucosa, larynx, and acral sites appears to be characteristic, the exact basis for this site localization remains elusive. A precedent has been established for a similar pattern of intraoral and laryngeal involvement in other ANCA-positive vasculitic syndromes, most notably Wegener granulomatosis.⁷ Similarly, there are certain occlusive vasculitic syndromes that show acral localization including chronic septic vasculitis and vasculitis of collagen vascular disease.

Serologic trends can aid in diagnosing hydralazine-induced vasculitis. In theory, the nonspecific cutaneous findings, often in association with joint pain and positive antinuclear antibodies, may lead clinicians to the misdiagnosis of a connective tissue disease, such as systemic lupus erythematosus (SLE). However, unlike SLE, hydralazine-induced vasculitis is associated with positive ANCAs, while antibodies against double-stranded DNA, a highly specific antibody for SLE, are uncommon.^8,9 Our patient had both positive perinuclear ANCA with cytoplasmic ANCA as well as a positive antihistone antibodies, a combination highly suggestive of a drug-induced process.

Despite the often acute presentation of hydralazine-induced ANCA-positive vasculitis, afflicted patients have characteristically been on the drug for a long period of time. Our patient is exemplary of most reported cases, as the time from initiation of hydralazine to onset of vasculitis was 2 years.⁴

The mechanism by which hydralazine causes this reaction is still a matter of debate. It seems clear that there are certain at-risk populations, such as slow acetylators and patients with an underlying hypercoagulable state. There are several theories by which hydralazine induces autoantibody formation. The first involves hydralazine metabolization by MPO released from activated neutrophils to form reactive intermediate metabolites. Such metabolites can be cytotoxic and may cause abnormal degradation of chromatin in susceptible individuals, leading to an autoimmune response against histone-DNA complexes. Alternatively, hydralazine may act as a hapten and bind to MPO, inducing an immune response against the hydralazine-MPO complex, with resultant formation of anti-MPO antibodies in susceptible individuals.¹⁰

Conclusion

Hydralazine-induced ANCA-positive vasculitis is a syndromic complex characterized by a distinctive clinical presentation comprising acral hemorrhagic vesiculopustules and necrotic ulcerations, at times with severe mucosal involvement along with a characteristic ANCA-positive serologic profile. Drug withdrawal is the cornerstone of therapy, and depending on the severity of symptoms, additional immunosuppressive treatment such as corticosteroids may be necessary. Older age of onset, female gender, and underlying autoimmune diatheses likely define important risk factors. With more recognition and reporting of this disease, further trends in both clinical and serological presentation will emerge.