Article

New imaging tools along with adaptations to existing technologies have been emerging in recent years, with the potential to improve hair diagnostics and treatment monitoring. We provide an overview of 4 noninvasive hair imaging technologies: global photography, trichoscopy, reflectance confocal microscopy (RCM), and optical coherence tomography (OCT). For each instrument, we discuss current and future applications in clinical practice and research along with advantages and disadvantages.

Global Photography

Global photography allows for the analysis of hair growth, volume, distribution, and density through serial standardized photographs.¹ Global photography was first introduced for hair growth studies in 1987 and soon after was used for hair and scalp assessments in finasteride clinical trials.²

Hair Assessment—Washed, dried, and combed hair, without hair product, are required for accurate imaging; wet conditions increase reflection and promote hair clumping, thus revealing more scalp and depicting the patient as having less hair.¹ Headshots are taken from short distances and use stereotactic positioning devices to create 4 global views: vertex, midline, frontal, and temporal.³ Stereotactic positioning involves fixing the patient’s chin and forehead as well as mounting the camera and flash device to ensure proper magnification. These adjustments ensure lighting remains consistent throughout consecutive study visits.⁴ Various grading scales are available for use in hair growth clinical studies to increase objectivity in the analysis of serial global photographs. A blinded evaluator should assess the before and after photographs to limit experimenter bias. Global photography often is combined with quantitative software analysis for improved detection of hair changes.¹

Advancements—Growing interest in improving global photography has resulted in various application-based, artificial intelligence (AI)–mediated tools to simplify photograph collection and analysis. For instance, new hair analysis software utilizes AI algorithms to account for facial features in determining the optimal angle for capturing global photographs (Figure 1), which simplifies the generation of global photography images through smartphone applications and obviates the need for additional stereotactic positioning equipment.^5,6

Limitations—Clinicians should be aware of global photography’s requirements for consistency in lighting, camera settings, film, and image processing, which can limit the accuracy of hair assessment over time if not replicated correctly.^7,8 Emerging global photography software has helped to overcome some of these limitations.

Global photography is less precise when a patient’s hair loss is less than 50%, as it is difficult to discern subtle hair changes. Thus, global photography provides limited utility in assessing minimal to moderate hair loss.⁹ Currently, global photography largely functions as an adjunct tool for other hair analysis methods rather than as a stand-alone tool.

Trichoscopy

Trichoscopy (also known as dermoscopy of the hair and scalp) may be performed with a manual dermoscope (with 10× magnification) or a digital videodermatoscope (up to 1000× magnification).^10-12 Unlike global photography, trichoscopy provides a detailed structural analysis of hair shafts, follicular openings, and perifollicular and interfollicular areas.¹³ Kinoshita-Ise and Sachdeva¹³ provided an in-depth, updated review of trichoscopy terminology with their definitions and associated conditions (with prevalence), which should be referenced when performing trichoscopic examination.

Hair Assessment—Trichoscopic assessment begins with inspection of follicular openings (also referred to as “dots”), which vary in color depending on the material filling them—degrading keratinocytes, keratin, sebaceous debris, melanin, or fractured hairs.¹³ The structure of hair shafts also is examined, showing broken hairs, short vellus hairs, and comma hairs, among others. Perifollicular areas are examined for scale, erythema, blue-gray dots, and whitish halos. Interfollicular areas are examined for pigment pattern as well as vascularization, which often presents in a looping configuration under dermoscopy. A combination of dot colorization, hair shaft structure, and perifollicular and interfollicular findings inform diagnostic algorithms of hair and scalp conditions. For example, central centrifugal cicatricial alopecia, the most common alopecia seen in Black women, has been associated with a combination of honeycomb pigment pattern, perifollicular whitish halo, pinpoint white dots, white patches, and perifollicular erythema.¹³

Advantages—Perhaps the most useful feature of trichoscopy is its ability to translate visualized features into simple diagnostic algorithms. For instance, if the clinician has diagnosed the patient with noncicatricial alopecia, they would next focus on dot colors. With black dots, the next step would be to determine whether the hairs are tapered or coiled, and so on. This systematic approach enables the clinician to narrow possible diagnoses.² An additional advantage of trichoscopy is that it examines large surface areas noninvasively as compared to hair-pull tests and scalp biopsy.^14,15 Trichoscopy allows temporal comparisons of the same area for disease and treatment monitoring with more diagnostic detail than global photography.¹⁶ Trichoscopy also is useful in selecting biopsy locations by discerning and avoiding areas of scar tissue.¹⁷

Limitations—Diagnosis via the trichoscopy algorithm is limiting because it is not comprehensive of all hair and scalp disease.¹⁸ Additionally, many pathologies exhibit overlapping follicular and interfollicular patterning. For example, almost all subtypes of scarring alopecia present with hair loss and scarred follicles once they have progressed to advanced stages. Further studies should identify more specific patterns of hair and scalp pathologies, which could then be incorporated into a diagnostic algorithm.¹³

Advancements—The advent of hair analysis software has expanded the role of videodermoscopy by rapidly quantifying hair growth parameters such as hair count, follicular density, and follicular diameter, as well as interfollicular distances (Figure 2).^14,17 Vellus and terminal hairs are differentiated according to their thickness and length.¹⁷ Moreover, the software can analyze the same area of the scalp over time by either virtual tattoos, semipermanent markings, or precise location measurements, increasing intra- and interclass correlation. The rate of hair growth, hair shedding, and parameters of anagen and telogen hairs can be studied by a method termed phototrichogram whereby a transitional area of hair loss and normal hair growth is identified and trimmed to less than 1 mm from the skin surface.¹⁹ A baseline photograph is taken using videodermoscopy. After approximately 3 days, the identical region is photographed and compared with the initial image to observe changes in the hair. Software programs can distinguish the growing hair as anagen and nongrowing hair as telogen, calculating the anagen-to-telogen ratio as well as hair growth rate, which are essential measurements in hair research and clinical studies. Software programs have replaced laborious and time-consuming manual hair counts and have rapidly grown in popularity in evaluating patterned hair loss.

Reflectance Confocal Microscopy

Reflectance confocal microscopy is a noninvasive imaging tool that visualizes skin and its appendages at near-histologic resolution (lateral resolution of 0.5–1 μm). It produces grayscale horizontal images that can be taken at levels ranging from the stratum corneum to the superficial papillary dermis, corresponding to a depth of approximately 100 to 150 µm. Thus, a hair follicle can be imaged starting from the follicular ostia down to the reachable papillary dermis (Figure 3).²⁰ Image contrast is provided by differences in the size and refractive indices of cellular organelles.^21,22 There are 2 commercially available RCM devices: VivaScope 1500 and VivaScope 3000 (Caliber Imaging & Diagnostics, Inc).

VivaScope 1500, a wide-probe microscope, requires the attachment of a plastic window to the desired imaging area. The plastic window is lined with medical adhesive tape to prevent movement during imaging. The adhesive tape can pull on hair upon removal, which is not ideal for patients with existing hair loss. Additionally, the image quality of VivaSope 1500 is best in flat areas and areas where hair is shaved.^20,23,24 Despite these disadvantages, VivaScope 1500 has successfully shown utility in research studies, which suggests that these obstacles can be overcome by experienced users. The handheld VivaScope 3000 is ergonomically designed and suitable for curved surfaces such as the scalp, with the advantage of not requiring any adhesive. However, the images acquired from the VivaScope 3000 cover a smaller surface area.

Structures Visualized—Structures distinguished with RCM include keratinocytes, melanocytes, inflammatory cells, hair follicles, hair shafts, adnexal infundibular epithelium, blood vessels, fibroblasts, and collagen.²³ Real-time visualization of blood flow also can be seen.

Applications of RCM—Reflectance confocal microscopy has been used to study scalp discoid lupus, lichen planopilaris, frontal fibrosing alopecia, folliculitis decalvans, chemotherapy-induced alopecia (CIA), alopecia areata, and androgenetic alopecia. Diagnostic RCM criteria for such alopecias have been developed based on their correspondence to histopathology. An RCM study of classic lichen planopilaris and frontal fibrosing alopecia identified features of epidermal disarray, infundibular hyperkeratosis, inflammatory cells, pigment incontinence, perifollicular fibrosis, bandlike scarring, melanophages in the dermis, dilated blood vessels, basal layer vacuolar degeneration, and necrotic keratinocytes.²⁵ Pigment incontinence in the superficial epidermis, perifollicular lichenoid inflammation, and hyperkeratosis were characteristic RCM features of early-stage lichen planopilaris, while perifollicular fibrosis and dilated blood vessels were characteristic RCM features of late-stage disease. The ability of RCM features to distinguish different stages of lichen planopilaris shows its potential in treating early disease and preventing irreversible hair loss.

Differentiating between scarring and nonscarring alopecia also is possible through RCM. The presence of periadnexal, epidermal, and dermal inflammatory cells, in addition to periadnexal sclerosis, are defining RCM features of scarring alopecia.²⁶ These features are absent in nonscarring alopecias. Reflectance confocal microscopy additionally has been shown to be useful in the treatment monitoring of lichen planopilaris and discoid lupus erythematosus.²⁰ Independent reviewers, blinded to the patients’ identities, were able to characterize and follow features of these scarring alopecias by RCM. The assessed RCM features were comparable to those observed by histopathologic evaluation: epidermal disarray, spongiosis, exocytosis of inflammatory cells in the epidermis, interface dermatitis, peri- and intra-adnexal infiltration of inflammatory cells, dilated vessels in the dermis, dermal infiltration of inflammatory cells and melanophages, and dermal sclerosis. A reduction in inflammatory cells across multiple skin layers and at the level of the adnexal epithelium correlated with clinical response to treatment. Reflectance confocal microscopy also was able to detect recurrence of inflammation in cases where treatment had been interrupted before clinical signs of disease recurrence were evident. The authors thus concluded that RCM’s sensitivity can guide timing of treatment and avoid delays in starting or restarting treatment.²⁰

Reflectance confocal microscopy also has served as a learning tool for new subclinical understandings of alopecia. In a study of CIA, the disease was found to be a dynamic process that could be categorized into 4 distinct phases distinguishable by combined confocal and dermoscopic features. This study also identified a new feature observable on RCM images—a CIA dot—defined as a dilated follicular infundibulum containing mashed, malted, nonhomogeneous material and normal or fragmented hair. This dot is thought to represent the initial microscopic sign of direct toxicity of chemotherapy on the hair follicle. Chemotherapy-induced alopecia dots persist throughout chemotherapy and subsequently disappear after chemotherapy ends.²⁷

Limitations and Advantages—Currently, subtypes of cicatricial alopecias cannot be characterized on RCM because inflammatory cell types are not distinguished from each other (eg, eosinophils vs neutrophils). Another limitation of RCM is the loss of resolution below the superficial papillary dermis (a depth of approximately 150 µm); thus, deeper structures, such as the hair bulb, cannot be visualized.

Unlike global photography and trichoscopy, which are low-cost methods, RCM is much more costly, ranging upwards of several thousand dollars, and it may require additional technical support fees, making it less accessible for clinical practice. However, RCM imaging continues to be recommended as an intermediate step between trichoscopy and histology for the diagnosis and management of hair disease.²⁶ If a biopsy is required, RCM can aid in the selection of a biopsy site, as areas with active inflammation are more informative than atrophic and fibrosed areas.²³ The role of RCM in trichoscopy can be expanded by designing a more cost-effective and ergonomically suited scope for hair and scalp assessment.

Optical Coherence Tomography

Optical coherence tomography is a noninvasive handheld device that emits low-power infrared light to visualize the skin and adnexal structures. Optical coherence tomography relies on the principle of interferometry to detect phase differences in optical backscattering at varying tissue depths.^28,29 It allows visualization up to 2 mm, which is 2 to 5 times deeper than RCM.³⁶ Unlike RCM, which has cellular resolution, OCT has an axial resolution of 3 to 15 μm, which allows only for the detection of structural boundaries.³⁰ There are various OCT modalities that differ in lateral and axial resolutions and maximum depth. Commercial software is available that measures changes in vascular density by depth, epidermal thickness, skin surface texture, and optical attenuation—the latter being an indirect measurement of collagen density and skin hydration.

Structures Visualized—Hair follicles can be well distinguished on OCT images, and as such, OCT is recognized as a diagnostic tool in trichology (Figure 4).³¹ Follicular openings, interfollicular collagen, and outlines of the hair shafts are visible; however, detailed components of the follicular unit cannot be visualized by OCT. Keratin hyperrefractivity identifies the hair shaft. Additionally, the hair matrix is denoted by a slightly granular texture in the dermis. Dynamic OCT produces colorized images that visualize blood flow within vessels.

Applications of OCT—Optical coherence tomography is utilized in investigative trichology because it provides highly reproducible measurements of hair shaft diameters, cross-sectional surface areas, and form factor, which is a surrogate parameter for hair shape. The cross-section of hair shafts provides insight into local metabolism and perifollicular inflammation. Cross-sections of hair shafts in areas of alopecia areata were found to be smaller than cross-sections in the unaffected scalp within the same individual.³² Follicular density can be manually quantified on OCT images, but there also is promise for automated quantification. A recent study by Urban et al³³ described training a convolutional neural network to automatically count hair as well as hair-bearing and non–hair-bearing follicles in OCT scans. These investigators also were able to color-code hair according to height, resulting in the creation of a “height” map.

Optical coherence tomography has furthered our understanding of the pathophysiology of cicatricial and nonscarring alopecias. Vazquez-Herrera et al³⁴ assessed the inflammatory and cicatricial stages of frontal fibrosing alopecia by OCT imaging. Inflammatory hairlines, which are seen in the early stages of frontal fibrosing alopecia, exhibited a thickened dermis, irregular distribution of collagen, and increased vascularity in both the superficial and deep dermal layers compared to cicatricial and healthy scalp. Conversely, late-stage cicatricial areas exhibited a thin dermis and collagen that appeared in a hyperreflective, concentric, onion-shaped pattern around remnant follicular openings. Vascular flow was reduced in the superficial dermis of a cicatricial scalp but increased in the deep dermal layers compared with a healthy scalp. The attenuation coefficients of these disease stages also were assessed. The attenuation coefficient of the inflammatory hairline was higher compared with normal skin, likely as a reflection of inflammatory infiltrate and edema, whereas the attenuation coefficient of cicatricial scalp was lower compared with normal skin, likely reflecting the reduced water content of atrophic skin.³⁴ This differentiation of early- and late-stage cicatricial alopecias has implications for early treatment and improved prognosis. Additionally, there is potential for OCT to assist in the differentiation of alopecia subtypes, as it can measure the epidermal thickness and follicular density and was previously used to compare scarring and nonscarring alopecia.³⁵

Advantages and Limitations—Similar to RCM, OCT may be cost prohibitive for some clinicians. In addition, OCT cannot visualize the follicular unit in cellular detail. However, the extent of OCT’s capabilities may not be fully realized. Dynamic OCT is a new angiographic type of OCT that shows potential in monitoring early subclinical responses to novel alopecia therapies, such as platelet-rich plasminogen, which is hypothesized to stimulate hair growth through angiogenesis. Additionally, OCT may improve outcomes of hair transplantation procedures by allowing for visualization of the subcutaneous angle of hair follicles. Blind extraction of hair follicles in follicular unit extraction procedures can result in inadvertent transection and damage to the hair follicle; OCT could help identify good candidates for follicular unit extraction, such as patients with hair follicles in parallel arrangement, who are predicted to have better results.³⁶

Conclusion

The field of trichology will continue to evolve with the emergence of noninvasive imaging technologies that diagnose hair disease in early stages and enable treatment monitoring with quantification of hair parameters. As discussed in this review, global photography, trichoscopy, RCM, and OCT have furthered our understanding of alopecia pathophysiology and provided objective methods of treatment evaluation. The capabilities of these tools will continue to expand with advancements in add-on software and AI algorithms.

New imaging tools along with adaptations to existing technologies have been emerging in recent years, with the potential to improve hair diagnostics and treatment monitoring. We provide an overview of 4 noninvasive hair imaging technologies: global photography, trichoscopy, reflectance confocal microscopy (RCM), and optical coherence tomography (OCT). For each instrument, we discuss current and future applications in clinical practice and research along with advantages and disadvantages.

Global Photography

Global photography allows for the analysis of hair growth, volume, distribution, and density through serial standardized photographs.¹ Global photography was first introduced for hair growth studies in 1987 and soon after was used for hair and scalp assessments in finasteride clinical trials.²

Hair Assessment—Washed, dried, and combed hair, without hair product, are required for accurate imaging; wet conditions increase reflection and promote hair clumping, thus revealing more scalp and depicting the patient as having less hair.¹ Headshots are taken from short distances and use stereotactic positioning devices to create 4 global views: vertex, midline, frontal, and temporal.³ Stereotactic positioning involves fixing the patient’s chin and forehead as well as mounting the camera and flash device to ensure proper magnification. These adjustments ensure lighting remains consistent throughout consecutive study visits.⁴ Various grading scales are available for use in hair growth clinical studies to increase objectivity in the analysis of serial global photographs. A blinded evaluator should assess the before and after photographs to limit experimenter bias. Global photography often is combined with quantitative software analysis for improved detection of hair changes.¹

Advancements—Growing interest in improving global photography has resulted in various application-based, artificial intelligence (AI)–mediated tools to simplify photograph collection and analysis. For instance, new hair analysis software utilizes AI algorithms to account for facial features in determining the optimal angle for capturing global photographs (Figure 1), which simplifies the generation of global photography images through smartphone applications and obviates the need for additional stereotactic positioning equipment.^5,6

Limitations—Clinicians should be aware of global photography’s requirements for consistency in lighting, camera settings, film, and image processing, which can limit the accuracy of hair assessment over time if not replicated correctly.^7,8 Emerging global photography software has helped to overcome some of these limitations.

Global photography is less precise when a patient’s hair loss is less than 50%, as it is difficult to discern subtle hair changes. Thus, global photography provides limited utility in assessing minimal to moderate hair loss.⁹ Currently, global photography largely functions as an adjunct tool for other hair analysis methods rather than as a stand-alone tool.

Trichoscopy

Trichoscopy (also known as dermoscopy of the hair and scalp) may be performed with a manual dermoscope (with 10× magnification) or a digital videodermatoscope (up to 1000× magnification).^10-12 Unlike global photography, trichoscopy provides a detailed structural analysis of hair shafts, follicular openings, and perifollicular and interfollicular areas.¹³ Kinoshita-Ise and Sachdeva¹³ provided an in-depth, updated review of trichoscopy terminology with their definitions and associated conditions (with prevalence), which should be referenced when performing trichoscopic examination.

Hair Assessment—Trichoscopic assessment begins with inspection of follicular openings (also referred to as “dots”), which vary in color depending on the material filling them—degrading keratinocytes, keratin, sebaceous debris, melanin, or fractured hairs.¹³ The structure of hair shafts also is examined, showing broken hairs, short vellus hairs, and comma hairs, among others. Perifollicular areas are examined for scale, erythema, blue-gray dots, and whitish halos. Interfollicular areas are examined for pigment pattern as well as vascularization, which often presents in a looping configuration under dermoscopy. A combination of dot colorization, hair shaft structure, and perifollicular and interfollicular findings inform diagnostic algorithms of hair and scalp conditions. For example, central centrifugal cicatricial alopecia, the most common alopecia seen in Black women, has been associated with a combination of honeycomb pigment pattern, perifollicular whitish halo, pinpoint white dots, white patches, and perifollicular erythema.¹³

Advantages—Perhaps the most useful feature of trichoscopy is its ability to translate visualized features into simple diagnostic algorithms. For instance, if the clinician has diagnosed the patient with noncicatricial alopecia, they would next focus on dot colors. With black dots, the next step would be to determine whether the hairs are tapered or coiled, and so on. This systematic approach enables the clinician to narrow possible diagnoses.² An additional advantage of trichoscopy is that it examines large surface areas noninvasively as compared to hair-pull tests and scalp biopsy.^14,15 Trichoscopy allows temporal comparisons of the same area for disease and treatment monitoring with more diagnostic detail than global photography.¹⁶ Trichoscopy also is useful in selecting biopsy locations by discerning and avoiding areas of scar tissue.¹⁷

Limitations—Diagnosis via the trichoscopy algorithm is limiting because it is not comprehensive of all hair and scalp disease.¹⁸ Additionally, many pathologies exhibit overlapping follicular and interfollicular patterning. For example, almost all subtypes of scarring alopecia present with hair loss and scarred follicles once they have progressed to advanced stages. Further studies should identify more specific patterns of hair and scalp pathologies, which could then be incorporated into a diagnostic algorithm.¹³

Advancements—The advent of hair analysis software has expanded the role of videodermoscopy by rapidly quantifying hair growth parameters such as hair count, follicular density, and follicular diameter, as well as interfollicular distances (Figure 2).^14,17 Vellus and terminal hairs are differentiated according to their thickness and length.¹⁷ Moreover, the software can analyze the same area of the scalp over time by either virtual tattoos, semipermanent markings, or precise location measurements, increasing intra- and interclass correlation. The rate of hair growth, hair shedding, and parameters of anagen and telogen hairs can be studied by a method termed phototrichogram whereby a transitional area of hair loss and normal hair growth is identified and trimmed to less than 1 mm from the skin surface.¹⁹ A baseline photograph is taken using videodermoscopy. After approximately 3 days, the identical region is photographed and compared with the initial image to observe changes in the hair. Software programs can distinguish the growing hair as anagen and nongrowing hair as telogen, calculating the anagen-to-telogen ratio as well as hair growth rate, which are essential measurements in hair research and clinical studies. Software programs have replaced laborious and time-consuming manual hair counts and have rapidly grown in popularity in evaluating patterned hair loss.

Reflectance Confocal Microscopy

Reflectance confocal microscopy is a noninvasive imaging tool that visualizes skin and its appendages at near-histologic resolution (lateral resolution of 0.5–1 μm). It produces grayscale horizontal images that can be taken at levels ranging from the stratum corneum to the superficial papillary dermis, corresponding to a depth of approximately 100 to 150 µm. Thus, a hair follicle can be imaged starting from the follicular ostia down to the reachable papillary dermis (Figure 3).²⁰ Image contrast is provided by differences in the size and refractive indices of cellular organelles.^21,22 There are 2 commercially available RCM devices: VivaScope 1500 and VivaScope 3000 (Caliber Imaging & Diagnostics, Inc).

VivaScope 1500, a wide-probe microscope, requires the attachment of a plastic window to the desired imaging area. The plastic window is lined with medical adhesive tape to prevent movement during imaging. The adhesive tape can pull on hair upon removal, which is not ideal for patients with existing hair loss. Additionally, the image quality of VivaSope 1500 is best in flat areas and areas where hair is shaved.^20,23,24 Despite these disadvantages, VivaScope 1500 has successfully shown utility in research studies, which suggests that these obstacles can be overcome by experienced users. The handheld VivaScope 3000 is ergonomically designed and suitable for curved surfaces such as the scalp, with the advantage of not requiring any adhesive. However, the images acquired from the VivaScope 3000 cover a smaller surface area.

Structures Visualized—Structures distinguished with RCM include keratinocytes, melanocytes, inflammatory cells, hair follicles, hair shafts, adnexal infundibular epithelium, blood vessels, fibroblasts, and collagen.²³ Real-time visualization of blood flow also can be seen.

Applications of RCM—Reflectance confocal microscopy has been used to study scalp discoid lupus, lichen planopilaris, frontal fibrosing alopecia, folliculitis decalvans, chemotherapy-induced alopecia (CIA), alopecia areata, and androgenetic alopecia. Diagnostic RCM criteria for such alopecias have been developed based on their correspondence to histopathology. An RCM study of classic lichen planopilaris and frontal fibrosing alopecia identified features of epidermal disarray, infundibular hyperkeratosis, inflammatory cells, pigment incontinence, perifollicular fibrosis, bandlike scarring, melanophages in the dermis, dilated blood vessels, basal layer vacuolar degeneration, and necrotic keratinocytes.²⁵ Pigment incontinence in the superficial epidermis, perifollicular lichenoid inflammation, and hyperkeratosis were characteristic RCM features of early-stage lichen planopilaris, while perifollicular fibrosis and dilated blood vessels were characteristic RCM features of late-stage disease. The ability of RCM features to distinguish different stages of lichen planopilaris shows its potential in treating early disease and preventing irreversible hair loss.

Differentiating between scarring and nonscarring alopecia also is possible through RCM. The presence of periadnexal, epidermal, and dermal inflammatory cells, in addition to periadnexal sclerosis, are defining RCM features of scarring alopecia.²⁶ These features are absent in nonscarring alopecias. Reflectance confocal microscopy additionally has been shown to be useful in the treatment monitoring of lichen planopilaris and discoid lupus erythematosus.²⁰ Independent reviewers, blinded to the patients’ identities, were able to characterize and follow features of these scarring alopecias by RCM. The assessed RCM features were comparable to those observed by histopathologic evaluation: epidermal disarray, spongiosis, exocytosis of inflammatory cells in the epidermis, interface dermatitis, peri- and intra-adnexal infiltration of inflammatory cells, dilated vessels in the dermis, dermal infiltration of inflammatory cells and melanophages, and dermal sclerosis. A reduction in inflammatory cells across multiple skin layers and at the level of the adnexal epithelium correlated with clinical response to treatment. Reflectance confocal microscopy also was able to detect recurrence of inflammation in cases where treatment had been interrupted before clinical signs of disease recurrence were evident. The authors thus concluded that RCM’s sensitivity can guide timing of treatment and avoid delays in starting or restarting treatment.²⁰

Reflectance confocal microscopy also has served as a learning tool for new subclinical understandings of alopecia. In a study of CIA, the disease was found to be a dynamic process that could be categorized into 4 distinct phases distinguishable by combined confocal and dermoscopic features. This study also identified a new feature observable on RCM images—a CIA dot—defined as a dilated follicular infundibulum containing mashed, malted, nonhomogeneous material and normal or fragmented hair. This dot is thought to represent the initial microscopic sign of direct toxicity of chemotherapy on the hair follicle. Chemotherapy-induced alopecia dots persist throughout chemotherapy and subsequently disappear after chemotherapy ends.²⁷

Limitations and Advantages—Currently, subtypes of cicatricial alopecias cannot be characterized on RCM because inflammatory cell types are not distinguished from each other (eg, eosinophils vs neutrophils). Another limitation of RCM is the loss of resolution below the superficial papillary dermis (a depth of approximately 150 µm); thus, deeper structures, such as the hair bulb, cannot be visualized.

Unlike global photography and trichoscopy, which are low-cost methods, RCM is much more costly, ranging upwards of several thousand dollars, and it may require additional technical support fees, making it less accessible for clinical practice. However, RCM imaging continues to be recommended as an intermediate step between trichoscopy and histology for the diagnosis and management of hair disease.²⁶ If a biopsy is required, RCM can aid in the selection of a biopsy site, as areas with active inflammation are more informative than atrophic and fibrosed areas.²³ The role of RCM in trichoscopy can be expanded by designing a more cost-effective and ergonomically suited scope for hair and scalp assessment.

Optical Coherence Tomography

Optical coherence tomography is a noninvasive handheld device that emits low-power infrared light to visualize the skin and adnexal structures. Optical coherence tomography relies on the principle of interferometry to detect phase differences in optical backscattering at varying tissue depths.^28,29 It allows visualization up to 2 mm, which is 2 to 5 times deeper than RCM.³⁶ Unlike RCM, which has cellular resolution, OCT has an axial resolution of 3 to 15 μm, which allows only for the detection of structural boundaries.³⁰ There are various OCT modalities that differ in lateral and axial resolutions and maximum depth. Commercial software is available that measures changes in vascular density by depth, epidermal thickness, skin surface texture, and optical attenuation—the latter being an indirect measurement of collagen density and skin hydration.

Structures Visualized—Hair follicles can be well distinguished on OCT images, and as such, OCT is recognized as a diagnostic tool in trichology (Figure 4).³¹ Follicular openings, interfollicular collagen, and outlines of the hair shafts are visible; however, detailed components of the follicular unit cannot be visualized by OCT. Keratin hyperrefractivity identifies the hair shaft. Additionally, the hair matrix is denoted by a slightly granular texture in the dermis. Dynamic OCT produces colorized images that visualize blood flow within vessels.

Applications of OCT—Optical coherence tomography is utilized in investigative trichology because it provides highly reproducible measurements of hair shaft diameters, cross-sectional surface areas, and form factor, which is a surrogate parameter for hair shape. The cross-section of hair shafts provides insight into local metabolism and perifollicular inflammation. Cross-sections of hair shafts in areas of alopecia areata were found to be smaller than cross-sections in the unaffected scalp within the same individual.³² Follicular density can be manually quantified on OCT images, but there also is promise for automated quantification. A recent study by Urban et al³³ described training a convolutional neural network to automatically count hair as well as hair-bearing and non–hair-bearing follicles in OCT scans. These investigators also were able to color-code hair according to height, resulting in the creation of a “height” map.

Optical coherence tomography has furthered our understanding of the pathophysiology of cicatricial and nonscarring alopecias. Vazquez-Herrera et al³⁴ assessed the inflammatory and cicatricial stages of frontal fibrosing alopecia by OCT imaging. Inflammatory hairlines, which are seen in the early stages of frontal fibrosing alopecia, exhibited a thickened dermis, irregular distribution of collagen, and increased vascularity in both the superficial and deep dermal layers compared to cicatricial and healthy scalp. Conversely, late-stage cicatricial areas exhibited a thin dermis and collagen that appeared in a hyperreflective, concentric, onion-shaped pattern around remnant follicular openings. Vascular flow was reduced in the superficial dermis of a cicatricial scalp but increased in the deep dermal layers compared with a healthy scalp. The attenuation coefficients of these disease stages also were assessed. The attenuation coefficient of the inflammatory hairline was higher compared with normal skin, likely as a reflection of inflammatory infiltrate and edema, whereas the attenuation coefficient of cicatricial scalp was lower compared with normal skin, likely reflecting the reduced water content of atrophic skin.³⁴ This differentiation of early- and late-stage cicatricial alopecias has implications for early treatment and improved prognosis. Additionally, there is potential for OCT to assist in the differentiation of alopecia subtypes, as it can measure the epidermal thickness and follicular density and was previously used to compare scarring and nonscarring alopecia.³⁵

Advantages and Limitations—Similar to RCM, OCT may be cost prohibitive for some clinicians. In addition, OCT cannot visualize the follicular unit in cellular detail. However, the extent of OCT’s capabilities may not be fully realized. Dynamic OCT is a new angiographic type of OCT that shows potential in monitoring early subclinical responses to novel alopecia therapies, such as platelet-rich plasminogen, which is hypothesized to stimulate hair growth through angiogenesis. Additionally, OCT may improve outcomes of hair transplantation procedures by allowing for visualization of the subcutaneous angle of hair follicles. Blind extraction of hair follicles in follicular unit extraction procedures can result in inadvertent transection and damage to the hair follicle; OCT could help identify good candidates for follicular unit extraction, such as patients with hair follicles in parallel arrangement, who are predicted to have better results.³⁶

Conclusion

The field of trichology will continue to evolve with the emergence of noninvasive imaging technologies that diagnose hair disease in early stages and enable treatment monitoring with quantification of hair parameters. As discussed in this review, global photography, trichoscopy, RCM, and OCT have furthered our understanding of alopecia pathophysiology and provided objective methods of treatment evaluation. The capabilities of these tools will continue to expand with advancements in add-on software and AI algorithms.

New imaging tools along with adaptations to existing technologies have been emerging in recent years, with the potential to improve hair diagnostics and treatment monitoring. We provide an overview of 4 noninvasive hair imaging technologies: global photography, trichoscopy, reflectance confocal microscopy (RCM), and optical coherence tomography (OCT). For each instrument, we discuss current and future applications in clinical practice and research along with advantages and disadvantages.

Global Photography

Global photography allows for the analysis of hair growth, volume, distribution, and density through serial standardized photographs.¹ Global photography was first introduced for hair growth studies in 1987 and soon after was used for hair and scalp assessments in finasteride clinical trials.²

Hair Assessment—Washed, dried, and combed hair, without hair product, are required for accurate imaging; wet conditions increase reflection and promote hair clumping, thus revealing more scalp and depicting the patient as having less hair.¹ Headshots are taken from short distances and use stereotactic positioning devices to create 4 global views: vertex, midline, frontal, and temporal.³ Stereotactic positioning involves fixing the patient’s chin and forehead as well as mounting the camera and flash device to ensure proper magnification. These adjustments ensure lighting remains consistent throughout consecutive study visits.⁴ Various grading scales are available for use in hair growth clinical studies to increase objectivity in the analysis of serial global photographs. A blinded evaluator should assess the before and after photographs to limit experimenter bias. Global photography often is combined with quantitative software analysis for improved detection of hair changes.¹

Advancements—Growing interest in improving global photography has resulted in various application-based, artificial intelligence (AI)–mediated tools to simplify photograph collection and analysis. For instance, new hair analysis software utilizes AI algorithms to account for facial features in determining the optimal angle for capturing global photographs (Figure 1), which simplifies the generation of global photography images through smartphone applications and obviates the need for additional stereotactic positioning equipment.^5,6

Limitations—Clinicians should be aware of global photography’s requirements for consistency in lighting, camera settings, film, and image processing, which can limit the accuracy of hair assessment over time if not replicated correctly.^7,8 Emerging global photography software has helped to overcome some of these limitations.

Global photography is less precise when a patient’s hair loss is less than 50%, as it is difficult to discern subtle hair changes. Thus, global photography provides limited utility in assessing minimal to moderate hair loss.⁹ Currently, global photography largely functions as an adjunct tool for other hair analysis methods rather than as a stand-alone tool.

Trichoscopy

Trichoscopy (also known as dermoscopy of the hair and scalp) may be performed with a manual dermoscope (with 10× magnification) or a digital videodermatoscope (up to 1000× magnification).^10-12 Unlike global photography, trichoscopy provides a detailed structural analysis of hair shafts, follicular openings, and perifollicular and interfollicular areas.¹³ Kinoshita-Ise and Sachdeva¹³ provided an in-depth, updated review of trichoscopy terminology with their definitions and associated conditions (with prevalence), which should be referenced when performing trichoscopic examination.

Hair Assessment—Trichoscopic assessment begins with inspection of follicular openings (also referred to as “dots”), which vary in color depending on the material filling them—degrading keratinocytes, keratin, sebaceous debris, melanin, or fractured hairs.¹³ The structure of hair shafts also is examined, showing broken hairs, short vellus hairs, and comma hairs, among others. Perifollicular areas are examined for scale, erythema, blue-gray dots, and whitish halos. Interfollicular areas are examined for pigment pattern as well as vascularization, which often presents in a looping configuration under dermoscopy. A combination of dot colorization, hair shaft structure, and perifollicular and interfollicular findings inform diagnostic algorithms of hair and scalp conditions. For example, central centrifugal cicatricial alopecia, the most common alopecia seen in Black women, has been associated with a combination of honeycomb pigment pattern, perifollicular whitish halo, pinpoint white dots, white patches, and perifollicular erythema.¹³

Advantages—Perhaps the most useful feature of trichoscopy is its ability to translate visualized features into simple diagnostic algorithms. For instance, if the clinician has diagnosed the patient with noncicatricial alopecia, they would next focus on dot colors. With black dots, the next step would be to determine whether the hairs are tapered or coiled, and so on. This systematic approach enables the clinician to narrow possible diagnoses.² An additional advantage of trichoscopy is that it examines large surface areas noninvasively as compared to hair-pull tests and scalp biopsy.^14,15 Trichoscopy allows temporal comparisons of the same area for disease and treatment monitoring with more diagnostic detail than global photography.¹⁶ Trichoscopy also is useful in selecting biopsy locations by discerning and avoiding areas of scar tissue.¹⁷

Limitations—Diagnosis via the trichoscopy algorithm is limiting because it is not comprehensive of all hair and scalp disease.¹⁸ Additionally, many pathologies exhibit overlapping follicular and interfollicular patterning. For example, almost all subtypes of scarring alopecia present with hair loss and scarred follicles once they have progressed to advanced stages. Further studies should identify more specific patterns of hair and scalp pathologies, which could then be incorporated into a diagnostic algorithm.¹³

Advancements—The advent of hair analysis software has expanded the role of videodermoscopy by rapidly quantifying hair growth parameters such as hair count, follicular density, and follicular diameter, as well as interfollicular distances (Figure 2).^14,17 Vellus and terminal hairs are differentiated according to their thickness and length.¹⁷ Moreover, the software can analyze the same area of the scalp over time by either virtual tattoos, semipermanent markings, or precise location measurements, increasing intra- and interclass correlation. The rate of hair growth, hair shedding, and parameters of anagen and telogen hairs can be studied by a method termed phototrichogram whereby a transitional area of hair loss and normal hair growth is identified and trimmed to less than 1 mm from the skin surface.¹⁹ A baseline photograph is taken using videodermoscopy. After approximately 3 days, the identical region is photographed and compared with the initial image to observe changes in the hair. Software programs can distinguish the growing hair as anagen and nongrowing hair as telogen, calculating the anagen-to-telogen ratio as well as hair growth rate, which are essential measurements in hair research and clinical studies. Software programs have replaced laborious and time-consuming manual hair counts and have rapidly grown in popularity in evaluating patterned hair loss.

Reflectance Confocal Microscopy

Reflectance confocal microscopy is a noninvasive imaging tool that visualizes skin and its appendages at near-histologic resolution (lateral resolution of 0.5–1 μm). It produces grayscale horizontal images that can be taken at levels ranging from the stratum corneum to the superficial papillary dermis, corresponding to a depth of approximately 100 to 150 µm. Thus, a hair follicle can be imaged starting from the follicular ostia down to the reachable papillary dermis (Figure 3).²⁰ Image contrast is provided by differences in the size and refractive indices of cellular organelles.^21,22 There are 2 commercially available RCM devices: VivaScope 1500 and VivaScope 3000 (Caliber Imaging & Diagnostics, Inc).

VivaScope 1500, a wide-probe microscope, requires the attachment of a plastic window to the desired imaging area. The plastic window is lined with medical adhesive tape to prevent movement during imaging. The adhesive tape can pull on hair upon removal, which is not ideal for patients with existing hair loss. Additionally, the image quality of VivaSope 1500 is best in flat areas and areas where hair is shaved.^20,23,24 Despite these disadvantages, VivaScope 1500 has successfully shown utility in research studies, which suggests that these obstacles can be overcome by experienced users. The handheld VivaScope 3000 is ergonomically designed and suitable for curved surfaces such as the scalp, with the advantage of not requiring any adhesive. However, the images acquired from the VivaScope 3000 cover a smaller surface area.

Structures Visualized—Structures distinguished with RCM include keratinocytes, melanocytes, inflammatory cells, hair follicles, hair shafts, adnexal infundibular epithelium, blood vessels, fibroblasts, and collagen.²³ Real-time visualization of blood flow also can be seen.

Applications of RCM—Reflectance confocal microscopy has been used to study scalp discoid lupus, lichen planopilaris, frontal fibrosing alopecia, folliculitis decalvans, chemotherapy-induced alopecia (CIA), alopecia areata, and androgenetic alopecia. Diagnostic RCM criteria for such alopecias have been developed based on their correspondence to histopathology. An RCM study of classic lichen planopilaris and frontal fibrosing alopecia identified features of epidermal disarray, infundibular hyperkeratosis, inflammatory cells, pigment incontinence, perifollicular fibrosis, bandlike scarring, melanophages in the dermis, dilated blood vessels, basal layer vacuolar degeneration, and necrotic keratinocytes.²⁵ Pigment incontinence in the superficial epidermis, perifollicular lichenoid inflammation, and hyperkeratosis were characteristic RCM features of early-stage lichen planopilaris, while perifollicular fibrosis and dilated blood vessels were characteristic RCM features of late-stage disease. The ability of RCM features to distinguish different stages of lichen planopilaris shows its potential in treating early disease and preventing irreversible hair loss.

Differentiating between scarring and nonscarring alopecia also is possible through RCM. The presence of periadnexal, epidermal, and dermal inflammatory cells, in addition to periadnexal sclerosis, are defining RCM features of scarring alopecia.²⁶ These features are absent in nonscarring alopecias. Reflectance confocal microscopy additionally has been shown to be useful in the treatment monitoring of lichen planopilaris and discoid lupus erythematosus.²⁰ Independent reviewers, blinded to the patients’ identities, were able to characterize and follow features of these scarring alopecias by RCM. The assessed RCM features were comparable to those observed by histopathologic evaluation: epidermal disarray, spongiosis, exocytosis of inflammatory cells in the epidermis, interface dermatitis, peri- and intra-adnexal infiltration of inflammatory cells, dilated vessels in the dermis, dermal infiltration of inflammatory cells and melanophages, and dermal sclerosis. A reduction in inflammatory cells across multiple skin layers and at the level of the adnexal epithelium correlated with clinical response to treatment. Reflectance confocal microscopy also was able to detect recurrence of inflammation in cases where treatment had been interrupted before clinical signs of disease recurrence were evident. The authors thus concluded that RCM’s sensitivity can guide timing of treatment and avoid delays in starting or restarting treatment.²⁰

Reflectance confocal microscopy also has served as a learning tool for new subclinical understandings of alopecia. In a study of CIA, the disease was found to be a dynamic process that could be categorized into 4 distinct phases distinguishable by combined confocal and dermoscopic features. This study also identified a new feature observable on RCM images—a CIA dot—defined as a dilated follicular infundibulum containing mashed, malted, nonhomogeneous material and normal or fragmented hair. This dot is thought to represent the initial microscopic sign of direct toxicity of chemotherapy on the hair follicle. Chemotherapy-induced alopecia dots persist throughout chemotherapy and subsequently disappear after chemotherapy ends.²⁷

Limitations and Advantages—Currently, subtypes of cicatricial alopecias cannot be characterized on RCM because inflammatory cell types are not distinguished from each other (eg, eosinophils vs neutrophils). Another limitation of RCM is the loss of resolution below the superficial papillary dermis (a depth of approximately 150 µm); thus, deeper structures, such as the hair bulb, cannot be visualized.

Unlike global photography and trichoscopy, which are low-cost methods, RCM is much more costly, ranging upwards of several thousand dollars, and it may require additional technical support fees, making it less accessible for clinical practice. However, RCM imaging continues to be recommended as an intermediate step between trichoscopy and histology for the diagnosis and management of hair disease.²⁶ If a biopsy is required, RCM can aid in the selection of a biopsy site, as areas with active inflammation are more informative than atrophic and fibrosed areas.²³ The role of RCM in trichoscopy can be expanded by designing a more cost-effective and ergonomically suited scope for hair and scalp assessment.

Optical Coherence Tomography

Optical coherence tomography is a noninvasive handheld device that emits low-power infrared light to visualize the skin and adnexal structures. Optical coherence tomography relies on the principle of interferometry to detect phase differences in optical backscattering at varying tissue depths.^28,29 It allows visualization up to 2 mm, which is 2 to 5 times deeper than RCM.³⁶ Unlike RCM, which has cellular resolution, OCT has an axial resolution of 3 to 15 μm, which allows only for the detection of structural boundaries.³⁰ There are various OCT modalities that differ in lateral and axial resolutions and maximum depth. Commercial software is available that measures changes in vascular density by depth, epidermal thickness, skin surface texture, and optical attenuation—the latter being an indirect measurement of collagen density and skin hydration.

Structures Visualized—Hair follicles can be well distinguished on OCT images, and as such, OCT is recognized as a diagnostic tool in trichology (Figure 4).³¹ Follicular openings, interfollicular collagen, and outlines of the hair shafts are visible; however, detailed components of the follicular unit cannot be visualized by OCT. Keratin hyperrefractivity identifies the hair shaft. Additionally, the hair matrix is denoted by a slightly granular texture in the dermis. Dynamic OCT produces colorized images that visualize blood flow within vessels.

Applications of OCT—Optical coherence tomography is utilized in investigative trichology because it provides highly reproducible measurements of hair shaft diameters, cross-sectional surface areas, and form factor, which is a surrogate parameter for hair shape. The cross-section of hair shafts provides insight into local metabolism and perifollicular inflammation. Cross-sections of hair shafts in areas of alopecia areata were found to be smaller than cross-sections in the unaffected scalp within the same individual.³² Follicular density can be manually quantified on OCT images, but there also is promise for automated quantification. A recent study by Urban et al³³ described training a convolutional neural network to automatically count hair as well as hair-bearing and non–hair-bearing follicles in OCT scans. These investigators also were able to color-code hair according to height, resulting in the creation of a “height” map.

Optical coherence tomography has furthered our understanding of the pathophysiology of cicatricial and nonscarring alopecias. Vazquez-Herrera et al³⁴ assessed the inflammatory and cicatricial stages of frontal fibrosing alopecia by OCT imaging. Inflammatory hairlines, which are seen in the early stages of frontal fibrosing alopecia, exhibited a thickened dermis, irregular distribution of collagen, and increased vascularity in both the superficial and deep dermal layers compared to cicatricial and healthy scalp. Conversely, late-stage cicatricial areas exhibited a thin dermis and collagen that appeared in a hyperreflective, concentric, onion-shaped pattern around remnant follicular openings. Vascular flow was reduced in the superficial dermis of a cicatricial scalp but increased in the deep dermal layers compared with a healthy scalp. The attenuation coefficients of these disease stages also were assessed. The attenuation coefficient of the inflammatory hairline was higher compared with normal skin, likely as a reflection of inflammatory infiltrate and edema, whereas the attenuation coefficient of cicatricial scalp was lower compared with normal skin, likely reflecting the reduced water content of atrophic skin.³⁴ This differentiation of early- and late-stage cicatricial alopecias has implications for early treatment and improved prognosis. Additionally, there is potential for OCT to assist in the differentiation of alopecia subtypes, as it can measure the epidermal thickness and follicular density and was previously used to compare scarring and nonscarring alopecia.³⁵

Advantages and Limitations—Similar to RCM, OCT may be cost prohibitive for some clinicians. In addition, OCT cannot visualize the follicular unit in cellular detail. However, the extent of OCT’s capabilities may not be fully realized. Dynamic OCT is a new angiographic type of OCT that shows potential in monitoring early subclinical responses to novel alopecia therapies, such as platelet-rich plasminogen, which is hypothesized to stimulate hair growth through angiogenesis. Additionally, OCT may improve outcomes of hair transplantation procedures by allowing for visualization of the subcutaneous angle of hair follicles. Blind extraction of hair follicles in follicular unit extraction procedures can result in inadvertent transection and damage to the hair follicle; OCT could help identify good candidates for follicular unit extraction, such as patients with hair follicles in parallel arrangement, who are predicted to have better results.³⁶

Conclusion

The field of trichology will continue to evolve with the emergence of noninvasive imaging technologies that diagnose hair disease in early stages and enable treatment monitoring with quantification of hair parameters. As discussed in this review, global photography, trichoscopy, RCM, and OCT have furthered our understanding of alopecia pathophysiology and provided objective methods of treatment evaluation. The capabilities of these tools will continue to expand with advancements in add-on software and AI algorithms.

Practice Gap

Wound dressings protect the skin and prevent contamination. The hair often makes it difficult to affix a dressing after a minor scalp trauma or local surgery on the head. Traditional approaches for fastening a dressing on the head include bandage winding or adhesive tape, but these methods often affect aesthetics or cause discomfort—bandage winding can make it inconvenient for the patient to move their head, and adhesive tape can cause pain by pulling the hair during removal.

To better position a scalp dressing, tie-over dressings, braid dressings, and paper clips have been used as fixators.^1-3 These methods have benefits and disadvantages.

Tie-over Dressing—The dressing is clasped with long sutures that were reserved during wound closure. This method is sturdy, can slightly compress the wound, and is applicable to any part of the scalp. However, it requires more sutures, and more careful wound care may be required due to the edge of the dressing being close to the wound.

Braid Dressing—Tape, a rubber band, or braided hair is used to bind the gauze pad. This dressing is simple and inexpensive. However, it is limited to patients with long hair; even then, it often is difficult to anchor the dressing by braiding hair. Moreover, removal of the rubber band and tape can cause discomfort or pain.

Paper Clip—This is a simple scalp dressing fixator. However, due to the short and circular structure of the clip, it is not conducive to affixing a gauze dressing for patients with short hair, and it often hooks the gauze and hair, making it inconvenient for the physician and a source of discomfort for the patient when the paper clip is being removed.

The Technique

To address shortcomings of traditional methods, we encourage the use of hairpins to affix a dressing after a scalp wound is sutured. Two steps are required:

• Position the gauze to cover the wound and press the gauze down with your hand.
• Clamp the 4 corners of the dressing and adjacent hair with hairpins (Figure, A).

Practical Implications

Hairpins are common for fixing hairstyles and decorating hair. They are inexpensive, easy to obtain, simple in structure, convenient to use without additional discomfort, and easy to remove (Figure, B). Because most hairpins have a powerful clamping force, they can affix dressings in short hair (Figure, A). All medical staff can use hairpins to anchor the scalp dressing. Even a patient’s family members can carry out simple dressing replacement and wound cleaning using this method. Patients also have many options for hairpin styles, which is especially useful in easing the apprehension of surgery in pediatric patients.

Practice Gap

Wound dressings protect the skin and prevent contamination. The hair often makes it difficult to affix a dressing after a minor scalp trauma or local surgery on the head. Traditional approaches for fastening a dressing on the head include bandage winding or adhesive tape, but these methods often affect aesthetics or cause discomfort—bandage winding can make it inconvenient for the patient to move their head, and adhesive tape can cause pain by pulling the hair during removal.

To better position a scalp dressing, tie-over dressings, braid dressings, and paper clips have been used as fixators.^1-3 These methods have benefits and disadvantages.

Tie-over Dressing—The dressing is clasped with long sutures that were reserved during wound closure. This method is sturdy, can slightly compress the wound, and is applicable to any part of the scalp. However, it requires more sutures, and more careful wound care may be required due to the edge of the dressing being close to the wound.

Braid Dressing—Tape, a rubber band, or braided hair is used to bind the gauze pad. This dressing is simple and inexpensive. However, it is limited to patients with long hair; even then, it often is difficult to anchor the dressing by braiding hair. Moreover, removal of the rubber band and tape can cause discomfort or pain.

Paper Clip—This is a simple scalp dressing fixator. However, due to the short and circular structure of the clip, it is not conducive to affixing a gauze dressing for patients with short hair, and it often hooks the gauze and hair, making it inconvenient for the physician and a source of discomfort for the patient when the paper clip is being removed.

The Technique

To address shortcomings of traditional methods, we encourage the use of hairpins to affix a dressing after a scalp wound is sutured. Two steps are required:

• Position the gauze to cover the wound and press the gauze down with your hand.
• Clamp the 4 corners of the dressing and adjacent hair with hairpins (Figure, A).

Practical Implications

Hairpins are common for fixing hairstyles and decorating hair. They are inexpensive, easy to obtain, simple in structure, convenient to use without additional discomfort, and easy to remove (Figure, B). Because most hairpins have a powerful clamping force, they can affix dressings in short hair (Figure, A). All medical staff can use hairpins to anchor the scalp dressing. Even a patient’s family members can carry out simple dressing replacement and wound cleaning using this method. Patients also have many options for hairpin styles, which is especially useful in easing the apprehension of surgery in pediatric patients.

Practice Gap

Wound dressings protect the skin and prevent contamination. The hair often makes it difficult to affix a dressing after a minor scalp trauma or local surgery on the head. Traditional approaches for fastening a dressing on the head include bandage winding or adhesive tape, but these methods often affect aesthetics or cause discomfort—bandage winding can make it inconvenient for the patient to move their head, and adhesive tape can cause pain by pulling the hair during removal.

To better position a scalp dressing, tie-over dressings, braid dressings, and paper clips have been used as fixators.^1-3 These methods have benefits and disadvantages.

Tie-over Dressing—The dressing is clasped with long sutures that were reserved during wound closure. This method is sturdy, can slightly compress the wound, and is applicable to any part of the scalp. However, it requires more sutures, and more careful wound care may be required due to the edge of the dressing being close to the wound.

Braid Dressing—Tape, a rubber band, or braided hair is used to bind the gauze pad. This dressing is simple and inexpensive. However, it is limited to patients with long hair; even then, it often is difficult to anchor the dressing by braiding hair. Moreover, removal of the rubber band and tape can cause discomfort or pain.

Paper Clip—This is a simple scalp dressing fixator. However, due to the short and circular structure of the clip, it is not conducive to affixing a gauze dressing for patients with short hair, and it often hooks the gauze and hair, making it inconvenient for the physician and a source of discomfort for the patient when the paper clip is being removed.

The Technique

To address shortcomings of traditional methods, we encourage the use of hairpins to affix a dressing after a scalp wound is sutured. Two steps are required:

• Position the gauze to cover the wound and press the gauze down with your hand.
• Clamp the 4 corners of the dressing and adjacent hair with hairpins (Figure, A).

Practical Implications

Hairpins are common for fixing hairstyles and decorating hair. They are inexpensive, easy to obtain, simple in structure, convenient to use without additional discomfort, and easy to remove (Figure, B). Because most hairpins have a powerful clamping force, they can affix dressings in short hair (Figure, A). All medical staff can use hairpins to anchor the scalp dressing. Even a patient’s family members can carry out simple dressing replacement and wound cleaning using this method. Patients also have many options for hairpin styles, which is especially useful in easing the apprehension of surgery in pediatric patients.

Dermatomyositis (DM) is an uncommon idiopathic inflammatory myopathy (IIM) characterized by muscle inflammation; proximal muscle weakness; and dermatologic findings, such as the heliotrope eruption and Gottron papules.^1-3 Dermatomyositis is associated with an increased malignancy risk compared to other IIMs, with a 13% to 42% lifetime risk for malignancy development.^4,5 The incidence for malignancy peaks during the first year following diagnosis and falls gradually over 5 years but remains increased compared to the general population.^6-11 Adenocarcinoma represents the majority of cancers associated with DM, particularly of the ovaries, lungs, breasts, gastrointestinal tract, pancreas, bladder, and prostate. The lymphatic system (non-Hodgkin lymphoma) also is overrepresented among cancers in DM.¹²

Because of the increased malignancy risk and cancer-related mortality in patients with DM, cancer screening generally is recommended following diagnosis.^13,14 However, consensus guidelines for screening modalities and frequency currently do not exist, resulting in widely varying practice patterns.¹⁵ Some experts advocate for a conventional cancer screening panel (CSP), as summarized in Table 1.^15-18 These tests may be repeated annually for 3 to 5 years following the diagnosis of DM. Although the use of myositis-specific antibodies (MSAs) recently has helped to risk-stratify DM patients, up to half of patients are MSA negative,¹⁹ and broad malignancy screening remains essential. Individualized discussions with patients about their risk factors, screening options, and risks and benefits of screening also are strongly encouraged.^19-22 Studies of the direct costs and effectiveness of streamlined screening with positron emission tomography/computed tomography (PET/CT) compared with a CSP have shown similar efficacy and lower out-of-pocket costs for patients receiving PET/CT imaging.^16-18

The goal of our study was to further characterize patients’ perspectives and experience of cancer screening in DM as well as indirect costs, both of which must be taken into consideration when developing consensus guidelines for DM malignancy screening. Inclusion of patient voice is essential given the similar efficacy of both screening methods. We assessed the indirect costs (eg, travel, lost work or wages, childcare) of a CSP in patients with DM. We theorized that the large quantity of tests involved in a CSP, which are performed at various locations on multiple days over the course of several years, may have substantial costs to patients beyond the co-pay and deductible. We also sought to measure patients’ perception of the burden associated with an annual CSP, which we defined to participants as the inconvenience or unpleasantness experienced by the patient, compared with an annual whole-body PET/CT. Finally, we examined the relative value of these screening methods to patients using a willingness-to-pay (WTP) analysis.

Materials and Methods

Patient Eligibility—Our study included Penn State Health (Hershey, Pennsylvania) patients 18 years or older with a recent diagnosis of DM—International Classification of Diseases, Ninth Revision code 710.3 or International Classification of Diseases, Tenth Revision codes M33.10 or M33.90—who were undergoing or had recently completed a CSP. Patients were excluded from the study if they had a concurrent or preceding diagnosis of malignancy (excluding nonmelanoma skin cancers) or had another IIM. The institutional review board at Penn State Health College of Medicine approved the study. Data for all patients were prospectively obtained.

Survey Design—A survey was generated to assess the burden and indirect costs associated with a CSP, which was modified from work done by Tchuenche et al²³ and Teni et al.²⁴ Focus groups were held in 2018 and 2019 with patients who met our inclusion criteria with the purpose of refining the survey instrument based on patient input. A summary explanation of research was provided to all participants, and informed consent was obtained. Patients were compensated for their time for focus groups. Audio of each focus group was then transcribed and analyzed for common themes. Following focus group feedback, a finalized survey was generated for assessing burden and indirect costs (survey instrument provided in the Supplementary Information). REDCap (Vanderbilt University), a secure web application, was used to construct the finalized survey and to collect and manage data.²⁵

Patients who fit our inclusion criteria were identified and recruited in multiple ways. Patients with appointments at the Penn State Milton S. Hershey Medical Center Department of Dermatology were presented with the opportunity to participate, Penn State Health records with the appropriate billing codes were collected and patients were contacted, and an advertisement for the study was posted on StudyFinder. Surveys constructed on REDCap were then sent electronically to patients who agreed to participate in the study. A second summary explanation of research was included on the first page of the survey to describe the process.

The survey had 3 main sections. The first section collected demographic information. In the second section, we surveyed patients regarding the various aspects of a CSP that focus groups identified as burdensome. In addition, patients were asked to compare their feelings regarding an annual CSP vs whole-body PET/CT for a 3-year period utilizing a rating scale of strongly disagree, somewhat disagree, somewhat agree, and strongly agree. This section also included a willingness-to-pay (WTP) analysis for each modality. We defined WTP as the maximum out-of-pocket cost that the patient would be willing to pay to receive testing, which was measured in a hypothetical scenario where neither whole-body PET/CT nor CSP was covered by insurance.²⁶ Although WTP may be influenced by external factors such as patient income, it can serve as a numerical measure of how much the patient values each service. Furthermore, these external factors become less relevant when comparing the relative value of 2 separate tests, as such factors apply equally in both scenarios. In the third section of the survey, patients were queried regarding various indirect costs associated with a CSP. Descriptions for a CSP and whole-body PET/CT, including risks and benefits, were provided to allow patients to make informed decisions.

Statistical Analysis—Because of the rarity of DM and the subsequently limited sample size, summary and descriptive statistics were utilized to characterize the sample and identify patterns in the results. Continuous variables are presented with means and standard deviations, and proportions are presented with frequencies and percentages. All analyses were done using SAS Version 9.4 (SAS Institute Inc).

Results

Patient Demographics—Fifty-four patients were identified using StudyFinder, physician referral, and search of the electronic health record. Nine patients agreed to take part in the focus groups, and 27 offered email addresses to be contacted for the survey. Of those 27 patients, 16 (59.3%) fit our inclusion criteria and completed the survey. Patient demographics are detailed in Table 2. The mean age was 55 years, and most patients were White (88% [14/16]), female (81% [13/16]), and had at least a bachelor’s degree (69% [11/16]). Most patients (69% [11/16]) had an annual income of less than $50,000, and half (50% [8/16]) were employed. All patients had been diagnosed with DM in or after 2013. Two patients were diagnosed with basal cell carcinoma during or after cancer screening.

Patient Preference for Screening and WTP—A majority (81% [13/16]) of patients desired some form of screening for occult malignancy following the diagnosis of DM, even in the hypothetical situation in which screening did not provide survival benefit (Figure 1). Twenty-five percent (4/16) of patients expressed that a CSP was burdensome, and 12.5% of patients (2/16) missed a CSP appointment; all of these patients rescheduled or were planning to reschedule. Assuming that both screening methods had similar predictive value in detecting malignancy, all 16 patients felt annual whole-body PET/CT for a 3-year period would be less burdensome than a CSP, and most (73% [11/15]) felt that it would decrease the likelihood of missed appointments. Overall, 93% (13/14) of patients preferred whole-body PET/CT over a CSP when given the choice between the 2 options (Figure 2). This preference was consistent with the patients’ WTP for these tests; patients reliably reported that they would pay more for annual whole-body PET/CT than for a CSP (Figure 3). Specifically, 75% (12/16) and 38% (6/16) of patients were willing to spend $250 or more and $1000 or more for annual whole-body PET/CT, respectively, compared with 56% (9/16) and 19% (3/16), respectively, for an annual CSP. Many patients (38% [6/16]) reported that they would not be willing to pay any out-of-pocket cost for a CSP compared with 13% (2/16) for PET/CT.Indirect Costs of Screening for Patients—Indirect costs incurred by patients undergoing a CSP are summarized in Table 3. Specifically, a large percentage of employed patients missed work (63% [5/8]) or had family miss work (38% [3/8]), necessitating the use of vacation and/or sick days to attend CSP appointments. A subset (25% [2/8]) lost income (average, $1500), and 1 patient reported that a family member lost income due to attending a CSP appointment. Most (75% [12/16]) patients also incurred substantial transportation costs (average, $243), with 1 patient spending $1000. No patients incurred child or elder care costs. One patient paid a small sum for lodging/meals while traveling to attend a CSP appointment.

Comment

Patients with DM have an increased incidence of malignancy, thus cancer screening serves a crucial role in the detection of occult disease.¹³ Up to half of DM patients are MSA negative, and most cancers in these patients are found with blind screening. Whole-body PET/CT has emerged as an alternative to a CSP. Evidence suggests that it has similar efficacy in detecting malignancy and may be particularly useful for identifying malignancies not routinely screened for in a CSP. In a prospective study of patients diagnosed with DM and polymyositis (N=55), whole-body PET/CT had a positive predictive value of 85.7% and negative predictive value for detecting occult malignancy of 93.8% compared with 77.8% and 95.7%, respectively, for a CSP.¹⁷

The results of our study showed that cancer screening is important to patients diagnosed with DM and that most of these patients desire some form of cancer screening. This finding held true even when patients were presented with a hypothetical situation in which screening was proven to have no survival benefit. Based on focus group data, this desire was likely driven by the fear generated by not knowing whether cancer is present, as reported by the following DM patients:

“I mean [cancer screening] is peace of mind. It is ultimately worth it. You know, better than . . . not doing the screenings and finding 3 years down the road that you have, you know, a serious problem . . . you had the cancer, and you didn’t have the screenings.” (DM patient 1)

“I would rather know than not know, even if it is bad news, just tell me. The sooner the better, and give me the whole spiel . . . maybe all the screenings don’t need to be done, done so much, so often afterwards if the initial ones are ok, but I think too, for peace of mind, I would rather know it all up front.” (DM patient 2)

Further, when presented with the hypothetical situation that insurance would not cover screenings, a few patients remarked they would relocate to obtain them:

“I would find a place where the screenings were done. I’d move.” (DM patient 4)

“If it was just sky high and [insurance companies] weren’t willing to negotiate, I would consider moving.” (DM patient 3).

Sentiments such as these emphasize the importance and value that DM patients place on being screened for cancer and also may explain why only 25% of patients felt a CSP was burdensome and only 13% reported missing appointments, all of whom planned on making them up at a later time.

When presented with the choice of a CSP or annual whole-body PET/CT for a 3-year period following the diagnosis of DM, all patients expressed that whole-body PET/CT would be less burdensome. Most preferred annual whole-body PET/CT despite the slightly increased radiation exposure associated and thought that it would limit missed appointments. Accordingly, more patients responded that they would pay more money out-of-pocket for annual whole-body PET/CT. Given that WTP can function as a numerical measure of value, our results showed that patients placed a higher value on whole-body PET/CT compared with a CSP. The indirect costs associated with a CSP also were substantial, particularly regarding missed work, use of vacation and/or sick days, and travel expenses, which is particularly important because most patients reported an annual income less than $50,000.

The direct costs of a CSP and whole-body PET/CT have been studied. Specifically, Kundrick et al¹⁸ found that whole-body PET/CT was less expensive for patients (by approximately $111) out-of-pocket compared with a CSP, though cost to insurance companies was slightly greater. The present study adds to these findings by better illustrating the burden and indirect costs that patients experience while undergoing a CSP and by characterizing the patient’s perception and preference of these 2 screening methods.

Limitations of our study include a small sample size willing to complete the survey. There also was a predominance of White and female participants, partially attributed to the greater number of female patients who develop DM compared to male patients. However, this still may limit applicability of this study to males and patients of other races. Another limitation includes recall bias on survey responses, particularly regarding indirect costs incurred with a CSP. A final limitation was that only patients with a recent diagnosis of DM who were actively undergoing screening or had recently completed malignancy screening were included in the study. Given that these patients were receiving (or had completed) exclusively a CSP, patients were comparing their personal experience with a described experience. In addition, only 2 patients were diagnosed with cancer—both with basal cell carcinoma diagnosed on physical examination—which may have influenced their perception of a CSP, given that nothing was found on an extensive number of tests. However, these patients still greatly valued their screening, as evidenced in the survey.

Conclusion

Our study contributes to a better understanding of the costs patients face while undergoing malignancy screening for DM and highlights the great value patients assign to undergoing screening regardless of impact on outcome. Our study also shows a preference for streamlined testing, which whole-body PET/CT may represent. Patients incurred substantial indirect costs with a CSP and perceived that a single test, such as whole-body PET/CT, would be less burdensome and result in better compliance with screening. As groups work to establish consensus guidelines for cancer screening in DM, it is important to include the patient’s perspective. Ultimately, prospective trials comparing these modalities are needed, at which time the efficacy, direct and indirect costs, and burden of each modality can be compared.

Dermatomyositis (DM) is an uncommon idiopathic inflammatory myopathy (IIM) characterized by muscle inflammation; proximal muscle weakness; and dermatologic findings, such as the heliotrope eruption and Gottron papules.^1-3 Dermatomyositis is associated with an increased malignancy risk compared to other IIMs, with a 13% to 42% lifetime risk for malignancy development.^4,5 The incidence for malignancy peaks during the first year following diagnosis and falls gradually over 5 years but remains increased compared to the general population.^6-11 Adenocarcinoma represents the majority of cancers associated with DM, particularly of the ovaries, lungs, breasts, gastrointestinal tract, pancreas, bladder, and prostate. The lymphatic system (non-Hodgkin lymphoma) also is overrepresented among cancers in DM.¹²

Because of the increased malignancy risk and cancer-related mortality in patients with DM, cancer screening generally is recommended following diagnosis.^13,14 However, consensus guidelines for screening modalities and frequency currently do not exist, resulting in widely varying practice patterns.¹⁵ Some experts advocate for a conventional cancer screening panel (CSP), as summarized in Table 1.^15-18 These tests may be repeated annually for 3 to 5 years following the diagnosis of DM. Although the use of myositis-specific antibodies (MSAs) recently has helped to risk-stratify DM patients, up to half of patients are MSA negative,¹⁹ and broad malignancy screening remains essential. Individualized discussions with patients about their risk factors, screening options, and risks and benefits of screening also are strongly encouraged.^19-22 Studies of the direct costs and effectiveness of streamlined screening with positron emission tomography/computed tomography (PET/CT) compared with a CSP have shown similar efficacy and lower out-of-pocket costs for patients receiving PET/CT imaging.^16-18

The goal of our study was to further characterize patients’ perspectives and experience of cancer screening in DM as well as indirect costs, both of which must be taken into consideration when developing consensus guidelines for DM malignancy screening. Inclusion of patient voice is essential given the similar efficacy of both screening methods. We assessed the indirect costs (eg, travel, lost work or wages, childcare) of a CSP in patients with DM. We theorized that the large quantity of tests involved in a CSP, which are performed at various locations on multiple days over the course of several years, may have substantial costs to patients beyond the co-pay and deductible. We also sought to measure patients’ perception of the burden associated with an annual CSP, which we defined to participants as the inconvenience or unpleasantness experienced by the patient, compared with an annual whole-body PET/CT. Finally, we examined the relative value of these screening methods to patients using a willingness-to-pay (WTP) analysis.

Materials and Methods

Patient Eligibility—Our study included Penn State Health (Hershey, Pennsylvania) patients 18 years or older with a recent diagnosis of DM—International Classification of Diseases, Ninth Revision code 710.3 or International Classification of Diseases, Tenth Revision codes M33.10 or M33.90—who were undergoing or had recently completed a CSP. Patients were excluded from the study if they had a concurrent or preceding diagnosis of malignancy (excluding nonmelanoma skin cancers) or had another IIM. The institutional review board at Penn State Health College of Medicine approved the study. Data for all patients were prospectively obtained.

Survey Design—A survey was generated to assess the burden and indirect costs associated with a CSP, which was modified from work done by Tchuenche et al²³ and Teni et al.²⁴ Focus groups were held in 2018 and 2019 with patients who met our inclusion criteria with the purpose of refining the survey instrument based on patient input. A summary explanation of research was provided to all participants, and informed consent was obtained. Patients were compensated for their time for focus groups. Audio of each focus group was then transcribed and analyzed for common themes. Following focus group feedback, a finalized survey was generated for assessing burden and indirect costs (survey instrument provided in the Supplementary Information). REDCap (Vanderbilt University), a secure web application, was used to construct the finalized survey and to collect and manage data.²⁵

Patients who fit our inclusion criteria were identified and recruited in multiple ways. Patients with appointments at the Penn State Milton S. Hershey Medical Center Department of Dermatology were presented with the opportunity to participate, Penn State Health records with the appropriate billing codes were collected and patients were contacted, and an advertisement for the study was posted on StudyFinder. Surveys constructed on REDCap were then sent electronically to patients who agreed to participate in the study. A second summary explanation of research was included on the first page of the survey to describe the process.

The survey had 3 main sections. The first section collected demographic information. In the second section, we surveyed patients regarding the various aspects of a CSP that focus groups identified as burdensome. In addition, patients were asked to compare their feelings regarding an annual CSP vs whole-body PET/CT for a 3-year period utilizing a rating scale of strongly disagree, somewhat disagree, somewhat agree, and strongly agree. This section also included a willingness-to-pay (WTP) analysis for each modality. We defined WTP as the maximum out-of-pocket cost that the patient would be willing to pay to receive testing, which was measured in a hypothetical scenario where neither whole-body PET/CT nor CSP was covered by insurance.²⁶ Although WTP may be influenced by external factors such as patient income, it can serve as a numerical measure of how much the patient values each service. Furthermore, these external factors become less relevant when comparing the relative value of 2 separate tests, as such factors apply equally in both scenarios. In the third section of the survey, patients were queried regarding various indirect costs associated with a CSP. Descriptions for a CSP and whole-body PET/CT, including risks and benefits, were provided to allow patients to make informed decisions.

Statistical Analysis—Because of the rarity of DM and the subsequently limited sample size, summary and descriptive statistics were utilized to characterize the sample and identify patterns in the results. Continuous variables are presented with means and standard deviations, and proportions are presented with frequencies and percentages. All analyses were done using SAS Version 9.4 (SAS Institute Inc).

Results

Patient Demographics—Fifty-four patients were identified using StudyFinder, physician referral, and search of the electronic health record. Nine patients agreed to take part in the focus groups, and 27 offered email addresses to be contacted for the survey. Of those 27 patients, 16 (59.3%) fit our inclusion criteria and completed the survey. Patient demographics are detailed in Table 2. The mean age was 55 years, and most patients were White (88% [14/16]), female (81% [13/16]), and had at least a bachelor’s degree (69% [11/16]). Most patients (69% [11/16]) had an annual income of less than $50,000, and half (50% [8/16]) were employed. All patients had been diagnosed with DM in or after 2013. Two patients were diagnosed with basal cell carcinoma during or after cancer screening.

Patient Preference for Screening and WTP—A majority (81% [13/16]) of patients desired some form of screening for occult malignancy following the diagnosis of DM, even in the hypothetical situation in which screening did not provide survival benefit (Figure 1). Twenty-five percent (4/16) of patients expressed that a CSP was burdensome, and 12.5% of patients (2/16) missed a CSP appointment; all of these patients rescheduled or were planning to reschedule. Assuming that both screening methods had similar predictive value in detecting malignancy, all 16 patients felt annual whole-body PET/CT for a 3-year period would be less burdensome than a CSP, and most (73% [11/15]) felt that it would decrease the likelihood of missed appointments. Overall, 93% (13/14) of patients preferred whole-body PET/CT over a CSP when given the choice between the 2 options (Figure 2). This preference was consistent with the patients’ WTP for these tests; patients reliably reported that they would pay more for annual whole-body PET/CT than for a CSP (Figure 3). Specifically, 75% (12/16) and 38% (6/16) of patients were willing to spend $250 or more and $1000 or more for annual whole-body PET/CT, respectively, compared with 56% (9/16) and 19% (3/16), respectively, for an annual CSP. Many patients (38% [6/16]) reported that they would not be willing to pay any out-of-pocket cost for a CSP compared with 13% (2/16) for PET/CT.Indirect Costs of Screening for Patients—Indirect costs incurred by patients undergoing a CSP are summarized in Table 3. Specifically, a large percentage of employed patients missed work (63% [5/8]) or had family miss work (38% [3/8]), necessitating the use of vacation and/or sick days to attend CSP appointments. A subset (25% [2/8]) lost income (average, $1500), and 1 patient reported that a family member lost income due to attending a CSP appointment. Most (75% [12/16]) patients also incurred substantial transportation costs (average, $243), with 1 patient spending $1000. No patients incurred child or elder care costs. One patient paid a small sum for lodging/meals while traveling to attend a CSP appointment.

Comment

Patients with DM have an increased incidence of malignancy, thus cancer screening serves a crucial role in the detection of occult disease.¹³ Up to half of DM patients are MSA negative, and most cancers in these patients are found with blind screening. Whole-body PET/CT has emerged as an alternative to a CSP. Evidence suggests that it has similar efficacy in detecting malignancy and may be particularly useful for identifying malignancies not routinely screened for in a CSP. In a prospective study of patients diagnosed with DM and polymyositis (N=55), whole-body PET/CT had a positive predictive value of 85.7% and negative predictive value for detecting occult malignancy of 93.8% compared with 77.8% and 95.7%, respectively, for a CSP.¹⁷

The results of our study showed that cancer screening is important to patients diagnosed with DM and that most of these patients desire some form of cancer screening. This finding held true even when patients were presented with a hypothetical situation in which screening was proven to have no survival benefit. Based on focus group data, this desire was likely driven by the fear generated by not knowing whether cancer is present, as reported by the following DM patients:

“I mean [cancer screening] is peace of mind. It is ultimately worth it. You know, better than . . . not doing the screenings and finding 3 years down the road that you have, you know, a serious problem . . . you had the cancer, and you didn’t have the screenings.” (DM patient 1)

“I would rather know than not know, even if it is bad news, just tell me. The sooner the better, and give me the whole spiel . . . maybe all the screenings don’t need to be done, done so much, so often afterwards if the initial ones are ok, but I think too, for peace of mind, I would rather know it all up front.” (DM patient 2)

Further, when presented with the hypothetical situation that insurance would not cover screenings, a few patients remarked they would relocate to obtain them:

“I would find a place where the screenings were done. I’d move.” (DM patient 4)

“If it was just sky high and [insurance companies] weren’t willing to negotiate, I would consider moving.” (DM patient 3).

Sentiments such as these emphasize the importance and value that DM patients place on being screened for cancer and also may explain why only 25% of patients felt a CSP was burdensome and only 13% reported missing appointments, all of whom planned on making them up at a later time.

When presented with the choice of a CSP or annual whole-body PET/CT for a 3-year period following the diagnosis of DM, all patients expressed that whole-body PET/CT would be less burdensome. Most preferred annual whole-body PET/CT despite the slightly increased radiation exposure associated and thought that it would limit missed appointments. Accordingly, more patients responded that they would pay more money out-of-pocket for annual whole-body PET/CT. Given that WTP can function as a numerical measure of value, our results showed that patients placed a higher value on whole-body PET/CT compared with a CSP. The indirect costs associated with a CSP also were substantial, particularly regarding missed work, use of vacation and/or sick days, and travel expenses, which is particularly important because most patients reported an annual income less than $50,000.

The direct costs of a CSP and whole-body PET/CT have been studied. Specifically, Kundrick et al¹⁸ found that whole-body PET/CT was less expensive for patients (by approximately $111) out-of-pocket compared with a CSP, though cost to insurance companies was slightly greater. The present study adds to these findings by better illustrating the burden and indirect costs that patients experience while undergoing a CSP and by characterizing the patient’s perception and preference of these 2 screening methods.

Limitations of our study include a small sample size willing to complete the survey. There also was a predominance of White and female participants, partially attributed to the greater number of female patients who develop DM compared to male patients. However, this still may limit applicability of this study to males and patients of other races. Another limitation includes recall bias on survey responses, particularly regarding indirect costs incurred with a CSP. A final limitation was that only patients with a recent diagnosis of DM who were actively undergoing screening or had recently completed malignancy screening were included in the study. Given that these patients were receiving (or had completed) exclusively a CSP, patients were comparing their personal experience with a described experience. In addition, only 2 patients were diagnosed with cancer—both with basal cell carcinoma diagnosed on physical examination—which may have influenced their perception of a CSP, given that nothing was found on an extensive number of tests. However, these patients still greatly valued their screening, as evidenced in the survey.

Conclusion

Our study contributes to a better understanding of the costs patients face while undergoing malignancy screening for DM and highlights the great value patients assign to undergoing screening regardless of impact on outcome. Our study also shows a preference for streamlined testing, which whole-body PET/CT may represent. Patients incurred substantial indirect costs with a CSP and perceived that a single test, such as whole-body PET/CT, would be less burdensome and result in better compliance with screening. As groups work to establish consensus guidelines for cancer screening in DM, it is important to include the patient’s perspective. Ultimately, prospective trials comparing these modalities are needed, at which time the efficacy, direct and indirect costs, and burden of each modality can be compared.

Dermatomyositis (DM) is an uncommon idiopathic inflammatory myopathy (IIM) characterized by muscle inflammation; proximal muscle weakness; and dermatologic findings, such as the heliotrope eruption and Gottron papules.^1-3 Dermatomyositis is associated with an increased malignancy risk compared to other IIMs, with a 13% to 42% lifetime risk for malignancy development.^4,5 The incidence for malignancy peaks during the first year following diagnosis and falls gradually over 5 years but remains increased compared to the general population.^6-11 Adenocarcinoma represents the majority of cancers associated with DM, particularly of the ovaries, lungs, breasts, gastrointestinal tract, pancreas, bladder, and prostate. The lymphatic system (non-Hodgkin lymphoma) also is overrepresented among cancers in DM.¹²

Because of the increased malignancy risk and cancer-related mortality in patients with DM, cancer screening generally is recommended following diagnosis.^13,14 However, consensus guidelines for screening modalities and frequency currently do not exist, resulting in widely varying practice patterns.¹⁵ Some experts advocate for a conventional cancer screening panel (CSP), as summarized in Table 1.^15-18 These tests may be repeated annually for 3 to 5 years following the diagnosis of DM. Although the use of myositis-specific antibodies (MSAs) recently has helped to risk-stratify DM patients, up to half of patients are MSA negative,¹⁹ and broad malignancy screening remains essential. Individualized discussions with patients about their risk factors, screening options, and risks and benefits of screening also are strongly encouraged.^19-22 Studies of the direct costs and effectiveness of streamlined screening with positron emission tomography/computed tomography (PET/CT) compared with a CSP have shown similar efficacy and lower out-of-pocket costs for patients receiving PET/CT imaging.^16-18

The goal of our study was to further characterize patients’ perspectives and experience of cancer screening in DM as well as indirect costs, both of which must be taken into consideration when developing consensus guidelines for DM malignancy screening. Inclusion of patient voice is essential given the similar efficacy of both screening methods. We assessed the indirect costs (eg, travel, lost work or wages, childcare) of a CSP in patients with DM. We theorized that the large quantity of tests involved in a CSP, which are performed at various locations on multiple days over the course of several years, may have substantial costs to patients beyond the co-pay and deductible. We also sought to measure patients’ perception of the burden associated with an annual CSP, which we defined to participants as the inconvenience or unpleasantness experienced by the patient, compared with an annual whole-body PET/CT. Finally, we examined the relative value of these screening methods to patients using a willingness-to-pay (WTP) analysis.

Materials and Methods

Patient Eligibility—Our study included Penn State Health (Hershey, Pennsylvania) patients 18 years or older with a recent diagnosis of DM—International Classification of Diseases, Ninth Revision code 710.3 or International Classification of Diseases, Tenth Revision codes M33.10 or M33.90—who were undergoing or had recently completed a CSP. Patients were excluded from the study if they had a concurrent or preceding diagnosis of malignancy (excluding nonmelanoma skin cancers) or had another IIM. The institutional review board at Penn State Health College of Medicine approved the study. Data for all patients were prospectively obtained.

Survey Design—A survey was generated to assess the burden and indirect costs associated with a CSP, which was modified from work done by Tchuenche et al²³ and Teni et al.²⁴ Focus groups were held in 2018 and 2019 with patients who met our inclusion criteria with the purpose of refining the survey instrument based on patient input. A summary explanation of research was provided to all participants, and informed consent was obtained. Patients were compensated for their time for focus groups. Audio of each focus group was then transcribed and analyzed for common themes. Following focus group feedback, a finalized survey was generated for assessing burden and indirect costs (survey instrument provided in the Supplementary Information). REDCap (Vanderbilt University), a secure web application, was used to construct the finalized survey and to collect and manage data.²⁵

Patients who fit our inclusion criteria were identified and recruited in multiple ways. Patients with appointments at the Penn State Milton S. Hershey Medical Center Department of Dermatology were presented with the opportunity to participate, Penn State Health records with the appropriate billing codes were collected and patients were contacted, and an advertisement for the study was posted on StudyFinder. Surveys constructed on REDCap were then sent electronically to patients who agreed to participate in the study. A second summary explanation of research was included on the first page of the survey to describe the process.

The survey had 3 main sections. The first section collected demographic information. In the second section, we surveyed patients regarding the various aspects of a CSP that focus groups identified as burdensome. In addition, patients were asked to compare their feelings regarding an annual CSP vs whole-body PET/CT for a 3-year period utilizing a rating scale of strongly disagree, somewhat disagree, somewhat agree, and strongly agree. This section also included a willingness-to-pay (WTP) analysis for each modality. We defined WTP as the maximum out-of-pocket cost that the patient would be willing to pay to receive testing, which was measured in a hypothetical scenario where neither whole-body PET/CT nor CSP was covered by insurance.²⁶ Although WTP may be influenced by external factors such as patient income, it can serve as a numerical measure of how much the patient values each service. Furthermore, these external factors become less relevant when comparing the relative value of 2 separate tests, as such factors apply equally in both scenarios. In the third section of the survey, patients were queried regarding various indirect costs associated with a CSP. Descriptions for a CSP and whole-body PET/CT, including risks and benefits, were provided to allow patients to make informed decisions.

Statistical Analysis—Because of the rarity of DM and the subsequently limited sample size, summary and descriptive statistics were utilized to characterize the sample and identify patterns in the results. Continuous variables are presented with means and standard deviations, and proportions are presented with frequencies and percentages. All analyses were done using SAS Version 9.4 (SAS Institute Inc).

Results

Patient Demographics—Fifty-four patients were identified using StudyFinder, physician referral, and search of the electronic health record. Nine patients agreed to take part in the focus groups, and 27 offered email addresses to be contacted for the survey. Of those 27 patients, 16 (59.3%) fit our inclusion criteria and completed the survey. Patient demographics are detailed in Table 2. The mean age was 55 years, and most patients were White (88% [14/16]), female (81% [13/16]), and had at least a bachelor’s degree (69% [11/16]). Most patients (69% [11/16]) had an annual income of less than $50,000, and half (50% [8/16]) were employed. All patients had been diagnosed with DM in or after 2013. Two patients were diagnosed with basal cell carcinoma during or after cancer screening.

Patient Preference for Screening and WTP—A majority (81% [13/16]) of patients desired some form of screening for occult malignancy following the diagnosis of DM, even in the hypothetical situation in which screening did not provide survival benefit (Figure 1). Twenty-five percent (4/16) of patients expressed that a CSP was burdensome, and 12.5% of patients (2/16) missed a CSP appointment; all of these patients rescheduled or were planning to reschedule. Assuming that both screening methods had similar predictive value in detecting malignancy, all 16 patients felt annual whole-body PET/CT for a 3-year period would be less burdensome than a CSP, and most (73% [11/15]) felt that it would decrease the likelihood of missed appointments. Overall, 93% (13/14) of patients preferred whole-body PET/CT over a CSP when given the choice between the 2 options (Figure 2). This preference was consistent with the patients’ WTP for these tests; patients reliably reported that they would pay more for annual whole-body PET/CT than for a CSP (Figure 3). Specifically, 75% (12/16) and 38% (6/16) of patients were willing to spend $250 or more and $1000 or more for annual whole-body PET/CT, respectively, compared with 56% (9/16) and 19% (3/16), respectively, for an annual CSP. Many patients (38% [6/16]) reported that they would not be willing to pay any out-of-pocket cost for a CSP compared with 13% (2/16) for PET/CT.Indirect Costs of Screening for Patients—Indirect costs incurred by patients undergoing a CSP are summarized in Table 3. Specifically, a large percentage of employed patients missed work (63% [5/8]) or had family miss work (38% [3/8]), necessitating the use of vacation and/or sick days to attend CSP appointments. A subset (25% [2/8]) lost income (average, $1500), and 1 patient reported that a family member lost income due to attending a CSP appointment. Most (75% [12/16]) patients also incurred substantial transportation costs (average, $243), with 1 patient spending $1000. No patients incurred child or elder care costs. One patient paid a small sum for lodging/meals while traveling to attend a CSP appointment.

Comment

Patients with DM have an increased incidence of malignancy, thus cancer screening serves a crucial role in the detection of occult disease.¹³ Up to half of DM patients are MSA negative, and most cancers in these patients are found with blind screening. Whole-body PET/CT has emerged as an alternative to a CSP. Evidence suggests that it has similar efficacy in detecting malignancy and may be particularly useful for identifying malignancies not routinely screened for in a CSP. In a prospective study of patients diagnosed with DM and polymyositis (N=55), whole-body PET/CT had a positive predictive value of 85.7% and negative predictive value for detecting occult malignancy of 93.8% compared with 77.8% and 95.7%, respectively, for a CSP.¹⁷

The results of our study showed that cancer screening is important to patients diagnosed with DM and that most of these patients desire some form of cancer screening. This finding held true even when patients were presented with a hypothetical situation in which screening was proven to have no survival benefit. Based on focus group data, this desire was likely driven by the fear generated by not knowing whether cancer is present, as reported by the following DM patients:

“I mean [cancer screening] is peace of mind. It is ultimately worth it. You know, better than . . . not doing the screenings and finding 3 years down the road that you have, you know, a serious problem . . . you had the cancer, and you didn’t have the screenings.” (DM patient 1)

“I would rather know than not know, even if it is bad news, just tell me. The sooner the better, and give me the whole spiel . . . maybe all the screenings don’t need to be done, done so much, so often afterwards if the initial ones are ok, but I think too, for peace of mind, I would rather know it all up front.” (DM patient 2)

Further, when presented with the hypothetical situation that insurance would not cover screenings, a few patients remarked they would relocate to obtain them:

“I would find a place where the screenings were done. I’d move.” (DM patient 4)

“If it was just sky high and [insurance companies] weren’t willing to negotiate, I would consider moving.” (DM patient 3).

Sentiments such as these emphasize the importance and value that DM patients place on being screened for cancer and also may explain why only 25% of patients felt a CSP was burdensome and only 13% reported missing appointments, all of whom planned on making them up at a later time.

When presented with the choice of a CSP or annual whole-body PET/CT for a 3-year period following the diagnosis of DM, all patients expressed that whole-body PET/CT would be less burdensome. Most preferred annual whole-body PET/CT despite the slightly increased radiation exposure associated and thought that it would limit missed appointments. Accordingly, more patients responded that they would pay more money out-of-pocket for annual whole-body PET/CT. Given that WTP can function as a numerical measure of value, our results showed that patients placed a higher value on whole-body PET/CT compared with a CSP. The indirect costs associated with a CSP also were substantial, particularly regarding missed work, use of vacation and/or sick days, and travel expenses, which is particularly important because most patients reported an annual income less than $50,000.

The direct costs of a CSP and whole-body PET/CT have been studied. Specifically, Kundrick et al¹⁸ found that whole-body PET/CT was less expensive for patients (by approximately $111) out-of-pocket compared with a CSP, though cost to insurance companies was slightly greater. The present study adds to these findings by better illustrating the burden and indirect costs that patients experience while undergoing a CSP and by characterizing the patient’s perception and preference of these 2 screening methods.

Limitations of our study include a small sample size willing to complete the survey. There also was a predominance of White and female participants, partially attributed to the greater number of female patients who develop DM compared to male patients. However, this still may limit applicability of this study to males and patients of other races. Another limitation includes recall bias on survey responses, particularly regarding indirect costs incurred with a CSP. A final limitation was that only patients with a recent diagnosis of DM who were actively undergoing screening or had recently completed malignancy screening were included in the study. Given that these patients were receiving (or had completed) exclusively a CSP, patients were comparing their personal experience with a described experience. In addition, only 2 patients were diagnosed with cancer—both with basal cell carcinoma diagnosed on physical examination—which may have influenced their perception of a CSP, given that nothing was found on an extensive number of tests. However, these patients still greatly valued their screening, as evidenced in the survey.

Conclusion

Our study contributes to a better understanding of the costs patients face while undergoing malignancy screening for DM and highlights the great value patients assign to undergoing screening regardless of impact on outcome. Our study also shows a preference for streamlined testing, which whole-body PET/CT may represent. Patients incurred substantial indirect costs with a CSP and perceived that a single test, such as whole-body PET/CT, would be less burdensome and result in better compliance with screening. As groups work to establish consensus guidelines for cancer screening in DM, it is important to include the patient’s perspective. Ultimately, prospective trials comparing these modalities are needed, at which time the efficacy, direct and indirect costs, and burden of each modality can be compared.

Brachioradial pruritus (BRP) is a neuropathic condition typically characterized by localized dysesthesia of the dorsolateral arms.¹ This dysesthesia has been described as a persistent painful itching, burning, tingling, or stinging sensation^2-4 and has a median duration of expression of 24 months.^5,6 The condition may be unilateral or bilateral in nature but tends to have a predilection for a bilateral distribution along the C5 to C6 dermatomes.^1,7,8 There are no primary skin lesions associated with BRP; however, excoriations, prurigo nodules, and lichenification may arise secondary to scratching of the irritated skin.^1,4,5,9 Brachioradial pruritus tends to have a predilection for adult females (3:1 ratio) with lighter skin. The mean age at diagnosis is 59 years, but cases have been reported in patients aged 12 to 84 years.^1,5 The diagnosis of BRP is based on clinical signs and symptoms, though the ice-pack sign tends to be pathognomonic for the diagnosis.^10,11 Although there is no clear evidence on the exact cause of BRP, there are 2 prevalent theories: cervical radiculopathy secondary to cervical spine pathology and/or excessive exposure to UV radiation (UVR) in the summer months.^3-5,12 Brachioradial pruritus remains poorly described in the literature, and even its origin is under debate. As such, the clinician may have difficulty deciding on the best course of management. The goal of this article is to identify and discuss known treatment options for BRP (Table).

Etiology 

Cervical Spine Pathology—A correlation appears to exist between BRP and cervical spine changes seen on plain film radiographs at the levels of C3 to C7, with increased incidence at the C5 to C6 levels. These plain film radiographs typically show degenerative joint disease and neural foraminal stenosis at levels that correlate to the dermatomal distribution of BRP.^1,7,10,12-14 In addition to plain film radiography, some studies have utilized magnetic resonance imaging to view the cervical spine and have documented evidence of intervertebral disc protrusion/bulging, central canal stenosis, neuroforaminal stenosis, and spondylosis at the affected regions.^5,15-17 Moreover, supporting the theory that the cervical spine is responsible for the emergence of BRP, Marziniak et al¹⁷ investigated 41 patients with BRP utilizing magnetic resonance tomography to find that 33 patients (80.5%) had changes in nerve compression, and 8 patients (19.5%) had degenerative changes. In addition to these findings, they found that there was a significant correlation (P<.01) between the dermatomal expression of BRP and the location of cervical anatomical changes.¹⁷ Further validating the relationship between cervical spine pathology and BRP is a case study of a patient who saw rapid and complete resolution of the pruritus following spinal decompression surgery.¹⁰ Another case study described an intramedullary tumor found in a patient with BRP that was diagnosed as an ependymoma after magnetic resonance imaging revealed an intramedullary lesion within the spinal cord between C4 and C7. The location of the tumor and dermatomal pattern of the neuropathic itch pointed to a possible association between nerve compression and BRP.¹⁴ Electromyography studies performed on individuals with BRP have shown an increase in polyphasic units, decreased motor units, and/or denervation changes along the C5/C6 or C6 nerve roots, which provides additional support for the theory of cervical spine pathology as a causative factor for BRP.¹⁶

UVR Exposure—Another etiologic theory for BRP is that UVR exposure may be responsible for the genesis of pruritus. Previously known as solar pruritus, BRP was deemed a clinical condition, as there was increased prevalence in patients living in warmer climates, such as Florida.⁹ Wallengren and Dahlbäck¹⁸ reported that sun exposure is a notable factor in the onset of BRP, as they saw an increase in symptoms during the late summer and a decrease in symptoms over the winter months. To further support the theory that UVR is linked to BRP, several studies have shown that the utilization of sun protection is linked to a reduction of symptoms, specifically in patients who showed seasonal variations of their symptoms.^9,12,19 Additionally, a study by Mirzoyev and Davis⁵ retrospectively reviewed 111 patients diagnosed with BRP. Of these patients, 84 (75.7%) presented with bilateral symptoms, and 54 (48.6%) reported prolonged sun exposure. Both of these findings demonstrate correlation between UVR and BRP.⁵ Interestingly, UV light exposure is known to release β-endorphin in the skin and may theoretically provide an area of exploration between UVR and cervical spine theories.

Conservative Treatment 

Chiropractic Manipulation—Because one etiologic theory includes disease of the cervical spine, there is evidence that targeting this region with treatment is beneficial.⁷ Two case reports found in the literature noted that cervical spine manipulation and cervical traction yielded positive results.^20,21 It has been established that pain generated by disc lesions can be the result of local nociceptive fiber activation, direct mechanical compression of the nerve roots, or inflammatory mediators.²² There are several postulated models describing the hypoalgesic effects of spinal manipulation, which contains both biomechanical and neurophysiological mechanisms. Biomechanical changes theorized to elicit analgesia include restoration of faulty biomechanical movement patterns, breaking up of periarticular adhesions, and reflexogenic muscle inhibition of hypertonic musculature. Hypothesized neurophysiological effects of joint manipulation include an increase in afferent information overwhelming the nociceptive input, reduction of temporal summation, and autonomic activation leading to non–opioid-induced hypoalgesia.²³ Cervical traction is another plausible treatment for BRP, wherein the physiological effects of traction allow for a separation of vertebral bodies and expansion of the intervertebral foramen circumference, thus decreasing compression of the nerve roots.²⁴

Acupuncture—Neurogenic pruritus, including BRP, is a group of conditions that have been treated using acupuncture. Acupuncture treatment consists of intramuscular needle stimulation and has been found to alleviate itching in patients with neurogenic pruritus. In 1 retrospective case series, acupuncture was used to treat 16 patients who were identified as having segmental pruritus. Acupuncture targeted the spasmed paravertebral muscles of the affected dermatomal levels as well as other regions of the body, and it was found that 12 patients (75%) experienced full resolution of symptoms. However, relapse did occur in 6 patients (37%) within 1 to 12 months following treatment.²⁵ Multiple theories exist as to why acupuncture may help. One is that it relieves muscle spasms, which in turn relieves neural irritation of the spinal nerves as they traverse the respective paraspinal musculature. Another is that acupuncture decreases nociception by stimulating release of opioid peptides in the dorsal horn.²⁶ A third proposed theory is that acupuncture acts on the afferent nerve fibers responsible for transmitting pain—Aδ and C fibers—activating these afferent nerves to produce an analgesic effect.²⁷

Physiotherapy—The literature suggests that possible first-line therapies for neurogenic pruritus, including BRP and notalgia paresthetica, consist of noninvasive nondermatologic treatments that target cervical spine disease. Notalgia paresthetica and BRP have similar proposed mechanisms of nerve impingement; therefore, they often are grouped together when discussing proposed manual treatment options. Physiotherapy treatment includes cervical muscle strengthening, increased range of motion, application of cervical soft collars, massage, transcutaneous electronic nerve stimulation, and cervical traction.⁷ A study of 12 patients by Raison-Peyron et al²⁸ in 1999 discussed the use of spinal and paraspinal ultrasound or radiation physiotherapy. Six patients underwent this treatment, and the symptoms subsided in 4 cases.²⁸ Another study by Fleischer et al²⁹ in 2011 discussed improvement in 2 patients with notalgia paresthetica by exercise involving active range of motion and strengthening.

Photoprotection—Avoidance of UVR exposure has been beneficial to some patients to reduce symptoms. Use of sunscreen and long-sleeved UV-protective clothing during outdoor activities or the warmer summer months may be beneficial.¹

 

 

Medical Treatment

Medication—Because of the nonspecific clinical presentation of BRP, initial treatment often involves prescription of first-line antipruritic agents, including steroid creams and systemic antihistamines, both of which generally fail to provide symptom relief.^1,30 Medications with neurologic mechanisms of action appear to provide potentially superior outcomes. Neuroleptics, including gabapentin and pregabalin, are typical therapeutic agents for neurogenic pruritus and inhibit nociceptive pain propagation.³¹ Intervention with pregabalin in 3 patients with BRP achieved complete symptom relief in all patients, with initial improvement occurring in as little as 1 week.⁸ Mirogabalin, operating under a similar mechanism, has shown preliminary success in treating BRP, causing anecdotal patient improvement within 4 months of initial dosage.³² Prolonged 1-month intravenous naloxone treatment also appars to be promising, offering symptom improvement of at least 80% six months posttreatment.¹⁵ 

Topical interventions for BRP and related neurogenic pruritus have shown limited success. A case series evaluating capsaicin for pruritus offered only transient relief, likely because of its temporary hyperstimulatory and desensitizing effect on neuropeptides.^7,33 In small populations, the use of topical antidepressants has yielded cutaneous and pathological relief for BRP. A case study of a 70-year-old woman evaluated the efficacy of a combination cream of ketamine and amitriptyline (a tricyclic antidepressant) yielding moderate pruritus improvement and notable improvement of secondary brachial skin lesions.³⁴ Oral steroids also have shown success in the treatment of chronic pruritus; however, limited research is available on the efficacy of such medications for BRP, and the long-term use of oral steroids is limited by many side effects.³⁰ 

Interventional Pain Procedure—A 2018 case series investigated 3 patients with a clinical diagnosis of BRP who were treated between 2010 and 2016 with epidural steroid injection using computed tomography guidance of the cervical spine.³⁵ The authors reported that 2 patients had near-complete resolution after 1 interventional procedure. The third patient had a total of 3 injections, with mild to moderate relief that continued to improve on mexiletine.³⁵ Another case in 2010 of a 56-year-old man with BRP documented use of a series of 2 epidural steroid injections that resulted in clinical resolution of symptoms.³⁶

Surgery—There are multiple case studies in the literature that discuss anterior cervical discectomy and fusion (ACDF) as a last resort in patients with refractory BRP of discogenic cause. In 2022, Morosanu et al³⁷ described a case of a 63-year-old woman with BRP in the C5–C6 distribution who had an associated disc protrusion at this level following magnetic resonance imaging. The patient underwent a C5/C6 ACDF after conservative and medical treatment failed, and at 3-month follow up her symptoms had resolved entirely.³⁷ Another case report described a 56-year-old man who ultimately underwent ACDF after failed multimodal treatment attempts, with instant improvement in symptoms. Four months after surgery, the patient reported a 95% improvement of symptoms.¹⁹ An older case in 2008 discussed the use of ACDF in a 64-year-old woman with severe distress and an identifiable surgical target. The patient’s symptoms resolved completely within 1 week after surgery.¹⁰

Conclusion 

The pathogenesis of BRP continues to be an area of debate—it may be secondary to cervical spine disease or UVR. This review found there is more research pointing to cervical spine disease. There is an abundance of literature discussing both conservative and invasive treatment strategies, both of which carry benefits. Further research is needed to better establish the etiology of BRP so that formal treatment guidelines may be established. 

Neuropathic itch can be a frustrating condition for providers and patients, and many treatment modalities often are tried before arriving at a helpful treatment for a particular patient. Clinicians who may encounter BRP in practice benefit from up-to-date literature reviews that provide a summary of management strategies.

Brachioradial pruritus (BRP) is a neuropathic condition typically characterized by localized dysesthesia of the dorsolateral arms.¹ This dysesthesia has been described as a persistent painful itching, burning, tingling, or stinging sensation^2-4 and has a median duration of expression of 24 months.^5,6 The condition may be unilateral or bilateral in nature but tends to have a predilection for a bilateral distribution along the C5 to C6 dermatomes.^1,7,8 There are no primary skin lesions associated with BRP; however, excoriations, prurigo nodules, and lichenification may arise secondary to scratching of the irritated skin.^1,4,5,9 Brachioradial pruritus tends to have a predilection for adult females (3:1 ratio) with lighter skin. The mean age at diagnosis is 59 years, but cases have been reported in patients aged 12 to 84 years.^1,5 The diagnosis of BRP is based on clinical signs and symptoms, though the ice-pack sign tends to be pathognomonic for the diagnosis.^10,11 Although there is no clear evidence on the exact cause of BRP, there are 2 prevalent theories: cervical radiculopathy secondary to cervical spine pathology and/or excessive exposure to UV radiation (UVR) in the summer months.^3-5,12 Brachioradial pruritus remains poorly described in the literature, and even its origin is under debate. As such, the clinician may have difficulty deciding on the best course of management. The goal of this article is to identify and discuss known treatment options for BRP (Table).

Etiology 

Cervical Spine Pathology—A correlation appears to exist between BRP and cervical spine changes seen on plain film radiographs at the levels of C3 to C7, with increased incidence at the C5 to C6 levels. These plain film radiographs typically show degenerative joint disease and neural foraminal stenosis at levels that correlate to the dermatomal distribution of BRP.^1,7,10,12-14 In addition to plain film radiography, some studies have utilized magnetic resonance imaging to view the cervical spine and have documented evidence of intervertebral disc protrusion/bulging, central canal stenosis, neuroforaminal stenosis, and spondylosis at the affected regions.^5,15-17 Moreover, supporting the theory that the cervical spine is responsible for the emergence of BRP, Marziniak et al¹⁷ investigated 41 patients with BRP utilizing magnetic resonance tomography to find that 33 patients (80.5%) had changes in nerve compression, and 8 patients (19.5%) had degenerative changes. In addition to these findings, they found that there was a significant correlation (P<.01) between the dermatomal expression of BRP and the location of cervical anatomical changes.¹⁷ Further validating the relationship between cervical spine pathology and BRP is a case study of a patient who saw rapid and complete resolution of the pruritus following spinal decompression surgery.¹⁰ Another case study described an intramedullary tumor found in a patient with BRP that was diagnosed as an ependymoma after magnetic resonance imaging revealed an intramedullary lesion within the spinal cord between C4 and C7. The location of the tumor and dermatomal pattern of the neuropathic itch pointed to a possible association between nerve compression and BRP.¹⁴ Electromyography studies performed on individuals with BRP have shown an increase in polyphasic units, decreased motor units, and/or denervation changes along the C5/C6 or C6 nerve roots, which provides additional support for the theory of cervical spine pathology as a causative factor for BRP.¹⁶

UVR Exposure—Another etiologic theory for BRP is that UVR exposure may be responsible for the genesis of pruritus. Previously known as solar pruritus, BRP was deemed a clinical condition, as there was increased prevalence in patients living in warmer climates, such as Florida.⁹ Wallengren and Dahlbäck¹⁸ reported that sun exposure is a notable factor in the onset of BRP, as they saw an increase in symptoms during the late summer and a decrease in symptoms over the winter months. To further support the theory that UVR is linked to BRP, several studies have shown that the utilization of sun protection is linked to a reduction of symptoms, specifically in patients who showed seasonal variations of their symptoms.^9,12,19 Additionally, a study by Mirzoyev and Davis⁵ retrospectively reviewed 111 patients diagnosed with BRP. Of these patients, 84 (75.7%) presented with bilateral symptoms, and 54 (48.6%) reported prolonged sun exposure. Both of these findings demonstrate correlation between UVR and BRP.⁵ Interestingly, UV light exposure is known to release β-endorphin in the skin and may theoretically provide an area of exploration between UVR and cervical spine theories.

Conservative Treatment 

Chiropractic Manipulation—Because one etiologic theory includes disease of the cervical spine, there is evidence that targeting this region with treatment is beneficial.⁷ Two case reports found in the literature noted that cervical spine manipulation and cervical traction yielded positive results.^20,21 It has been established that pain generated by disc lesions can be the result of local nociceptive fiber activation, direct mechanical compression of the nerve roots, or inflammatory mediators.²² There are several postulated models describing the hypoalgesic effects of spinal manipulation, which contains both biomechanical and neurophysiological mechanisms. Biomechanical changes theorized to elicit analgesia include restoration of faulty biomechanical movement patterns, breaking up of periarticular adhesions, and reflexogenic muscle inhibition of hypertonic musculature. Hypothesized neurophysiological effects of joint manipulation include an increase in afferent information overwhelming the nociceptive input, reduction of temporal summation, and autonomic activation leading to non–opioid-induced hypoalgesia.²³ Cervical traction is another plausible treatment for BRP, wherein the physiological effects of traction allow for a separation of vertebral bodies and expansion of the intervertebral foramen circumference, thus decreasing compression of the nerve roots.²⁴

Acupuncture—Neurogenic pruritus, including BRP, is a group of conditions that have been treated using acupuncture. Acupuncture treatment consists of intramuscular needle stimulation and has been found to alleviate itching in patients with neurogenic pruritus. In 1 retrospective case series, acupuncture was used to treat 16 patients who were identified as having segmental pruritus. Acupuncture targeted the spasmed paravertebral muscles of the affected dermatomal levels as well as other regions of the body, and it was found that 12 patients (75%) experienced full resolution of symptoms. However, relapse did occur in 6 patients (37%) within 1 to 12 months following treatment.²⁵ Multiple theories exist as to why acupuncture may help. One is that it relieves muscle spasms, which in turn relieves neural irritation of the spinal nerves as they traverse the respective paraspinal musculature. Another is that acupuncture decreases nociception by stimulating release of opioid peptides in the dorsal horn.²⁶ A third proposed theory is that acupuncture acts on the afferent nerve fibers responsible for transmitting pain—Aδ and C fibers—activating these afferent nerves to produce an analgesic effect.²⁷

Physiotherapy—The literature suggests that possible first-line therapies for neurogenic pruritus, including BRP and notalgia paresthetica, consist of noninvasive nondermatologic treatments that target cervical spine disease. Notalgia paresthetica and BRP have similar proposed mechanisms of nerve impingement; therefore, they often are grouped together when discussing proposed manual treatment options. Physiotherapy treatment includes cervical muscle strengthening, increased range of motion, application of cervical soft collars, massage, transcutaneous electronic nerve stimulation, and cervical traction.⁷ A study of 12 patients by Raison-Peyron et al²⁸ in 1999 discussed the use of spinal and paraspinal ultrasound or radiation physiotherapy. Six patients underwent this treatment, and the symptoms subsided in 4 cases.²⁸ Another study by Fleischer et al²⁹ in 2011 discussed improvement in 2 patients with notalgia paresthetica by exercise involving active range of motion and strengthening.

Photoprotection—Avoidance of UVR exposure has been beneficial to some patients to reduce symptoms. Use of sunscreen and long-sleeved UV-protective clothing during outdoor activities or the warmer summer months may be beneficial.¹

 

 

Medical Treatment

Medication—Because of the nonspecific clinical presentation of BRP, initial treatment often involves prescription of first-line antipruritic agents, including steroid creams and systemic antihistamines, both of which generally fail to provide symptom relief.^1,30 Medications with neurologic mechanisms of action appear to provide potentially superior outcomes. Neuroleptics, including gabapentin and pregabalin, are typical therapeutic agents for neurogenic pruritus and inhibit nociceptive pain propagation.³¹ Intervention with pregabalin in 3 patients with BRP achieved complete symptom relief in all patients, with initial improvement occurring in as little as 1 week.⁸ Mirogabalin, operating under a similar mechanism, has shown preliminary success in treating BRP, causing anecdotal patient improvement within 4 months of initial dosage.³² Prolonged 1-month intravenous naloxone treatment also appars to be promising, offering symptom improvement of at least 80% six months posttreatment.¹⁵ 

Topical interventions for BRP and related neurogenic pruritus have shown limited success. A case series evaluating capsaicin for pruritus offered only transient relief, likely because of its temporary hyperstimulatory and desensitizing effect on neuropeptides.^7,33 In small populations, the use of topical antidepressants has yielded cutaneous and pathological relief for BRP. A case study of a 70-year-old woman evaluated the efficacy of a combination cream of ketamine and amitriptyline (a tricyclic antidepressant) yielding moderate pruritus improvement and notable improvement of secondary brachial skin lesions.³⁴ Oral steroids also have shown success in the treatment of chronic pruritus; however, limited research is available on the efficacy of such medications for BRP, and the long-term use of oral steroids is limited by many side effects.³⁰ 

Interventional Pain Procedure—A 2018 case series investigated 3 patients with a clinical diagnosis of BRP who were treated between 2010 and 2016 with epidural steroid injection using computed tomography guidance of the cervical spine.³⁵ The authors reported that 2 patients had near-complete resolution after 1 interventional procedure. The third patient had a total of 3 injections, with mild to moderate relief that continued to improve on mexiletine.³⁵ Another case in 2010 of a 56-year-old man with BRP documented use of a series of 2 epidural steroid injections that resulted in clinical resolution of symptoms.³⁶

Surgery—There are multiple case studies in the literature that discuss anterior cervical discectomy and fusion (ACDF) as a last resort in patients with refractory BRP of discogenic cause. In 2022, Morosanu et al³⁷ described a case of a 63-year-old woman with BRP in the C5–C6 distribution who had an associated disc protrusion at this level following magnetic resonance imaging. The patient underwent a C5/C6 ACDF after conservative and medical treatment failed, and at 3-month follow up her symptoms had resolved entirely.³⁷ Another case report described a 56-year-old man who ultimately underwent ACDF after failed multimodal treatment attempts, with instant improvement in symptoms. Four months after surgery, the patient reported a 95% improvement of symptoms.¹⁹ An older case in 2008 discussed the use of ACDF in a 64-year-old woman with severe distress and an identifiable surgical target. The patient’s symptoms resolved completely within 1 week after surgery.¹⁰

Conclusion 

The pathogenesis of BRP continues to be an area of debate—it may be secondary to cervical spine disease or UVR. This review found there is more research pointing to cervical spine disease. There is an abundance of literature discussing both conservative and invasive treatment strategies, both of which carry benefits. Further research is needed to better establish the etiology of BRP so that formal treatment guidelines may be established. 

Neuropathic itch can be a frustrating condition for providers and patients, and many treatment modalities often are tried before arriving at a helpful treatment for a particular patient. Clinicians who may encounter BRP in practice benefit from up-to-date literature reviews that provide a summary of management strategies.

Brachioradial pruritus (BRP) is a neuropathic condition typically characterized by localized dysesthesia of the dorsolateral arms.¹ This dysesthesia has been described as a persistent painful itching, burning, tingling, or stinging sensation^2-4 and has a median duration of expression of 24 months.^5,6 The condition may be unilateral or bilateral in nature but tends to have a predilection for a bilateral distribution along the C5 to C6 dermatomes.^1,7,8 There are no primary skin lesions associated with BRP; however, excoriations, prurigo nodules, and lichenification may arise secondary to scratching of the irritated skin.^1,4,5,9 Brachioradial pruritus tends to have a predilection for adult females (3:1 ratio) with lighter skin. The mean age at diagnosis is 59 years, but cases have been reported in patients aged 12 to 84 years.^1,5 The diagnosis of BRP is based on clinical signs and symptoms, though the ice-pack sign tends to be pathognomonic for the diagnosis.^10,11 Although there is no clear evidence on the exact cause of BRP, there are 2 prevalent theories: cervical radiculopathy secondary to cervical spine pathology and/or excessive exposure to UV radiation (UVR) in the summer months.^3-5,12 Brachioradial pruritus remains poorly described in the literature, and even its origin is under debate. As such, the clinician may have difficulty deciding on the best course of management. The goal of this article is to identify and discuss known treatment options for BRP (Table).

Etiology 

Cervical Spine Pathology—A correlation appears to exist between BRP and cervical spine changes seen on plain film radiographs at the levels of C3 to C7, with increased incidence at the C5 to C6 levels. These plain film radiographs typically show degenerative joint disease and neural foraminal stenosis at levels that correlate to the dermatomal distribution of BRP.^1,7,10,12-14 In addition to plain film radiography, some studies have utilized magnetic resonance imaging to view the cervical spine and have documented evidence of intervertebral disc protrusion/bulging, central canal stenosis, neuroforaminal stenosis, and spondylosis at the affected regions.^5,15-17 Moreover, supporting the theory that the cervical spine is responsible for the emergence of BRP, Marziniak et al¹⁷ investigated 41 patients with BRP utilizing magnetic resonance tomography to find that 33 patients (80.5%) had changes in nerve compression, and 8 patients (19.5%) had degenerative changes. In addition to these findings, they found that there was a significant correlation (P<.01) between the dermatomal expression of BRP and the location of cervical anatomical changes.¹⁷ Further validating the relationship between cervical spine pathology and BRP is a case study of a patient who saw rapid and complete resolution of the pruritus following spinal decompression surgery.¹⁰ Another case study described an intramedullary tumor found in a patient with BRP that was diagnosed as an ependymoma after magnetic resonance imaging revealed an intramedullary lesion within the spinal cord between C4 and C7. The location of the tumor and dermatomal pattern of the neuropathic itch pointed to a possible association between nerve compression and BRP.¹⁴ Electromyography studies performed on individuals with BRP have shown an increase in polyphasic units, decreased motor units, and/or denervation changes along the C5/C6 or C6 nerve roots, which provides additional support for the theory of cervical spine pathology as a causative factor for BRP.¹⁶

UVR Exposure—Another etiologic theory for BRP is that UVR exposure may be responsible for the genesis of pruritus. Previously known as solar pruritus, BRP was deemed a clinical condition, as there was increased prevalence in patients living in warmer climates, such as Florida.⁹ Wallengren and Dahlbäck¹⁸ reported that sun exposure is a notable factor in the onset of BRP, as they saw an increase in symptoms during the late summer and a decrease in symptoms over the winter months. To further support the theory that UVR is linked to BRP, several studies have shown that the utilization of sun protection is linked to a reduction of symptoms, specifically in patients who showed seasonal variations of their symptoms.^9,12,19 Additionally, a study by Mirzoyev and Davis⁵ retrospectively reviewed 111 patients diagnosed with BRP. Of these patients, 84 (75.7%) presented with bilateral symptoms, and 54 (48.6%) reported prolonged sun exposure. Both of these findings demonstrate correlation between UVR and BRP.⁵ Interestingly, UV light exposure is known to release β-endorphin in the skin and may theoretically provide an area of exploration between UVR and cervical spine theories.

Conservative Treatment 

Chiropractic Manipulation—Because one etiologic theory includes disease of the cervical spine, there is evidence that targeting this region with treatment is beneficial.⁷ Two case reports found in the literature noted that cervical spine manipulation and cervical traction yielded positive results.^20,21 It has been established that pain generated by disc lesions can be the result of local nociceptive fiber activation, direct mechanical compression of the nerve roots, or inflammatory mediators.²² There are several postulated models describing the hypoalgesic effects of spinal manipulation, which contains both biomechanical and neurophysiological mechanisms. Biomechanical changes theorized to elicit analgesia include restoration of faulty biomechanical movement patterns, breaking up of periarticular adhesions, and reflexogenic muscle inhibition of hypertonic musculature. Hypothesized neurophysiological effects of joint manipulation include an increase in afferent information overwhelming the nociceptive input, reduction of temporal summation, and autonomic activation leading to non–opioid-induced hypoalgesia.²³ Cervical traction is another plausible treatment for BRP, wherein the physiological effects of traction allow for a separation of vertebral bodies and expansion of the intervertebral foramen circumference, thus decreasing compression of the nerve roots.²⁴

Acupuncture—Neurogenic pruritus, including BRP, is a group of conditions that have been treated using acupuncture. Acupuncture treatment consists of intramuscular needle stimulation and has been found to alleviate itching in patients with neurogenic pruritus. In 1 retrospective case series, acupuncture was used to treat 16 patients who were identified as having segmental pruritus. Acupuncture targeted the spasmed paravertebral muscles of the affected dermatomal levels as well as other regions of the body, and it was found that 12 patients (75%) experienced full resolution of symptoms. However, relapse did occur in 6 patients (37%) within 1 to 12 months following treatment.²⁵ Multiple theories exist as to why acupuncture may help. One is that it relieves muscle spasms, which in turn relieves neural irritation of the spinal nerves as they traverse the respective paraspinal musculature. Another is that acupuncture decreases nociception by stimulating release of opioid peptides in the dorsal horn.²⁶ A third proposed theory is that acupuncture acts on the afferent nerve fibers responsible for transmitting pain—Aδ and C fibers—activating these afferent nerves to produce an analgesic effect.²⁷

Physiotherapy—The literature suggests that possible first-line therapies for neurogenic pruritus, including BRP and notalgia paresthetica, consist of noninvasive nondermatologic treatments that target cervical spine disease. Notalgia paresthetica and BRP have similar proposed mechanisms of nerve impingement; therefore, they often are grouped together when discussing proposed manual treatment options. Physiotherapy treatment includes cervical muscle strengthening, increased range of motion, application of cervical soft collars, massage, transcutaneous electronic nerve stimulation, and cervical traction.⁷ A study of 12 patients by Raison-Peyron et al²⁸ in 1999 discussed the use of spinal and paraspinal ultrasound or radiation physiotherapy. Six patients underwent this treatment, and the symptoms subsided in 4 cases.²⁸ Another study by Fleischer et al²⁹ in 2011 discussed improvement in 2 patients with notalgia paresthetica by exercise involving active range of motion and strengthening.

Photoprotection—Avoidance of UVR exposure has been beneficial to some patients to reduce symptoms. Use of sunscreen and long-sleeved UV-protective clothing during outdoor activities or the warmer summer months may be beneficial.¹

 

 

Medical Treatment

Medication—Because of the nonspecific clinical presentation of BRP, initial treatment often involves prescription of first-line antipruritic agents, including steroid creams and systemic antihistamines, both of which generally fail to provide symptom relief.^1,30 Medications with neurologic mechanisms of action appear to provide potentially superior outcomes. Neuroleptics, including gabapentin and pregabalin, are typical therapeutic agents for neurogenic pruritus and inhibit nociceptive pain propagation.³¹ Intervention with pregabalin in 3 patients with BRP achieved complete symptom relief in all patients, with initial improvement occurring in as little as 1 week.⁸ Mirogabalin, operating under a similar mechanism, has shown preliminary success in treating BRP, causing anecdotal patient improvement within 4 months of initial dosage.³² Prolonged 1-month intravenous naloxone treatment also appars to be promising, offering symptom improvement of at least 80% six months posttreatment.¹⁵ 

Topical interventions for BRP and related neurogenic pruritus have shown limited success. A case series evaluating capsaicin for pruritus offered only transient relief, likely because of its temporary hyperstimulatory and desensitizing effect on neuropeptides.^7,33 In small populations, the use of topical antidepressants has yielded cutaneous and pathological relief for BRP. A case study of a 70-year-old woman evaluated the efficacy of a combination cream of ketamine and amitriptyline (a tricyclic antidepressant) yielding moderate pruritus improvement and notable improvement of secondary brachial skin lesions.³⁴ Oral steroids also have shown success in the treatment of chronic pruritus; however, limited research is available on the efficacy of such medications for BRP, and the long-term use of oral steroids is limited by many side effects.³⁰ 

Interventional Pain Procedure—A 2018 case series investigated 3 patients with a clinical diagnosis of BRP who were treated between 2010 and 2016 with epidural steroid injection using computed tomography guidance of the cervical spine.³⁵ The authors reported that 2 patients had near-complete resolution after 1 interventional procedure. The third patient had a total of 3 injections, with mild to moderate relief that continued to improve on mexiletine.³⁵ Another case in 2010 of a 56-year-old man with BRP documented use of a series of 2 epidural steroid injections that resulted in clinical resolution of symptoms.³⁶

Surgery—There are multiple case studies in the literature that discuss anterior cervical discectomy and fusion (ACDF) as a last resort in patients with refractory BRP of discogenic cause. In 2022, Morosanu et al³⁷ described a case of a 63-year-old woman with BRP in the C5–C6 distribution who had an associated disc protrusion at this level following magnetic resonance imaging. The patient underwent a C5/C6 ACDF after conservative and medical treatment failed, and at 3-month follow up her symptoms had resolved entirely.³⁷ Another case report described a 56-year-old man who ultimately underwent ACDF after failed multimodal treatment attempts, with instant improvement in symptoms. Four months after surgery, the patient reported a 95% improvement of symptoms.¹⁹ An older case in 2008 discussed the use of ACDF in a 64-year-old woman with severe distress and an identifiable surgical target. The patient’s symptoms resolved completely within 1 week after surgery.¹⁰

Conclusion 

The pathogenesis of BRP continues to be an area of debate—it may be secondary to cervical spine disease or UVR. This review found there is more research pointing to cervical spine disease. There is an abundance of literature discussing both conservative and invasive treatment strategies, both of which carry benefits. Further research is needed to better establish the etiology of BRP so that formal treatment guidelines may be established. 

Neuropathic itch can be a frustrating condition for providers and patients, and many treatment modalities often are tried before arriving at a helpful treatment for a particular patient. Clinicians who may encounter BRP in practice benefit from up-to-date literature reviews that provide a summary of management strategies.

The Diagnosis: Mycobacterial Infection

Mycobacterium marinum is a waterborne nontuberculous mycobacterium prevailing in salt water, brackish water, and still or streaming fresh water that infects fish and amphibians worldwide.^1,2 Although first described in 1926 as the organism responsible for the demise of fish in an aquarium in Philadelphia, Pennsylvania, it was not until 1954 that the organism was linked to the cause of infection in humans after it was identified in 80 individuals who had utilized the same swimming pool.¹ Due to its ability to secondarily contaminate aquariums, swimming pools, and rivers, this species can give rise to infection in humans, likely though an impaired skin barrier or points of trauma. It commonly is known as swimming pool or fish tank granuloma.^3,4

Infection by M marinum commonly presents with lesions on the upper extremities, particularly the hands, that appear approximately 2 to 3 weeks following exposure to the organism.² Lesions are categorized as superficial (type 1), granulomatous (type 2), or deep (type 3).¹ Superficial lesions usually are solitary and painless; may exhibit purulent secretions; and consist of papulonodular, verrucose, or ulcerated granulomatous inflammation.¹ These lesions may spread in a sporotrichoidlike pattern or in a linear fashion along lymphatic channels, similar to sporotrichosis. Granulomatous lesions present as solitary or numerous granulomas that typically are swollen, tender, and purulent. Deep lesions are the rarest form and primarily are seen in immunocompromised patients, particularly transplant recipients. Infection can lead to arthritis, tenosynovitis, or osteomyelitis.¹

Mycobacterium marinum infection is diagnosed via tissue biopsy for concomitant histopathologic examination and culture from a nonulcerated area close to the lesion.^1,2 If cultures do not grow, polymerase chain reaction (PCR) or PCR restriction fragment length polymorphism analysis can be conducted. These techniques can exclude other potential diagnoses; however, PCR is unable to provide information on antibiotic susceptibility.1 Biopsy of lesions reveals a nonspecific inflammatory type of reaction within the dermis consisting of lymphocytes, polymorphonuclear cells, and histiocytes.^1,4 Additionally, a granulomatous inflammatory infiltrate resembling tuberculoid granuloma, sarcoidlike granuloma, or rheumatoidlike nodules also may be observed.1 With staining, the acid-fast organisms can be viewed within histiocytes, sometimes demonstrating transverse bands.⁴

The preferred treatment of M marinum infection is antibiotic therapy.² It generally is not recommended to obtain in vitro drug sensitivity testing, as mutational resistance to the commonly utilized drugs is minimal. Microbiologic investigation may be warranted in cases of treatment failure or persistently positive cultures over a period of several months.^1,2 Due to its rarity, no clinical trials exist to guide optimal management of M marinum infection, according to a search of ClinicalTrials.gov. Nonetheless, anecdotal evidence of prior cases can direct the selection of antibiotics. Mycobacterium marinum appears to respond to certain tetracyclines, including minocycline followed by doxycycline. Other options include clarithromycin, clarithromycin in combination with rifampin, rifampin in combination with ethambutol, trimethoprimsulfamethoxazole, and ciprofloxacin.^1,2 Surgical debridement or excision may be indicated, especially in an infection involving deep structures, though recurrences have been reported in some individuals following surgery.^2,4 Nonspecific treatment such as hyperthermic or liquid nitrogen local treatment have been used experimentally with positive outcomes; however, experience with this treatment modality is limited.²

Sarcoidosis is an immune-mediated systemic disorder that most commonly affects the lungs and skin. Histopathology shows sarcoidal granulomas with features similar to M marinum infection. The clinical presentation often is described as red-brown macules or papules affecting the face, rarely with overlying scale or ulceration.⁵ Majocchi granuloma is a dermatophyte fungal infection involving the hair follicles. Although application of topical steroids can worsen the involvement, it commonly displays perifollicular pustules,⁶ which were not seen in our patient. Granuloma annulare is a benign granulomatous disorder that will spontaneously resolve, typically within 2 years of onset. It presents as an annular or arcuate red-brown papule or plaque without overlying scale or ulceration,⁷ unlike the lesion seen in our patient. Cutaneous lymphoma is a malignant lymphoproliferative disease most commonly affecting middle-aged White men. The presentation is variable and may include an ulcerated plaque⁸; the lack of systemic symptoms and notable progression over several years in our patient made this a less likely diagnosis.

The Diagnosis: Mycobacterial Infection

Mycobacterium marinum is a waterborne nontuberculous mycobacterium prevailing in salt water, brackish water, and still or streaming fresh water that infects fish and amphibians worldwide.^1,2 Although first described in 1926 as the organism responsible for the demise of fish in an aquarium in Philadelphia, Pennsylvania, it was not until 1954 that the organism was linked to the cause of infection in humans after it was identified in 80 individuals who had utilized the same swimming pool.¹ Due to its ability to secondarily contaminate aquariums, swimming pools, and rivers, this species can give rise to infection in humans, likely though an impaired skin barrier or points of trauma. It commonly is known as swimming pool or fish tank granuloma.^3,4

Infection by M marinum commonly presents with lesions on the upper extremities, particularly the hands, that appear approximately 2 to 3 weeks following exposure to the organism.² Lesions are categorized as superficial (type 1), granulomatous (type 2), or deep (type 3).¹ Superficial lesions usually are solitary and painless; may exhibit purulent secretions; and consist of papulonodular, verrucose, or ulcerated granulomatous inflammation.¹ These lesions may spread in a sporotrichoidlike pattern or in a linear fashion along lymphatic channels, similar to sporotrichosis. Granulomatous lesions present as solitary or numerous granulomas that typically are swollen, tender, and purulent. Deep lesions are the rarest form and primarily are seen in immunocompromised patients, particularly transplant recipients. Infection can lead to arthritis, tenosynovitis, or osteomyelitis.¹

Mycobacterium marinum infection is diagnosed via tissue biopsy for concomitant histopathologic examination and culture from a nonulcerated area close to the lesion.^1,2 If cultures do not grow, polymerase chain reaction (PCR) or PCR restriction fragment length polymorphism analysis can be conducted. These techniques can exclude other potential diagnoses; however, PCR is unable to provide information on antibiotic susceptibility.1 Biopsy of lesions reveals a nonspecific inflammatory type of reaction within the dermis consisting of lymphocytes, polymorphonuclear cells, and histiocytes.^1,4 Additionally, a granulomatous inflammatory infiltrate resembling tuberculoid granuloma, sarcoidlike granuloma, or rheumatoidlike nodules also may be observed.1 With staining, the acid-fast organisms can be viewed within histiocytes, sometimes demonstrating transverse bands.⁴

The preferred treatment of M marinum infection is antibiotic therapy.² It generally is not recommended to obtain in vitro drug sensitivity testing, as mutational resistance to the commonly utilized drugs is minimal. Microbiologic investigation may be warranted in cases of treatment failure or persistently positive cultures over a period of several months.^1,2 Due to its rarity, no clinical trials exist to guide optimal management of M marinum infection, according to a search of ClinicalTrials.gov. Nonetheless, anecdotal evidence of prior cases can direct the selection of antibiotics. Mycobacterium marinum appears to respond to certain tetracyclines, including minocycline followed by doxycycline. Other options include clarithromycin, clarithromycin in combination with rifampin, rifampin in combination with ethambutol, trimethoprimsulfamethoxazole, and ciprofloxacin.^1,2 Surgical debridement or excision may be indicated, especially in an infection involving deep structures, though recurrences have been reported in some individuals following surgery.^2,4 Nonspecific treatment such as hyperthermic or liquid nitrogen local treatment have been used experimentally with positive outcomes; however, experience with this treatment modality is limited.²

Sarcoidosis is an immune-mediated systemic disorder that most commonly affects the lungs and skin. Histopathology shows sarcoidal granulomas with features similar to M marinum infection. The clinical presentation often is described as red-brown macules or papules affecting the face, rarely with overlying scale or ulceration.⁵ Majocchi granuloma is a dermatophyte fungal infection involving the hair follicles. Although application of topical steroids can worsen the involvement, it commonly displays perifollicular pustules,⁶ which were not seen in our patient. Granuloma annulare is a benign granulomatous disorder that will spontaneously resolve, typically within 2 years of onset. It presents as an annular or arcuate red-brown papule or plaque without overlying scale or ulceration,⁷ unlike the lesion seen in our patient. Cutaneous lymphoma is a malignant lymphoproliferative disease most commonly affecting middle-aged White men. The presentation is variable and may include an ulcerated plaque⁸; the lack of systemic symptoms and notable progression over several years in our patient made this a less likely diagnosis.

The Diagnosis: Mycobacterial Infection

Mycobacterium marinum is a waterborne nontuberculous mycobacterium prevailing in salt water, brackish water, and still or streaming fresh water that infects fish and amphibians worldwide.^1,2 Although first described in 1926 as the organism responsible for the demise of fish in an aquarium in Philadelphia, Pennsylvania, it was not until 1954 that the organism was linked to the cause of infection in humans after it was identified in 80 individuals who had utilized the same swimming pool.¹ Due to its ability to secondarily contaminate aquariums, swimming pools, and rivers, this species can give rise to infection in humans, likely though an impaired skin barrier or points of trauma. It commonly is known as swimming pool or fish tank granuloma.^3,4

Infection by M marinum commonly presents with lesions on the upper extremities, particularly the hands, that appear approximately 2 to 3 weeks following exposure to the organism.² Lesions are categorized as superficial (type 1), granulomatous (type 2), or deep (type 3).¹ Superficial lesions usually are solitary and painless; may exhibit purulent secretions; and consist of papulonodular, verrucose, or ulcerated granulomatous inflammation.¹ These lesions may spread in a sporotrichoidlike pattern or in a linear fashion along lymphatic channels, similar to sporotrichosis. Granulomatous lesions present as solitary or numerous granulomas that typically are swollen, tender, and purulent. Deep lesions are the rarest form and primarily are seen in immunocompromised patients, particularly transplant recipients. Infection can lead to arthritis, tenosynovitis, or osteomyelitis.¹

Mycobacterium marinum infection is diagnosed via tissue biopsy for concomitant histopathologic examination and culture from a nonulcerated area close to the lesion.^1,2 If cultures do not grow, polymerase chain reaction (PCR) or PCR restriction fragment length polymorphism analysis can be conducted. These techniques can exclude other potential diagnoses; however, PCR is unable to provide information on antibiotic susceptibility.1 Biopsy of lesions reveals a nonspecific inflammatory type of reaction within the dermis consisting of lymphocytes, polymorphonuclear cells, and histiocytes.^1,4 Additionally, a granulomatous inflammatory infiltrate resembling tuberculoid granuloma, sarcoidlike granuloma, or rheumatoidlike nodules also may be observed.1 With staining, the acid-fast organisms can be viewed within histiocytes, sometimes demonstrating transverse bands.⁴

The preferred treatment of M marinum infection is antibiotic therapy.² It generally is not recommended to obtain in vitro drug sensitivity testing, as mutational resistance to the commonly utilized drugs is minimal. Microbiologic investigation may be warranted in cases of treatment failure or persistently positive cultures over a period of several months.^1,2 Due to its rarity, no clinical trials exist to guide optimal management of M marinum infection, according to a search of ClinicalTrials.gov. Nonetheless, anecdotal evidence of prior cases can direct the selection of antibiotics. Mycobacterium marinum appears to respond to certain tetracyclines, including minocycline followed by doxycycline. Other options include clarithromycin, clarithromycin in combination with rifampin, rifampin in combination with ethambutol, trimethoprimsulfamethoxazole, and ciprofloxacin.^1,2 Surgical debridement or excision may be indicated, especially in an infection involving deep structures, though recurrences have been reported in some individuals following surgery.^2,4 Nonspecific treatment such as hyperthermic or liquid nitrogen local treatment have been used experimentally with positive outcomes; however, experience with this treatment modality is limited.²

Sarcoidosis is an immune-mediated systemic disorder that most commonly affects the lungs and skin. Histopathology shows sarcoidal granulomas with features similar to M marinum infection. The clinical presentation often is described as red-brown macules or papules affecting the face, rarely with overlying scale or ulceration.⁵ Majocchi granuloma is a dermatophyte fungal infection involving the hair follicles. Although application of topical steroids can worsen the involvement, it commonly displays perifollicular pustules,⁶ which were not seen in our patient. Granuloma annulare is a benign granulomatous disorder that will spontaneously resolve, typically within 2 years of onset. It presents as an annular or arcuate red-brown papule or plaque without overlying scale or ulceration,⁷ unlike the lesion seen in our patient. Cutaneous lymphoma is a malignant lymphoproliferative disease most commonly affecting middle-aged White men. The presentation is variable and may include an ulcerated plaque⁸; the lack of systemic symptoms and notable progression over several years in our patient made this a less likely diagnosis.

To the Editor:

Palifermin is a recombinant keratinocyte growth factor (KGF) approved by the US Food and Drug Administration to prevent oral mucositis following radiation therapy or chemotherapy. Cutaneous reactions associated with palifermin have been reported.^1-5 One case described a distinctive polymorphous eruption in a patient treated with palifermin.⁶ On histologic analysis, papules demonstrated findings similar to verrucae, with evidence of papillomatosis, hypergranulosis, and hyperorthokeratosis. Given its mechanism of action as a KGF, it was concluded that these findings were likely the direct result of palifermin.⁶ We report a similar case of a patient who was given palifermin prior to an autologous stem cell transplant. Histopathologic analysis confirmed epidermal dysmaturation and marked hypergranulosis. We present this case to expand the paucity of data on palifermin-associated cutaneous reactions.

A 63-year-old man with a history of psoriasis, eczema, and relapsed diffuse large B-cell lymphoma was admitted to the hospital for routine management of an autologous stem cell transplant with a conditioning regimen involving thiotepa, busulfan, and cyclophosphamide. The patient had completed a 3-day course of palifermin 1 day prior to the current presentation. On admission, he developed a pruritic erythematous rash over the face and axillae. Within 24 hours, the facial rash progressed with appreciable edema, and he reported difficulty opening his eyes. He denied any fever, nausea, vomiting, diarrhea, or increased fatigue. He also denied use of any other medications other than starting a course of prophylactic trimethoprim-sulfamethoxazole 3 times weekly 2 months prior to admission.

Diffuse blanching erythema with a well-demarcated linear border was noted along the lower anterior neck extending to the posterior hairline. There was notable edema but no evidence of pustules or overlying scale. Similar areas of blanchable erythema were present along the axillae and inguinal folds. There also were flesh-colored to pink papules within the axillary vaults and on the back that occasionally coalesced into plaques. There was no involvement of the mucous membranes or acral sites.

A complete blood cell count with differential and a comprehensive metabolic profile largely were unremarkable. A potassium hydroxide preparation of the face and groin was negative for hyphae and Demodex mites. Histopathologic analysis from a punch biopsy of a representative papule from the posterior neck demonstrated epidermal dysmaturation with marked thickening of the granular cell layer with notably large keratohyalin granules (Figure 1).

In the setting of treatment with thiotepa, we recommended supportive care with cool compresses rather than topical medication because he was neutropenic, and we wanted to avoid further immunosuppression or toxicity. By 24 hours after completing the course of palifermin, the patient experienced complete resolution of the rash. At his request, the trial of palifermin was restarted 10 days into conditioning therapy. A similar rash with less facial edema but more prominent involvement of the chest appeared 3 days into the retrial (Figure 2). The medication was discontinued, which resulted in resolution of the rash. Again, the patient remained afebrile without involvement of the mucous membranes. Liver enzyme and creatinine levels remained within reference range.Eosinophilia and the level of atypical lymphocytes could not be assessed because of leukopenia in the setting of recent chemotherapy. The rash self-resolved in 4 days.

Palifermin is a recombinant form of human KGF that is more stable than the endogenous form but retains all vital properties of the protein.^5-7 Similar to other growth factors, KGF induces differentiation, proliferation, and migration of cells in vivo.⁸ However, it uniquely produces a targeted effect on epithelial cells in the skin, oral mucosa, lungs, gastrointestinal tract, and genitourinary system.^7-9

Palifermin was approved by the US Food and Drug Administration in 2004 for the prevention and treatment of severe oral mucositis in patients receiving myelotoxic therapy prior to stem cell transplantation.^7,9 Severe mucositis occurs in approximately 70% to 80% of patients receiving radiation or chemotherapy-based conditioning treatments.^4,7 Compared to placebo, palifermin has been shown to greatly reduce the incidence of Grade 4 oral mucositis, defined as severe enough to prevent alimentation.¹⁰

The proliferative effect of palifermin on the oral mucosa is beneficial to patients but likely is the driving force behind its cutaneous adverse effects. A nonspecific rash is the most commonly cited treatment-related adverse event associated with palifermin, occurring in approximately 62% of patients.^5,7,9

Our case is a rare report of a palifermin-associated cutaneous reaction. Previous cases have cited the occurrence of palmoplantar erythrodysesthesias, papulopustular eruptions involving the face and chest, and a papular rash involving the dorsal hands and intertriginous areas.^1-4 Another report documented a “mild rash” but failed to further characterize the morphology or the body site involved.⁵

In 2009, King et al⁶ reported the occurrence of a lichen planus–like eruption involving the intertriginous regions and of white oral plaques in a patient treated with palifermin. Hematoxylin and eosin staining of a representative lesion in that patient demonstrated an appearance similar to that of verrucae, including papillomatosis, hypergranulosis, and hyperorthokeratosis.

King et al⁶ expanded analysis of the reaction to include immunohistochemical study, using targeted antibody stains for cytokeratin 5/6 and Ki-67 protein. Staining with Ki-67 showed dramatically increased activity within basilar and suprabasilar keratinocytes in a biopsy taken at the height of the reaction. Biopsy specimens obtained when the eruption was clinically resolving—2 days after the first biopsy—showed decreased Ki-67 staining. These findings taken together suggest a direct causal effect of palifermin inducing hyperkeratotic changes appreciated on examination of treated patients.⁶

We present this case to add to current data regarding palifermin-induced cutaneous changes. Unique to our patient was a strikingly well-demarcated rash confined to the head and neck. Although a photosensitive eruption due to trimethoprim-sulfamethoxazole is conceivable, the fixed time course of the eruption—corresponding to (1) initiation and discontinuation of palifermin and (2) histologic findings—led us to conclude that this self-limited eruption likely was due to palifermin.

To the Editor:

Palifermin is a recombinant keratinocyte growth factor (KGF) approved by the US Food and Drug Administration to prevent oral mucositis following radiation therapy or chemotherapy. Cutaneous reactions associated with palifermin have been reported.^1-5 One case described a distinctive polymorphous eruption in a patient treated with palifermin.⁶ On histologic analysis, papules demonstrated findings similar to verrucae, with evidence of papillomatosis, hypergranulosis, and hyperorthokeratosis. Given its mechanism of action as a KGF, it was concluded that these findings were likely the direct result of palifermin.⁶ We report a similar case of a patient who was given palifermin prior to an autologous stem cell transplant. Histopathologic analysis confirmed epidermal dysmaturation and marked hypergranulosis. We present this case to expand the paucity of data on palifermin-associated cutaneous reactions.

A 63-year-old man with a history of psoriasis, eczema, and relapsed diffuse large B-cell lymphoma was admitted to the hospital for routine management of an autologous stem cell transplant with a conditioning regimen involving thiotepa, busulfan, and cyclophosphamide. The patient had completed a 3-day course of palifermin 1 day prior to the current presentation. On admission, he developed a pruritic erythematous rash over the face and axillae. Within 24 hours, the facial rash progressed with appreciable edema, and he reported difficulty opening his eyes. He denied any fever, nausea, vomiting, diarrhea, or increased fatigue. He also denied use of any other medications other than starting a course of prophylactic trimethoprim-sulfamethoxazole 3 times weekly 2 months prior to admission.

Diffuse blanching erythema with a well-demarcated linear border was noted along the lower anterior neck extending to the posterior hairline. There was notable edema but no evidence of pustules or overlying scale. Similar areas of blanchable erythema were present along the axillae and inguinal folds. There also were flesh-colored to pink papules within the axillary vaults and on the back that occasionally coalesced into plaques. There was no involvement of the mucous membranes or acral sites.

A complete blood cell count with differential and a comprehensive metabolic profile largely were unremarkable. A potassium hydroxide preparation of the face and groin was negative for hyphae and Demodex mites. Histopathologic analysis from a punch biopsy of a representative papule from the posterior neck demonstrated epidermal dysmaturation with marked thickening of the granular cell layer with notably large keratohyalin granules (Figure 1).

In the setting of treatment with thiotepa, we recommended supportive care with cool compresses rather than topical medication because he was neutropenic, and we wanted to avoid further immunosuppression or toxicity. By 24 hours after completing the course of palifermin, the patient experienced complete resolution of the rash. At his request, the trial of palifermin was restarted 10 days into conditioning therapy. A similar rash with less facial edema but more prominent involvement of the chest appeared 3 days into the retrial (Figure 2). The medication was discontinued, which resulted in resolution of the rash. Again, the patient remained afebrile without involvement of the mucous membranes. Liver enzyme and creatinine levels remained within reference range.Eosinophilia and the level of atypical lymphocytes could not be assessed because of leukopenia in the setting of recent chemotherapy. The rash self-resolved in 4 days.

Palifermin is a recombinant form of human KGF that is more stable than the endogenous form but retains all vital properties of the protein.^5-7 Similar to other growth factors, KGF induces differentiation, proliferation, and migration of cells in vivo.⁸ However, it uniquely produces a targeted effect on epithelial cells in the skin, oral mucosa, lungs, gastrointestinal tract, and genitourinary system.^7-9

Palifermin was approved by the US Food and Drug Administration in 2004 for the prevention and treatment of severe oral mucositis in patients receiving myelotoxic therapy prior to stem cell transplantation.^7,9 Severe mucositis occurs in approximately 70% to 80% of patients receiving radiation or chemotherapy-based conditioning treatments.^4,7 Compared to placebo, palifermin has been shown to greatly reduce the incidence of Grade 4 oral mucositis, defined as severe enough to prevent alimentation.¹⁰

The proliferative effect of palifermin on the oral mucosa is beneficial to patients but likely is the driving force behind its cutaneous adverse effects. A nonspecific rash is the most commonly cited treatment-related adverse event associated with palifermin, occurring in approximately 62% of patients.^5,7,9

Our case is a rare report of a palifermin-associated cutaneous reaction. Previous cases have cited the occurrence of palmoplantar erythrodysesthesias, papulopustular eruptions involving the face and chest, and a papular rash involving the dorsal hands and intertriginous areas.^1-4 Another report documented a “mild rash” but failed to further characterize the morphology or the body site involved.⁵

In 2009, King et al⁶ reported the occurrence of a lichen planus–like eruption involving the intertriginous regions and of white oral plaques in a patient treated with palifermin. Hematoxylin and eosin staining of a representative lesion in that patient demonstrated an appearance similar to that of verrucae, including papillomatosis, hypergranulosis, and hyperorthokeratosis.

King et al⁶ expanded analysis of the reaction to include immunohistochemical study, using targeted antibody stains for cytokeratin 5/6 and Ki-67 protein. Staining with Ki-67 showed dramatically increased activity within basilar and suprabasilar keratinocytes in a biopsy taken at the height of the reaction. Biopsy specimens obtained when the eruption was clinically resolving—2 days after the first biopsy—showed decreased Ki-67 staining. These findings taken together suggest a direct causal effect of palifermin inducing hyperkeratotic changes appreciated on examination of treated patients.⁶

We present this case to add to current data regarding palifermin-induced cutaneous changes. Unique to our patient was a strikingly well-demarcated rash confined to the head and neck. Although a photosensitive eruption due to trimethoprim-sulfamethoxazole is conceivable, the fixed time course of the eruption—corresponding to (1) initiation and discontinuation of palifermin and (2) histologic findings—led us to conclude that this self-limited eruption likely was due to palifermin.

To the Editor:

Palifermin is a recombinant keratinocyte growth factor (KGF) approved by the US Food and Drug Administration to prevent oral mucositis following radiation therapy or chemotherapy. Cutaneous reactions associated with palifermin have been reported.^1-5 One case described a distinctive polymorphous eruption in a patient treated with palifermin.⁶ On histologic analysis, papules demonstrated findings similar to verrucae, with evidence of papillomatosis, hypergranulosis, and hyperorthokeratosis. Given its mechanism of action as a KGF, it was concluded that these findings were likely the direct result of palifermin.⁶ We report a similar case of a patient who was given palifermin prior to an autologous stem cell transplant. Histopathologic analysis confirmed epidermal dysmaturation and marked hypergranulosis. We present this case to expand the paucity of data on palifermin-associated cutaneous reactions.

A 63-year-old man with a history of psoriasis, eczema, and relapsed diffuse large B-cell lymphoma was admitted to the hospital for routine management of an autologous stem cell transplant with a conditioning regimen involving thiotepa, busulfan, and cyclophosphamide. The patient had completed a 3-day course of palifermin 1 day prior to the current presentation. On admission, he developed a pruritic erythematous rash over the face and axillae. Within 24 hours, the facial rash progressed with appreciable edema, and he reported difficulty opening his eyes. He denied any fever, nausea, vomiting, diarrhea, or increased fatigue. He also denied use of any other medications other than starting a course of prophylactic trimethoprim-sulfamethoxazole 3 times weekly 2 months prior to admission.

Diffuse blanching erythema with a well-demarcated linear border was noted along the lower anterior neck extending to the posterior hairline. There was notable edema but no evidence of pustules or overlying scale. Similar areas of blanchable erythema were present along the axillae and inguinal folds. There also were flesh-colored to pink papules within the axillary vaults and on the back that occasionally coalesced into plaques. There was no involvement of the mucous membranes or acral sites.

A complete blood cell count with differential and a comprehensive metabolic profile largely were unremarkable. A potassium hydroxide preparation of the face and groin was negative for hyphae and Demodex mites. Histopathologic analysis from a punch biopsy of a representative papule from the posterior neck demonstrated epidermal dysmaturation with marked thickening of the granular cell layer with notably large keratohyalin granules (Figure 1).

In the setting of treatment with thiotepa, we recommended supportive care with cool compresses rather than topical medication because he was neutropenic, and we wanted to avoid further immunosuppression or toxicity. By 24 hours after completing the course of palifermin, the patient experienced complete resolution of the rash. At his request, the trial of palifermin was restarted 10 days into conditioning therapy. A similar rash with less facial edema but more prominent involvement of the chest appeared 3 days into the retrial (Figure 2). The medication was discontinued, which resulted in resolution of the rash. Again, the patient remained afebrile without involvement of the mucous membranes. Liver enzyme and creatinine levels remained within reference range.Eosinophilia and the level of atypical lymphocytes could not be assessed because of leukopenia in the setting of recent chemotherapy. The rash self-resolved in 4 days.

Palifermin is a recombinant form of human KGF that is more stable than the endogenous form but retains all vital properties of the protein.^5-7 Similar to other growth factors, KGF induces differentiation, proliferation, and migration of cells in vivo.⁸ However, it uniquely produces a targeted effect on epithelial cells in the skin, oral mucosa, lungs, gastrointestinal tract, and genitourinary system.^7-9

Palifermin was approved by the US Food and Drug Administration in 2004 for the prevention and treatment of severe oral mucositis in patients receiving myelotoxic therapy prior to stem cell transplantation.^7,9 Severe mucositis occurs in approximately 70% to 80% of patients receiving radiation or chemotherapy-based conditioning treatments.^4,7 Compared to placebo, palifermin has been shown to greatly reduce the incidence of Grade 4 oral mucositis, defined as severe enough to prevent alimentation.¹⁰

The proliferative effect of palifermin on the oral mucosa is beneficial to patients but likely is the driving force behind its cutaneous adverse effects. A nonspecific rash is the most commonly cited treatment-related adverse event associated with palifermin, occurring in approximately 62% of patients.^5,7,9

Our case is a rare report of a palifermin-associated cutaneous reaction. Previous cases have cited the occurrence of palmoplantar erythrodysesthesias, papulopustular eruptions involving the face and chest, and a papular rash involving the dorsal hands and intertriginous areas.^1-4 Another report documented a “mild rash” but failed to further characterize the morphology or the body site involved.⁵

In 2009, King et al⁶ reported the occurrence of a lichen planus–like eruption involving the intertriginous regions and of white oral plaques in a patient treated with palifermin. Hematoxylin and eosin staining of a representative lesion in that patient demonstrated an appearance similar to that of verrucae, including papillomatosis, hypergranulosis, and hyperorthokeratosis.

King et al⁶ expanded analysis of the reaction to include immunohistochemical study, using targeted antibody stains for cytokeratin 5/6 and Ki-67 protein. Staining with Ki-67 showed dramatically increased activity within basilar and suprabasilar keratinocytes in a biopsy taken at the height of the reaction. Biopsy specimens obtained when the eruption was clinically resolving—2 days after the first biopsy—showed decreased Ki-67 staining. These findings taken together suggest a direct causal effect of palifermin inducing hyperkeratotic changes appreciated on examination of treated patients.⁶

We present this case to add to current data regarding palifermin-induced cutaneous changes. Unique to our patient was a strikingly well-demarcated rash confined to the head and neck. Although a photosensitive eruption due to trimethoprim-sulfamethoxazole is conceivable, the fixed time course of the eruption—corresponding to (1) initiation and discontinuation of palifermin and (2) histologic findings—led us to conclude that this self-limited eruption likely was due to palifermin.

Although it’s easy to jump to the conclusion that facial erythema is rosacea, there are multiple other conditions that can lead to reddening of the face. In this case, excessive sun exposure had resulted in a diffuse actinic change of the malar and lateral aspects of this patient’s face. The palpably rough lesions were actinic keratoses.

Actinic keratoses are caused by exposure to ultraviolet radiation. These lesions are premalignant and common. Areas of the body at greatest risk include those not typically covered by clothing (eg, face, hands, arms, ears, forehead, and top of the scalp—especially in individuals with hair loss). There is a range of estimates regarding the percentage of actinic keratoses that will progress to squamous cell carcinoma in situ, and then invasive squamous cell carcinoma. One study determined that 10% of actinic keratoses progress to squamous cell carcinoma over the course of 2 years.¹

In patients with broad areas of multiple clinically palpable lesions with rough sandpapery texture or visible white scale, there are likely preclinical lesions in the same areas. With so many lesions, field therapy of the entire region is often performed instead of treating the lesions 1 at a time.

There are multiple topical agents for field therapy, including 5-fluorouracil, diclofenac gel, and imiquimod gel.² Since significant erythema and inflammation usually follow application of the topical agent, clinicians may want to have patients treat in segments to make the process more tolerable.

5-fluorouracil has a complete clearance rate (CCR) of 75% to 90% and is usually applied twice daily for 2 weeks, although there are multiple different protocols. Diclofenac has a CCR of 58% over a 60- to 90-day course, and imiquimod has a CCR of 54% after a 120-day course. Photodynamic therapy (PDT) has the advantage of a single treatment but a CCR of 38%. PDT may be advantageous for a patient who has difficulty applying topical medication over a period of weeks.

Niacinamide has been shown to help with skin repair and reduce the risk of additional nonmelanoma skin cancers (NMSC) by 23% and additional actinic keratoses by about 15% in individuals with a history of actinic keratoses or NMSC.³ In contrast to niacin, niacinamide does not cause flushing. Niacinamide is used long term; if discontinued, it no longer confers benefit in helping the skin repair itself.

The patient in this case was prescribed topical 5% fluorouracil cream to be applied twice daily to the malar regions bilaterally for 2 weeks and, if not inflamed by 2 weeks, to extend the treatment until there is robust inflammation (but not to exceed 3 weeks). He was scheduled to follow up in 3 months for reexamination. He was also advised to start taking niacinamide 500 mg twice daily to reduce his risk of additional precancerous and cancerous skin lesions and counseled on the importance of sunscreen, hats, and sun-protective clothing.

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

Although it’s easy to jump to the conclusion that facial erythema is rosacea, there are multiple other conditions that can lead to reddening of the face. In this case, excessive sun exposure had resulted in a diffuse actinic change of the malar and lateral aspects of this patient’s face. The palpably rough lesions were actinic keratoses.

Actinic keratoses are caused by exposure to ultraviolet radiation. These lesions are premalignant and common. Areas of the body at greatest risk include those not typically covered by clothing (eg, face, hands, arms, ears, forehead, and top of the scalp—especially in individuals with hair loss). There is a range of estimates regarding the percentage of actinic keratoses that will progress to squamous cell carcinoma in situ, and then invasive squamous cell carcinoma. One study determined that 10% of actinic keratoses progress to squamous cell carcinoma over the course of 2 years.¹

In patients with broad areas of multiple clinically palpable lesions with rough sandpapery texture or visible white scale, there are likely preclinical lesions in the same areas. With so many lesions, field therapy of the entire region is often performed instead of treating the lesions 1 at a time.

There are multiple topical agents for field therapy, including 5-fluorouracil, diclofenac gel, and imiquimod gel.² Since significant erythema and inflammation usually follow application of the topical agent, clinicians may want to have patients treat in segments to make the process more tolerable.

5-fluorouracil has a complete clearance rate (CCR) of 75% to 90% and is usually applied twice daily for 2 weeks, although there are multiple different protocols. Diclofenac has a CCR of 58% over a 60- to 90-day course, and imiquimod has a CCR of 54% after a 120-day course. Photodynamic therapy (PDT) has the advantage of a single treatment but a CCR of 38%. PDT may be advantageous for a patient who has difficulty applying topical medication over a period of weeks.

Niacinamide has been shown to help with skin repair and reduce the risk of additional nonmelanoma skin cancers (NMSC) by 23% and additional actinic keratoses by about 15% in individuals with a history of actinic keratoses or NMSC.³ In contrast to niacin, niacinamide does not cause flushing. Niacinamide is used long term; if discontinued, it no longer confers benefit in helping the skin repair itself.

The patient in this case was prescribed topical 5% fluorouracil cream to be applied twice daily to the malar regions bilaterally for 2 weeks and, if not inflamed by 2 weeks, to extend the treatment until there is robust inflammation (but not to exceed 3 weeks). He was scheduled to follow up in 3 months for reexamination. He was also advised to start taking niacinamide 500 mg twice daily to reduce his risk of additional precancerous and cancerous skin lesions and counseled on the importance of sunscreen, hats, and sun-protective clothing.

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

Although it’s easy to jump to the conclusion that facial erythema is rosacea, there are multiple other conditions that can lead to reddening of the face. In this case, excessive sun exposure had resulted in a diffuse actinic change of the malar and lateral aspects of this patient’s face. The palpably rough lesions were actinic keratoses.

Actinic keratoses are caused by exposure to ultraviolet radiation. These lesions are premalignant and common. Areas of the body at greatest risk include those not typically covered by clothing (eg, face, hands, arms, ears, forehead, and top of the scalp—especially in individuals with hair loss). There is a range of estimates regarding the percentage of actinic keratoses that will progress to squamous cell carcinoma in situ, and then invasive squamous cell carcinoma. One study determined that 10% of actinic keratoses progress to squamous cell carcinoma over the course of 2 years.¹

In patients with broad areas of multiple clinically palpable lesions with rough sandpapery texture or visible white scale, there are likely preclinical lesions in the same areas. With so many lesions, field therapy of the entire region is often performed instead of treating the lesions 1 at a time.

There are multiple topical agents for field therapy, including 5-fluorouracil, diclofenac gel, and imiquimod gel.² Since significant erythema and inflammation usually follow application of the topical agent, clinicians may want to have patients treat in segments to make the process more tolerable.

5-fluorouracil has a complete clearance rate (CCR) of 75% to 90% and is usually applied twice daily for 2 weeks, although there are multiple different protocols. Diclofenac has a CCR of 58% over a 60- to 90-day course, and imiquimod has a CCR of 54% after a 120-day course. Photodynamic therapy (PDT) has the advantage of a single treatment but a CCR of 38%. PDT may be advantageous for a patient who has difficulty applying topical medication over a period of weeks.

Niacinamide has been shown to help with skin repair and reduce the risk of additional nonmelanoma skin cancers (NMSC) by 23% and additional actinic keratoses by about 15% in individuals with a history of actinic keratoses or NMSC.³ In contrast to niacin, niacinamide does not cause flushing. Niacinamide is used long term; if discontinued, it no longer confers benefit in helping the skin repair itself.

The patient in this case was prescribed topical 5% fluorouracil cream to be applied twice daily to the malar regions bilaterally for 2 weeks and, if not inflamed by 2 weeks, to extend the treatment until there is robust inflammation (but not to exceed 3 weeks). He was scheduled to follow up in 3 months for reexamination. He was also advised to start taking niacinamide 500 mg twice daily to reduce his risk of additional precancerous and cancerous skin lesions and counseled on the importance of sunscreen, hats, and sun-protective clothing.

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

The treatment landscape of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) has been transformed over the past decade with the advent of targeted therapies, including Bruton tyrosine kinase (BTK) inhibitors. Covalent BTK inhibitors, which are available in both the frontline and relapsed/refractory settings, include ibrutinib, acalabrutinib, and zanubrutinib.^1-3

BTK inhibitors have also demonstrated activity in higher-risk subgroups, including patients harboring TP53 aberrations. Clinical trials have shown encouraging outcomes of BTK inhibitors in these patients, and real-world studies have demonstrated similar findings.^4-6 Recently, a real-world Italian registry study similarly showed favorable outcomes in 747 patients with CLL carrying 17p- or TP53 or both mutations treated with first-line ibrutinib. in what appears to be the largest real-world analysis of this patient population (Rigolin et al). At 24 months, the median overall survival was not reached; the estimated treatment persistence and survival rates were 63.4% (95% CI 60.0%-67.0%) and 82.6% (95% CI 79.9%-85.4%), respectively. The median time to treatment discontinuation was 37.4 months (95% CI 34.8-42.2 months). Disease progression or death was the reason for discontinuation in 45.8% of patients. Although ibrutinib is not generally the favored BTK inhibitor given an improved safety profile with next-generation options, these data provide real-world estimates for outcomes with BTK inhibitors in this large dataset of high-risk patients.

Although outcomes have improved for patients with CLL or SLL, it is common for resistance to targeted therapy to eventually occur. Noncovalent BTK inhibitors, such as pirtobrutinib, offer a promising approach for this population. The BRUIN trial was a phase 1/2 trial of pirtobrutinib in patients with relapsed/refractory CLL or SLL (Mato et al). A total of 317 patients were treated, including 247 who had previously received a BTK inhibitor. Patients had been treated with a median of three prior lines of therapy and over 40% had been treated with a BCL-2 inhibitor. The overall response rate was 73.3% (95% CI 67.3%-78.7%) and increased to 82.2% (95% CI 76.8%-86.7%) when partial response with lymphocytosis was included. At a 19.4-month median follow-up, the median progression-free survival was 19.6 (95% CI 16.9-22.1) months. The drug was also well-tolerated, with 2.8% of patients discontinuing therapy owing to treatment-related adverse events. Adverse events that can be seen with BTK inhibition, including hypertension, atrial fibrillation or flutter, and bleeding, were rare. This trial demonstrates that CLL/SLL cells can maintain dependency on the B-cell receptor pathway following treatment with a covalent inhibitor and that ongoing BTK inhibition using a novel mechanism is a feasible strategy. The optimal sequencing of pirtobrutinib with other available therapies, including BCL-2 inhibitors, remains unknown.

BTK inhibitors are also active in mantle cell lymphoma (MCL). They are approved for relapsed/refractory disease and are being studied in earlier lines of therapy. Whereas early progression of disease (POD) has been shown to be an important prognostic marker in MCL, the impact of early relapse on outcome specifically after BTK inhibitor initiation is less clear.⁷ A recent multicente retrospective observational study aimed to determine the impact on time-to-POD between rituximab-containing front-line therapy and second-line BTK inhibitor and overall outcomes (Villa et al). This study included 360 adult patients with relapsed or refractory MCL treated with second-line BTK inhibitor. Not surprisingly, the authors found that patients with POD within 24 months of first-line therapy had significantly shorter median progression-free survival (0.45 year vs 2.3 years; P < .001) and overall survival (0.9 year vs 5.5 years P < .001) compared with patients with relapse beyond 24 months. Furthermore, they found that Ki-67 ≥ 30% and Mantle Cell Lymphoma International Prognostic Index (MIPI) were also associated with progression‐free survival and overall survival from the start of a second-line BTK inhibitor, though to a lesser extent than time-to-POD. These variables were subsequently used to determine a second-line BTK MIPI, which can help inform which patients are most likely to benefit from a BTK inhibitor compared with other available options, such as chimeric antigen receptor (CAR) T-cell therapy or a clinical trial strategy.

BTK inhibitors are an important drug class for the treatment of lymphoid cancers and have changed the treatment paradigms in CLL/SLL and MCL. Additional studies evaluating combination strategies, sequencing approaches, time-limited options, and predictors of response are likely to further refine optimization of use in these diseases.

Additional References

1.         Barr PM, Owen C, Robak T, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6:3440-3450. doi:10.1182/bloodadvances.2021006434

2.         Sharman JP, Egyed M, Jurczak W, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naive chronic lymphocytic leukemia. Leukemia. 2022;36:1171-1175. doi:10.1038/s41375-021-01485-x

3.         Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23:1031-1043. doi:10.1016/S1470-2045(22)00293-5

4.         Ahn IE, Tian X, Wiestner A. Ibrutinib for chronic lymphocytic leukemia with TP53 alterations. N Engl J Med. 2020;383:498-500. doi:10.1056/NEJMc2005943

5.         Allan JN, Shanafelt T, Wiestner A, et al. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials. Br J Haematol. 2022;196:947-953. doi:10.1111/bjh.17984

6.         Mato AR, Tang B, Azmi S, et al. A clinical practice comparison of patients with chronic lymphocytic leukemia with and without deletion 17p receiving first-line treatment with ibrutinib. Haematologica. 2022;107:2630-2640. doi:10.3324/haematol.2021.280376

7.         Bond DA, Switchenko JM, Villa D, et al. Early relapse identifies MCL patients with inferior survival after intensive or less intensive frontline therapy. Blood Adv. 2021;5:5179-5189. doi:10.1182/bloodadvances.2021004765

The treatment landscape of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) has been transformed over the past decade with the advent of targeted therapies, including Bruton tyrosine kinase (BTK) inhibitors. Covalent BTK inhibitors, which are available in both the frontline and relapsed/refractory settings, include ibrutinib, acalabrutinib, and zanubrutinib.^1-3

BTK inhibitors have also demonstrated activity in higher-risk subgroups, including patients harboring TP53 aberrations. Clinical trials have shown encouraging outcomes of BTK inhibitors in these patients, and real-world studies have demonstrated similar findings.^4-6 Recently, a real-world Italian registry study similarly showed favorable outcomes in 747 patients with CLL carrying 17p- or TP53 or both mutations treated with first-line ibrutinib. in what appears to be the largest real-world analysis of this patient population (Rigolin et al). At 24 months, the median overall survival was not reached; the estimated treatment persistence and survival rates were 63.4% (95% CI 60.0%-67.0%) and 82.6% (95% CI 79.9%-85.4%), respectively. The median time to treatment discontinuation was 37.4 months (95% CI 34.8-42.2 months). Disease progression or death was the reason for discontinuation in 45.8% of patients. Although ibrutinib is not generally the favored BTK inhibitor given an improved safety profile with next-generation options, these data provide real-world estimates for outcomes with BTK inhibitors in this large dataset of high-risk patients.

Although outcomes have improved for patients with CLL or SLL, it is common for resistance to targeted therapy to eventually occur. Noncovalent BTK inhibitors, such as pirtobrutinib, offer a promising approach for this population. The BRUIN trial was a phase 1/2 trial of pirtobrutinib in patients with relapsed/refractory CLL or SLL (Mato et al). A total of 317 patients were treated, including 247 who had previously received a BTK inhibitor. Patients had been treated with a median of three prior lines of therapy and over 40% had been treated with a BCL-2 inhibitor. The overall response rate was 73.3% (95% CI 67.3%-78.7%) and increased to 82.2% (95% CI 76.8%-86.7%) when partial response with lymphocytosis was included. At a 19.4-month median follow-up, the median progression-free survival was 19.6 (95% CI 16.9-22.1) months. The drug was also well-tolerated, with 2.8% of patients discontinuing therapy owing to treatment-related adverse events. Adverse events that can be seen with BTK inhibition, including hypertension, atrial fibrillation or flutter, and bleeding, were rare. This trial demonstrates that CLL/SLL cells can maintain dependency on the B-cell receptor pathway following treatment with a covalent inhibitor and that ongoing BTK inhibition using a novel mechanism is a feasible strategy. The optimal sequencing of pirtobrutinib with other available therapies, including BCL-2 inhibitors, remains unknown.

BTK inhibitors are also active in mantle cell lymphoma (MCL). They are approved for relapsed/refractory disease and are being studied in earlier lines of therapy. Whereas early progression of disease (POD) has been shown to be an important prognostic marker in MCL, the impact of early relapse on outcome specifically after BTK inhibitor initiation is less clear.⁷ A recent multicente retrospective observational study aimed to determine the impact on time-to-POD between rituximab-containing front-line therapy and second-line BTK inhibitor and overall outcomes (Villa et al). This study included 360 adult patients with relapsed or refractory MCL treated with second-line BTK inhibitor. Not surprisingly, the authors found that patients with POD within 24 months of first-line therapy had significantly shorter median progression-free survival (0.45 year vs 2.3 years; P < .001) and overall survival (0.9 year vs 5.5 years P < .001) compared with patients with relapse beyond 24 months. Furthermore, they found that Ki-67 ≥ 30% and Mantle Cell Lymphoma International Prognostic Index (MIPI) were also associated with progression‐free survival and overall survival from the start of a second-line BTK inhibitor, though to a lesser extent than time-to-POD. These variables were subsequently used to determine a second-line BTK MIPI, which can help inform which patients are most likely to benefit from a BTK inhibitor compared with other available options, such as chimeric antigen receptor (CAR) T-cell therapy or a clinical trial strategy.

BTK inhibitors are an important drug class for the treatment of lymphoid cancers and have changed the treatment paradigms in CLL/SLL and MCL. Additional studies evaluating combination strategies, sequencing approaches, time-limited options, and predictors of response are likely to further refine optimization of use in these diseases.

Additional References

1.         Barr PM, Owen C, Robak T, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6:3440-3450. doi:10.1182/bloodadvances.2021006434

2.         Sharman JP, Egyed M, Jurczak W, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naive chronic lymphocytic leukemia. Leukemia. 2022;36:1171-1175. doi:10.1038/s41375-021-01485-x

3.         Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23:1031-1043. doi:10.1016/S1470-2045(22)00293-5

4.         Ahn IE, Tian X, Wiestner A. Ibrutinib for chronic lymphocytic leukemia with TP53 alterations. N Engl J Med. 2020;383:498-500. doi:10.1056/NEJMc2005943

5.         Allan JN, Shanafelt T, Wiestner A, et al. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials. Br J Haematol. 2022;196:947-953. doi:10.1111/bjh.17984

6.         Mato AR, Tang B, Azmi S, et al. A clinical practice comparison of patients with chronic lymphocytic leukemia with and without deletion 17p receiving first-line treatment with ibrutinib. Haematologica. 2022;107:2630-2640. doi:10.3324/haematol.2021.280376

7.         Bond DA, Switchenko JM, Villa D, et al. Early relapse identifies MCL patients with inferior survival after intensive or less intensive frontline therapy. Blood Adv. 2021;5:5179-5189. doi:10.1182/bloodadvances.2021004765

The treatment landscape of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) has been transformed over the past decade with the advent of targeted therapies, including Bruton tyrosine kinase (BTK) inhibitors. Covalent BTK inhibitors, which are available in both the frontline and relapsed/refractory settings, include ibrutinib, acalabrutinib, and zanubrutinib.^1-3

BTK inhibitors have also demonstrated activity in higher-risk subgroups, including patients harboring TP53 aberrations. Clinical trials have shown encouraging outcomes of BTK inhibitors in these patients, and real-world studies have demonstrated similar findings.^4-6 Recently, a real-world Italian registry study similarly showed favorable outcomes in 747 patients with CLL carrying 17p- or TP53 or both mutations treated with first-line ibrutinib. in what appears to be the largest real-world analysis of this patient population (Rigolin et al). At 24 months, the median overall survival was not reached; the estimated treatment persistence and survival rates were 63.4% (95% CI 60.0%-67.0%) and 82.6% (95% CI 79.9%-85.4%), respectively. The median time to treatment discontinuation was 37.4 months (95% CI 34.8-42.2 months). Disease progression or death was the reason for discontinuation in 45.8% of patients. Although ibrutinib is not generally the favored BTK inhibitor given an improved safety profile with next-generation options, these data provide real-world estimates for outcomes with BTK inhibitors in this large dataset of high-risk patients.

Although outcomes have improved for patients with CLL or SLL, it is common for resistance to targeted therapy to eventually occur. Noncovalent BTK inhibitors, such as pirtobrutinib, offer a promising approach for this population. The BRUIN trial was a phase 1/2 trial of pirtobrutinib in patients with relapsed/refractory CLL or SLL (Mato et al). A total of 317 patients were treated, including 247 who had previously received a BTK inhibitor. Patients had been treated with a median of three prior lines of therapy and over 40% had been treated with a BCL-2 inhibitor. The overall response rate was 73.3% (95% CI 67.3%-78.7%) and increased to 82.2% (95% CI 76.8%-86.7%) when partial response with lymphocytosis was included. At a 19.4-month median follow-up, the median progression-free survival was 19.6 (95% CI 16.9-22.1) months. The drug was also well-tolerated, with 2.8% of patients discontinuing therapy owing to treatment-related adverse events. Adverse events that can be seen with BTK inhibition, including hypertension, atrial fibrillation or flutter, and bleeding, were rare. This trial demonstrates that CLL/SLL cells can maintain dependency on the B-cell receptor pathway following treatment with a covalent inhibitor and that ongoing BTK inhibition using a novel mechanism is a feasible strategy. The optimal sequencing of pirtobrutinib with other available therapies, including BCL-2 inhibitors, remains unknown.

BTK inhibitors are also active in mantle cell lymphoma (MCL). They are approved for relapsed/refractory disease and are being studied in earlier lines of therapy. Whereas early progression of disease (POD) has been shown to be an important prognostic marker in MCL, the impact of early relapse on outcome specifically after BTK inhibitor initiation is less clear.⁷ A recent multicente retrospective observational study aimed to determine the impact on time-to-POD between rituximab-containing front-line therapy and second-line BTK inhibitor and overall outcomes (Villa et al). This study included 360 adult patients with relapsed or refractory MCL treated with second-line BTK inhibitor. Not surprisingly, the authors found that patients with POD within 24 months of first-line therapy had significantly shorter median progression-free survival (0.45 year vs 2.3 years; P < .001) and overall survival (0.9 year vs 5.5 years P < .001) compared with patients with relapse beyond 24 months. Furthermore, they found that Ki-67 ≥ 30% and Mantle Cell Lymphoma International Prognostic Index (MIPI) were also associated with progression‐free survival and overall survival from the start of a second-line BTK inhibitor, though to a lesser extent than time-to-POD. These variables were subsequently used to determine a second-line BTK MIPI, which can help inform which patients are most likely to benefit from a BTK inhibitor compared with other available options, such as chimeric antigen receptor (CAR) T-cell therapy or a clinical trial strategy.

BTK inhibitors are an important drug class for the treatment of lymphoid cancers and have changed the treatment paradigms in CLL/SLL and MCL. Additional studies evaluating combination strategies, sequencing approaches, time-limited options, and predictors of response are likely to further refine optimization of use in these diseases.

Additional References

1.         Barr PM, Owen C, Robak T, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6:3440-3450. doi:10.1182/bloodadvances.2021006434

2.         Sharman JP, Egyed M, Jurczak W, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naive chronic lymphocytic leukemia. Leukemia. 2022;36:1171-1175. doi:10.1038/s41375-021-01485-x

3.         Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23:1031-1043. doi:10.1016/S1470-2045(22)00293-5

4.         Ahn IE, Tian X, Wiestner A. Ibrutinib for chronic lymphocytic leukemia with TP53 alterations. N Engl J Med. 2020;383:498-500. doi:10.1056/NEJMc2005943

5.         Allan JN, Shanafelt T, Wiestner A, et al. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials. Br J Haematol. 2022;196:947-953. doi:10.1111/bjh.17984

6.         Mato AR, Tang B, Azmi S, et al. A clinical practice comparison of patients with chronic lymphocytic leukemia with and without deletion 17p receiving first-line treatment with ibrutinib. Haematologica. 2022;107:2630-2640. doi:10.3324/haematol.2021.280376

7.         Bond DA, Switchenko JM, Villa D, et al. Early relapse identifies MCL patients with inferior survival after intensive or less intensive frontline therapy. Blood Adv. 2021;5:5179-5189. doi:10.1182/bloodadvances.2021004765

The Diagnosis: Majocchi Granuloma

Histopathology showed rare follicular-based organisms highlighted by periodic acid–Schiff staining. This finding along with her use of clobetasol ointment on the hands led to a diagnosis of Majocchi granuloma in our patient. Clobetasol and crisaborole ointments were discontinued, and she was started on oral terbinafine 250 mg daily for 4 weeks, which resulted in resolution of the rash.

Majocchi granuloma (also known as nodular granulomatous perifolliculitis) is a perifollicular granulomatous process caused by a dermatophyte infection of the hair follicles. Trichophyton rubrum is the most commonly implicated organism, followed by Trichophyton mentagrophytes and Epidermophyton floccosum, which also cause tinea corporis and tinea pedis.¹ This condition most commonly occurs in women aged 20 to 35 years. Risk factors include trauma, occlusion of the hair follicles, immunosuppression, and use of potent topical corticosteroids in patients with tinea.^2,3 Immunocompetent patients present with perifollicular papules or pustules with erythematous scaly plaques on the extremities, while immunocompromised patients may have subcutaneous nodules or abscesses on any hair-bearing parts of the body.³

Majocchi granuloma is considered a dermal fungal infection in which the disruption of hair follicles from occlusion or trauma allows fungal organisms and keratinaceous material substrates to be introduced into the dermis. The differential diagnosis is based on the types of presenting lesions. The papules of Majocchi granuloma can resemble folliculitis, acne, or insect bites, while nodules can resemble erythema nodosum or furunculosis.⁴ Plaques, such as those seen in our patient, can mimic cellulitis and allergic or irritant contact dermatitis.⁴ Additionally, the plaques may appear annular or figurate, which may resemble erythema gyratum repens or erythema annulare centrifugum.

The diagnosis of Majocchi granuloma often requires fungal culture and biopsy because a potassium hydroxide preparation is unable to distinguish between superficial and invasive dermatophytes.³ Histopathology will show perifollicular granulomatous inflammation. Fungal elements can be detected with periodic acid–Schiff or Grocott-Gomori methenamine-silver staining of the hairs and hair follicles as well as dermal infiltrates.⁴

Topical corticosteroids should be discontinued. Systemic antifungals are the treatment of choice for Majocchi granuloma, as topical antifungals are not effective against deep fungal infections. Although there are no standard guidelines on duration or dosage, recommended regimens in immunocompetent patients include terbinafine 250 mg/d for 4 weeks; itraconazole pulse therapy consisting of 200 mg twice daily for 1 week with 2 weeks off therapy, then repeat the cycle for a total of 2 to 3 pulses; and griseofulvin 500 mg twice daily for 8 to 12 weeks (Table).³ For immunocompromised patients, combination therapy with more than one antifungal may be necessary.

The Diagnosis: Majocchi Granuloma

Histopathology showed rare follicular-based organisms highlighted by periodic acid–Schiff staining. This finding along with her use of clobetasol ointment on the hands led to a diagnosis of Majocchi granuloma in our patient. Clobetasol and crisaborole ointments were discontinued, and she was started on oral terbinafine 250 mg daily for 4 weeks, which resulted in resolution of the rash.

Majocchi granuloma (also known as nodular granulomatous perifolliculitis) is a perifollicular granulomatous process caused by a dermatophyte infection of the hair follicles. Trichophyton rubrum is the most commonly implicated organism, followed by Trichophyton mentagrophytes and Epidermophyton floccosum, which also cause tinea corporis and tinea pedis.¹ This condition most commonly occurs in women aged 20 to 35 years. Risk factors include trauma, occlusion of the hair follicles, immunosuppression, and use of potent topical corticosteroids in patients with tinea.^2,3 Immunocompetent patients present with perifollicular papules or pustules with erythematous scaly plaques on the extremities, while immunocompromised patients may have subcutaneous nodules or abscesses on any hair-bearing parts of the body.³

Majocchi granuloma is considered a dermal fungal infection in which the disruption of hair follicles from occlusion or trauma allows fungal organisms and keratinaceous material substrates to be introduced into the dermis. The differential diagnosis is based on the types of presenting lesions. The papules of Majocchi granuloma can resemble folliculitis, acne, or insect bites, while nodules can resemble erythema nodosum or furunculosis.⁴ Plaques, such as those seen in our patient, can mimic cellulitis and allergic or irritant contact dermatitis.⁴ Additionally, the plaques may appear annular or figurate, which may resemble erythema gyratum repens or erythema annulare centrifugum.

The diagnosis of Majocchi granuloma often requires fungal culture and biopsy because a potassium hydroxide preparation is unable to distinguish between superficial and invasive dermatophytes.³ Histopathology will show perifollicular granulomatous inflammation. Fungal elements can be detected with periodic acid–Schiff or Grocott-Gomori methenamine-silver staining of the hairs and hair follicles as well as dermal infiltrates.⁴

Topical corticosteroids should be discontinued. Systemic antifungals are the treatment of choice for Majocchi granuloma, as topical antifungals are not effective against deep fungal infections. Although there are no standard guidelines on duration or dosage, recommended regimens in immunocompetent patients include terbinafine 250 mg/d for 4 weeks; itraconazole pulse therapy consisting of 200 mg twice daily for 1 week with 2 weeks off therapy, then repeat the cycle for a total of 2 to 3 pulses; and griseofulvin 500 mg twice daily for 8 to 12 weeks (Table).³ For immunocompromised patients, combination therapy with more than one antifungal may be necessary.

The Diagnosis: Majocchi Granuloma

Histopathology showed rare follicular-based organisms highlighted by periodic acid–Schiff staining. This finding along with her use of clobetasol ointment on the hands led to a diagnosis of Majocchi granuloma in our patient. Clobetasol and crisaborole ointments were discontinued, and she was started on oral terbinafine 250 mg daily for 4 weeks, which resulted in resolution of the rash.

Majocchi granuloma (also known as nodular granulomatous perifolliculitis) is a perifollicular granulomatous process caused by a dermatophyte infection of the hair follicles. Trichophyton rubrum is the most commonly implicated organism, followed by Trichophyton mentagrophytes and Epidermophyton floccosum, which also cause tinea corporis and tinea pedis.¹ This condition most commonly occurs in women aged 20 to 35 years. Risk factors include trauma, occlusion of the hair follicles, immunosuppression, and use of potent topical corticosteroids in patients with tinea.^2,3 Immunocompetent patients present with perifollicular papules or pustules with erythematous scaly plaques on the extremities, while immunocompromised patients may have subcutaneous nodules or abscesses on any hair-bearing parts of the body.³

Majocchi granuloma is considered a dermal fungal infection in which the disruption of hair follicles from occlusion or trauma allows fungal organisms and keratinaceous material substrates to be introduced into the dermis. The differential diagnosis is based on the types of presenting lesions. The papules of Majocchi granuloma can resemble folliculitis, acne, or insect bites, while nodules can resemble erythema nodosum or furunculosis.⁴ Plaques, such as those seen in our patient, can mimic cellulitis and allergic or irritant contact dermatitis.⁴ Additionally, the plaques may appear annular or figurate, which may resemble erythema gyratum repens or erythema annulare centrifugum.

The diagnosis of Majocchi granuloma often requires fungal culture and biopsy because a potassium hydroxide preparation is unable to distinguish between superficial and invasive dermatophytes.³ Histopathology will show perifollicular granulomatous inflammation. Fungal elements can be detected with periodic acid–Schiff or Grocott-Gomori methenamine-silver staining of the hairs and hair follicles as well as dermal infiltrates.⁴

Topical corticosteroids should be discontinued. Systemic antifungals are the treatment of choice for Majocchi granuloma, as topical antifungals are not effective against deep fungal infections. Although there are no standard guidelines on duration or dosage, recommended regimens in immunocompetent patients include terbinafine 250 mg/d for 4 weeks; itraconazole pulse therapy consisting of 200 mg twice daily for 1 week with 2 weeks off therapy, then repeat the cycle for a total of 2 to 3 pulses; and griseofulvin 500 mg twice daily for 8 to 12 weeks (Table).³ For immunocompromised patients, combination therapy with more than one antifungal may be necessary.