Cutis

To the Editor:

Pityriasis rubra pilaris (PRP) is a rare papulosquamous condition with an unknown pathogenesis and limited efficacy data, which can make treatment challenging. Some cases of PRP spontaneously resolve in a few months, which is most common in the pediatric population.¹ Pityriasis rubra pilaris in adults is likely to persist for years, and spontaneous resolution is unpredictable. Randomized clinical trials are difficult to perform due to the rarity of PRP.

Although there is no cure and no standard protocol for treating PRP, systemic retinoids historically are considered first-line therapy for moderate to severe cases.² Additional management approaches include symptomatic control with moisturizers and psychological support. Alternative systemic treatments for moderate to severe cases include methotrexate, phototherapy, and cyclosporine.²

Pityriasis rubra pilaris demonstrates a favorable response to methotrexate treatment, especially in type I cases; however, patients on this alternative therapy should be monitored for severe adverse effects (eg, hepatotoxicity, pancytopenia, pneumonitis).² Phototherapy should be approached with caution. Narrowband UVB, UVA1, and psoralen plus UVA therapy have successfully treated PRP; however, the response is variable. In some cases, the opposite effect can occur, in which the condition is photoaggravated. Phototherapy is a valid alternative form of treatment when used in combination with acitretin, and a phototest should be performed prior to starting this regimen. Cyclosporine is another immunosuppressant that can be considered for PRP treatment, though there are limited data demonstrating its efficacy.²

The introduction of biologic agents has changed the treatment approach for many dermatologic diseases, including PRP. Given the similar features between psoriasis and PRP, the biologics prescribed for psoriasis therapy also are used for patients with PRP that is challenging to treat, such as anti–tumor necrosis factor α inhibitors and IL inhibitors—specifically IL-17 and IL-23. Remission has been achieved with the use of biologics in combination with retinoid therapy.²

Biologic therapies used for PRP effectively inhibit cytokines and reduce the overall inflammatory processes involved in the development of the scaly patches and plaques seen in this condition. However, most reported clinical experiences are case studies, and more research in the form of randomized clinical trials is needed to understand the efficacy and long-term effects of this form of treatment in PRP. We present a case of a patient with refractory adult subtype I PRP that was successfully treated with the IL-23 inhibitor risankizumab.

A 65-year-old man was referred to Florida Academic Dermatology Center (Coral Gables, Florida) with biopsy-proven PRP diagnosed 1 year prior. The patient reported experiencing a debilitating quality of life in the year since diagnosis (Figure 1). Treatment attempts with dupilumab, tralokinumab, intramuscular steroid injections, and topical corticosteroids had failed (Figure 2). Following evaluation at Florida Academic Dermatology Center, the patient was started on acitretin 25 mg every other day and received an initial subcutaneous injection of ixekizumab 160 mg (an IL-17 inhibitor) followed 2 weeks later by a second injection of 80 mg. After the 2 doses of ixekizumab, the patient’s condition worsened with the development of pinpoint hemorrhagic lesions. The medication was discontinued, and he was started on risankizumab 150 mg at the approved dosing regimen for plaque psoriasis in combination with the acitretin therapy. Prior to starting risankizumab, the affected body surface area (BSA) was 80%. At 1-month follow-up, he showed improvement with reduction in scaling and erythema and an affected BSA of 30% (Figure 3). At 4-month follow-up, he continued showing improvement with an affected BSA of 10% (Figure 4). Acitretin was discontinued, and the patient has been successfully maintained on risankizumab 150 mg/mL subcutaneous injections every 12 weeks since.

To the Editor:

Pityriasis rubra pilaris (PRP) is a rare papulosquamous condition with an unknown pathogenesis and limited efficacy data, which can make treatment challenging. Some cases of PRP spontaneously resolve in a few months, which is most common in the pediatric population.¹ Pityriasis rubra pilaris in adults is likely to persist for years, and spontaneous resolution is unpredictable. Randomized clinical trials are difficult to perform due to the rarity of PRP.

Although there is no cure and no standard protocol for treating PRP, systemic retinoids historically are considered first-line therapy for moderate to severe cases.² Additional management approaches include symptomatic control with moisturizers and psychological support. Alternative systemic treatments for moderate to severe cases include methotrexate, phototherapy, and cyclosporine.²

Pityriasis rubra pilaris demonstrates a favorable response to methotrexate treatment, especially in type I cases; however, patients on this alternative therapy should be monitored for severe adverse effects (eg, hepatotoxicity, pancytopenia, pneumonitis).² Phototherapy should be approached with caution. Narrowband UVB, UVA1, and psoralen plus UVA therapy have successfully treated PRP; however, the response is variable. In some cases, the opposite effect can occur, in which the condition is photoaggravated. Phototherapy is a valid alternative form of treatment when used in combination with acitretin, and a phototest should be performed prior to starting this regimen. Cyclosporine is another immunosuppressant that can be considered for PRP treatment, though there are limited data demonstrating its efficacy.²

The introduction of biologic agents has changed the treatment approach for many dermatologic diseases, including PRP. Given the similar features between psoriasis and PRP, the biologics prescribed for psoriasis therapy also are used for patients with PRP that is challenging to treat, such as anti–tumor necrosis factor α inhibitors and IL inhibitors—specifically IL-17 and IL-23. Remission has been achieved with the use of biologics in combination with retinoid therapy.²

Biologic therapies used for PRP effectively inhibit cytokines and reduce the overall inflammatory processes involved in the development of the scaly patches and plaques seen in this condition. However, most reported clinical experiences are case studies, and more research in the form of randomized clinical trials is needed to understand the efficacy and long-term effects of this form of treatment in PRP. We present a case of a patient with refractory adult subtype I PRP that was successfully treated with the IL-23 inhibitor risankizumab.

A 65-year-old man was referred to Florida Academic Dermatology Center (Coral Gables, Florida) with biopsy-proven PRP diagnosed 1 year prior. The patient reported experiencing a debilitating quality of life in the year since diagnosis (Figure 1). Treatment attempts with dupilumab, tralokinumab, intramuscular steroid injections, and topical corticosteroids had failed (Figure 2). Following evaluation at Florida Academic Dermatology Center, the patient was started on acitretin 25 mg every other day and received an initial subcutaneous injection of ixekizumab 160 mg (an IL-17 inhibitor) followed 2 weeks later by a second injection of 80 mg. After the 2 doses of ixekizumab, the patient’s condition worsened with the development of pinpoint hemorrhagic lesions. The medication was discontinued, and he was started on risankizumab 150 mg at the approved dosing regimen for plaque psoriasis in combination with the acitretin therapy. Prior to starting risankizumab, the affected body surface area (BSA) was 80%. At 1-month follow-up, he showed improvement with reduction in scaling and erythema and an affected BSA of 30% (Figure 3). At 4-month follow-up, he continued showing improvement with an affected BSA of 10% (Figure 4). Acitretin was discontinued, and the patient has been successfully maintained on risankizumab 150 mg/mL subcutaneous injections every 12 weeks since.

To the Editor:

Pityriasis rubra pilaris (PRP) is a rare papulosquamous condition with an unknown pathogenesis and limited efficacy data, which can make treatment challenging. Some cases of PRP spontaneously resolve in a few months, which is most common in the pediatric population.¹ Pityriasis rubra pilaris in adults is likely to persist for years, and spontaneous resolution is unpredictable. Randomized clinical trials are difficult to perform due to the rarity of PRP.

Although there is no cure and no standard protocol for treating PRP, systemic retinoids historically are considered first-line therapy for moderate to severe cases.² Additional management approaches include symptomatic control with moisturizers and psychological support. Alternative systemic treatments for moderate to severe cases include methotrexate, phototherapy, and cyclosporine.²

Pityriasis rubra pilaris demonstrates a favorable response to methotrexate treatment, especially in type I cases; however, patients on this alternative therapy should be monitored for severe adverse effects (eg, hepatotoxicity, pancytopenia, pneumonitis).² Phototherapy should be approached with caution. Narrowband UVB, UVA1, and psoralen plus UVA therapy have successfully treated PRP; however, the response is variable. In some cases, the opposite effect can occur, in which the condition is photoaggravated. Phototherapy is a valid alternative form of treatment when used in combination with acitretin, and a phototest should be performed prior to starting this regimen. Cyclosporine is another immunosuppressant that can be considered for PRP treatment, though there are limited data demonstrating its efficacy.²

The introduction of biologic agents has changed the treatment approach for many dermatologic diseases, including PRP. Given the similar features between psoriasis and PRP, the biologics prescribed for psoriasis therapy also are used for patients with PRP that is challenging to treat, such as anti–tumor necrosis factor α inhibitors and IL inhibitors—specifically IL-17 and IL-23. Remission has been achieved with the use of biologics in combination with retinoid therapy.²

Biologic therapies used for PRP effectively inhibit cytokines and reduce the overall inflammatory processes involved in the development of the scaly patches and plaques seen in this condition. However, most reported clinical experiences are case studies, and more research in the form of randomized clinical trials is needed to understand the efficacy and long-term effects of this form of treatment in PRP. We present a case of a patient with refractory adult subtype I PRP that was successfully treated with the IL-23 inhibitor risankizumab.

A 65-year-old man was referred to Florida Academic Dermatology Center (Coral Gables, Florida) with biopsy-proven PRP diagnosed 1 year prior. The patient reported experiencing a debilitating quality of life in the year since diagnosis (Figure 1). Treatment attempts with dupilumab, tralokinumab, intramuscular steroid injections, and topical corticosteroids had failed (Figure 2). Following evaluation at Florida Academic Dermatology Center, the patient was started on acitretin 25 mg every other day and received an initial subcutaneous injection of ixekizumab 160 mg (an IL-17 inhibitor) followed 2 weeks later by a second injection of 80 mg. After the 2 doses of ixekizumab, the patient’s condition worsened with the development of pinpoint hemorrhagic lesions. The medication was discontinued, and he was started on risankizumab 150 mg at the approved dosing regimen for plaque psoriasis in combination with the acitretin therapy. Prior to starting risankizumab, the affected body surface area (BSA) was 80%. At 1-month follow-up, he showed improvement with reduction in scaling and erythema and an affected BSA of 30% (Figure 3). At 4-month follow-up, he continued showing improvement with an affected BSA of 10% (Figure 4). Acitretin was discontinued, and the patient has been successfully maintained on risankizumab 150 mg/mL subcutaneous injections every 12 weeks since.

Dermatology remains one of the most competitive specialties in the residency match, with successful applicants demonstrating a well-rounded application reflecting not only their academic excellence but also their dedication to research, community service, and hands-on clinical experience.¹ A growing emphasis on scholarly activities has made it crucial for applicants to stand out, with an increasing number opting to take gap years to engage in focused research endeavors.² In highly competitive specialties such as dermatology, successful applicants now report more than 20 research items on average.^3,4 This trend also is evident in primary care specialties, which have seen a 2- to 3-fold increase in reported research activities. The average unmatched applicant today lists more research items than the average matched applicant did a decade ago, underscoring the growing emphasis on scholarly activity.³

Ideally, graduate medical education should foster an environment of inquiry and scholarship, where residents develop new knowledge, evaluate research findings, and cultivate lifelong habits of inquiry. The Accreditation Council for Graduate Medical Education requires residents to engage in scholarship, such as case reports, research reviews, and original research.⁵ Research during residency has been linked to several benefits, including enhanced patient care through improved critical appraisal skills, clinical reasoning, and lifelong learning.^6,7 Additionally, students and residents who publish research are more likely to achieve higher rank during residency and pursue careers in academic medicine, potentially helping to address the decline in clinician investigators.^8,9 Publishing and presenting research also can enhance a residency program’s reputation, making it more attractive to competitive applicants, and may be beneficial for residents seeking jobs or fellowships.⁶

Dermatology residency programs vary in their structure and support for resident research. One survey revealed that many programs lack the necessary support, structure, and resources to effectively promote and maintain research training.¹ Additionally, residents have less exposure to researchers who could serve as mentors due to the growing demands placed on attending physicians in teaching hospitals.¹⁰

The Research Arms Race

The growing emphasis on scholarly activity for residency and fellowship applicants coupled with the use of research productivity to differentiate candidates has led some to declare a “research arms race” in residency selection.³ As one author stated, “We need less research, better research, and research done for the right reasons.”¹¹ Indeed, most articles authored by medical students are short reviews or case reports, with the majority (59% [207/350]) being cited zero times, according to one analysis.¹² Given the variable research infrastructure between programs and the decreasing availability of research mentors despite the growing emphasis on scholarly activity, applicants face an unfortunate dilemma. Until the system changes, those who protest this research arms race by not engaging in substantial scholarly activity are less likely to match into competitive specialties. Thus, the race continues.

The Value of Mentorship

Resident research success is impacted by having an effective faculty research mentor.¹³ Although all medical research at the student or resident levels should be conducted with a faculty mentor to oversee it, finding a mentor can be challenging. If a resident’s program boasts a strong research infrastructure or prolific faculty, building relationships with potential mentors is a logical first step for residents wishing to engage in research; however, if suitable mentors are lacking, efforts should be made by residents to establish these connections elsewhere, such as attending society meetings to network with potential mentors and applying to formal mentorship programs (eg, the American Society for Dermatologic Surgery’s Preceptor Program, the Women’s Dermatologic Society’s Mentorship Award). Unsolicited email inquiries asking, “Hi Dr. X, my name is Y, and I was wondering if you have any research projects I could help with?” often go unanswered. Instead, consider emailing or approaching potential mentors with a more developed proposition, such as the following example:

Hello Dr. X, my name is Y. I have enjoyed reading your publications on A, which inspired me to think about B. I reviewed the literature and noticed a potential to enhance our current understanding on the topic. My team and I conducted a systematic review of the available literature and drafted a manuscript summarizing our findings. Given your expertise in this field, would you be willing to collaborate on this paper? We would be grateful for your critical eye, suggestions for improvement, and overall thoughts.

This approach demonstrates initiative, provides a clear plan, and shows respect for the mentor’s expertise, increasing the likelihood of a positive response and fruitful collaboration. Assuming the resident’s working draft meets the potential mentor’s basic expectations, such a display of initiative is likely to impress them, and they may then offer opportunities to engage in meaningful research projects in the future. Everyone benefits! These efforts to establish connections with mentors can pave the way to further collaboration and meaningful research opportunities for dermatology residents.

The Systematic Review: An Attractive Option For Residents

There are several potential avenues for students or residents interested in pursuing research. Case reports and case series are relatively easy to compile, can be completed quickly, and often require minimal guidance from a faculty mentor; however, case reports rank low in the research hierarchy. Conversely, prospective blinded clinical trials provide some of the highest-quality evidence available but are challenging to conduct without a practicing faculty member to provide a patient cohort, often require extensive funding, and may involve complex statistical analyses beyond the expertise of most students or residents. Additionally, they may take years to complete, often extending beyond residency or fellowship application deadlines.

Most medical applicants likely hold at least some hesitation in churning out vast amounts of low-quality research merely to boost their publication count for the match process. Ideally, those who pursue scholarly activity should be driven by a genuine desire to contribute meaningfully to the medical literature. One particularly valuable avenue for trainees wishing to engage in research is the systematic review, which aims to identify, evaluate, and summarize the findings of all relevant individual studies regarding a research topic and answer a focused question. If performed thoughtfully, a systematic review can meaningfully contribute to the medical literature without requiring access to a prospectively followed cohort of patients or the constant supervision of a faculty mentor. Sure, systematic reviews may not be as robust as prospective cohort clinical trials, but they often provide comprehensive insights and are considered valuable contributions to evidence-based medicine. With the help of co-residents or medical students, a medical reference librarian, and a statistician—along with a working understanding of universally accepted quality measures—a resident physician and their team can produce a systematic review that ultimately may merit publication in a top-tier medical journal.

The remainder of this column will outline a streamlined approach to the systematic review writing process, specifically tailored for medical residents who may not have affiliations to a prolific research department or established relationships with faculty mentors in their field of interest. The aim is to offer a basic framework to help residents navigate the complexities of conducting and writing a high-quality, impactful systematic review. It is important to emphasize that resident research should always be conducted under the guidance of a faculty mentor, and this approach is not intended to encourage independent research and publication by residents. Instead, it provides steps that can be undertaken with a foundational understanding of accepted principles, allowing residents to compile a working draft of a manuscript in collaboration with a trusted faculty mentor.

The Systematic Review: A Simple Approach

Step 1: Choose a Topic—Once a resident has decided to embark on conducting a systematic review, the first step is to choose a topic, which requires consideration of several factors to ensure relevance, feasibility, and impact. Begin by identifying areas of clinical uncertainty or controversy in which a comprehensive synthesis of the literature could provide valuable insights. Often, such a topic can be gleaned from the conclusion section of other primary studies; statements such as “further study is needed to determine the efficacy of X” or “systematic reviews would be beneficial to ascertaining the impact of Y” may be a great place to start.

Next, ensure that sufficient primary studies exist to support a robust review or meta-analysis by conducting a preliminary literature search, which will confirm that the chosen topic is both researchable and relevant. A narrow, focused, well-defined topic likely will prove more feasible to review than a broad, ill-defined one. Once a topic is selected, it is advisable to discuss it with a faculty mentor before starting the literature search to ensure the topic’s feasibility and clinical relevance, helping to guide your research in a meaningful direction.

When deciding between a systematic review and a meta-analysis, the nature of the research question is an influential factor. A systematic review is particularly suitable for addressing broad questions or topics when the aim is to summarize and synthesize all relevant research studies; for example, a systematic review may investigate the various treatment options for atopic dermatitis and their efficacy, which allows for a comprehensive overview of the available treatments—both the interventions and the outcomes. In contrast, a meta-analysis is ideal for collecting and statistically combining quantitative data from multiple primary studies, provided there are enough relevant studies available in the literature.

Step 2: Build a Team—Recruiting a skilled librarian to assist with Medical Subject Headings (MeSH) terms and retrieving relevant papers is crucial for conducting a high-quality systematic review or meta-analysis. Medical librarians specializing in health sciences enhance the efficiency, comprehensiveness, and reliability of your literature search, substantially boosting your work’s credibility. These librarians are well versed in medical databases such as PubMed and Embase. Begin by contacting your institution’s library services, as there often are valuable resources and personnel available to assist you. Personally, I was surprised to find a librarian at my institution specifically dedicated to helping medical residents with such projects! These professionals are eager to help, and if provided with the scope and goal of your project, they can deliver literature search results in a digestible format. Similarly, seeking the expertise of a medical statistician is crucial to the accuracy and legitimacy of your study. In your final paper, it is important to recognize the contributions of the librarian and statistician, either as co-authors or in the acknowledgments section.

In addition, recruiting colleagues or medical students can be an effective strategy to make the project more feasible and offer collaborative benefits for all parties involved. Given the growing emphasis on research for residency and fellowship admissions, there usually is no shortage of motivated volunteers.

Next, identify the software tool you will use for your systematic review. Options range from simple spreadsheets such as Microsoft Excel to reference managers such as EndNote or Mendeley or dedicated systematic review tools. Academic institutions may subscribe to paid services such as Covidence (https://www.covidence.org), or you can utilize free alternatives such as Rayyan (https://www.rayyan.ai). Investing time in learning to navigate dedicated systematic review software can greatly enhance efficiency and reduce frustrations compared to more basic methods. Ultimately, staying organized, thorough, and committed is key.

Step 3: Conduct the Literature Review—At this point, your research topic has been decided, a medical reference librarian has provided the results of a comprehensive literature search, and a software tool has been chosen. The next task is to read hundreds or thousands of papers—easy, right? With your dedicated team assembled, the workload can be divided and conquered. The first step involves screening out duplicate and irrelevant studies based on titles and abstracts. Next, review the remaining papers in more detail. Those that pass this preliminary screen should be read in their entirety, and only the papers relevant to the research topic should be included in the final synthesis. If there are uncertainties about a study’s relevance, consulting a faculty mentor is advisable. To ensure the systematic review is as thorough as possible, pay special attention to the references section of each paper, as cited references can reveal relevant studies that may have been missed in the literature search.

Once all relevant papers are compiled and read, the relevant data points should be extracted and imputed into a data sheet. Collaborating with a medical statistician is crucial at this stage, as they can provide guidance on the most effective ways to structure and input data. After all studies are included, the relevant statistical analyses on the resultant dataset can be run.

Step 4: Write the Paper—In 2020, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was developed to ensure transparent and complete reporting of systematic reviews. A full discussion of PRISMA guidelines is beyond the scope of this paper; Page et al¹⁴ provided a summary, checklist, and flow diagram that is available online (https://www.prisma-statement.org). Following the PRISMA checklist and guidelines ensures a high-quality, transparent, and reliable systematic review. These guidelines not only help streamline and simplify the writing process but also enhance its efficiency and effectiveness. Discovering the PRISMA checklist can be transformative, providing a valuable roadmap that guides the author through each step of the reporting process, helping to avoid common pitfalls. This structured approach ultimately leads to a more comprehensive and trustworthy review.

Step 5: Make Finishing Touches—At this stage in the systematic review process, the studies have been compiled and thoroughly analyzed and the statistical analysis has been conducted. The results have been organized within a structured framework following the PRISMA checklist. With these steps completed, the next task is to finalize the manuscript and seek a final review from the senior author or faculty mentor. To streamline this process, it is beneficial to adhere to the formatting guidelines of the specific medical journal you intend to submit to. Check the author guidelines on the journal’s website and review recent systematic reviews published there as a reference. Even if you have not chosen a journal yet, formatting your manuscript according to a prestigious journal’s general style provides a strong foundation that can be easily adapted to fit another journal’s requirements if necessary.

Final Thoughts

Designing and conducting a systematic review is no easy task, but it can be a valuable skill for dermatology residents aiming to contribute meaningfully to the medical literature. The process of compiling a systematic review offers an opportunity for developing critical research skills, from formulating a research question to synthesizing evidence and presenting findings in a clear methodical way. Engaging in systematic review writing not only enhances the resident’s understanding of a particular topic but also demonstrates a commitment to scholarly activity—a key factor in an increasingly competitive residency and fellowship application environment.

The basic steps outlined in this article are just one way in which residents can begin to navigate the complexities of medical research, specifically the systematic review process. By assembling a supportive team, utilizing available resources, and adhering to established guidelines such as PRISMA, one can produce a high-quality, impactful review. Ultimately, the systematic review process is not just about publication—it is about fostering a habit of inquiry, improving patient care, and contributing to the ever-evolving field of medicine. With dedication and collaboration, even the most challenging aspects of research can be tackled, paving the way for future opportunities and professional growth. In this way, perhaps one day the spirit of the “research race” can shift from a frantic sprint to a graceful marathon, where each mile is run with heart and every step is filled with purpose.

Dermatology remains one of the most competitive specialties in the residency match, with successful applicants demonstrating a well-rounded application reflecting not only their academic excellence but also their dedication to research, community service, and hands-on clinical experience.¹ A growing emphasis on scholarly activities has made it crucial for applicants to stand out, with an increasing number opting to take gap years to engage in focused research endeavors.² In highly competitive specialties such as dermatology, successful applicants now report more than 20 research items on average.^3,4 This trend also is evident in primary care specialties, which have seen a 2- to 3-fold increase in reported research activities. The average unmatched applicant today lists more research items than the average matched applicant did a decade ago, underscoring the growing emphasis on scholarly activity.³

Ideally, graduate medical education should foster an environment of inquiry and scholarship, where residents develop new knowledge, evaluate research findings, and cultivate lifelong habits of inquiry. The Accreditation Council for Graduate Medical Education requires residents to engage in scholarship, such as case reports, research reviews, and original research.⁵ Research during residency has been linked to several benefits, including enhanced patient care through improved critical appraisal skills, clinical reasoning, and lifelong learning.^6,7 Additionally, students and residents who publish research are more likely to achieve higher rank during residency and pursue careers in academic medicine, potentially helping to address the decline in clinician investigators.^8,9 Publishing and presenting research also can enhance a residency program’s reputation, making it more attractive to competitive applicants, and may be beneficial for residents seeking jobs or fellowships.⁶

Dermatology residency programs vary in their structure and support for resident research. One survey revealed that many programs lack the necessary support, structure, and resources to effectively promote and maintain research training.¹ Additionally, residents have less exposure to researchers who could serve as mentors due to the growing demands placed on attending physicians in teaching hospitals.¹⁰

The Research Arms Race

The growing emphasis on scholarly activity for residency and fellowship applicants coupled with the use of research productivity to differentiate candidates has led some to declare a “research arms race” in residency selection.³ As one author stated, “We need less research, better research, and research done for the right reasons.”¹¹ Indeed, most articles authored by medical students are short reviews or case reports, with the majority (59% [207/350]) being cited zero times, according to one analysis.¹² Given the variable research infrastructure between programs and the decreasing availability of research mentors despite the growing emphasis on scholarly activity, applicants face an unfortunate dilemma. Until the system changes, those who protest this research arms race by not engaging in substantial scholarly activity are less likely to match into competitive specialties. Thus, the race continues.

The Value of Mentorship

Resident research success is impacted by having an effective faculty research mentor.¹³ Although all medical research at the student or resident levels should be conducted with a faculty mentor to oversee it, finding a mentor can be challenging. If a resident’s program boasts a strong research infrastructure or prolific faculty, building relationships with potential mentors is a logical first step for residents wishing to engage in research; however, if suitable mentors are lacking, efforts should be made by residents to establish these connections elsewhere, such as attending society meetings to network with potential mentors and applying to formal mentorship programs (eg, the American Society for Dermatologic Surgery’s Preceptor Program, the Women’s Dermatologic Society’s Mentorship Award). Unsolicited email inquiries asking, “Hi Dr. X, my name is Y, and I was wondering if you have any research projects I could help with?” often go unanswered. Instead, consider emailing or approaching potential mentors with a more developed proposition, such as the following example:

Hello Dr. X, my name is Y. I have enjoyed reading your publications on A, which inspired me to think about B. I reviewed the literature and noticed a potential to enhance our current understanding on the topic. My team and I conducted a systematic review of the available literature and drafted a manuscript summarizing our findings. Given your expertise in this field, would you be willing to collaborate on this paper? We would be grateful for your critical eye, suggestions for improvement, and overall thoughts.

This approach demonstrates initiative, provides a clear plan, and shows respect for the mentor’s expertise, increasing the likelihood of a positive response and fruitful collaboration. Assuming the resident’s working draft meets the potential mentor’s basic expectations, such a display of initiative is likely to impress them, and they may then offer opportunities to engage in meaningful research projects in the future. Everyone benefits! These efforts to establish connections with mentors can pave the way to further collaboration and meaningful research opportunities for dermatology residents.

The Systematic Review: An Attractive Option For Residents

There are several potential avenues for students or residents interested in pursuing research. Case reports and case series are relatively easy to compile, can be completed quickly, and often require minimal guidance from a faculty mentor; however, case reports rank low in the research hierarchy. Conversely, prospective blinded clinical trials provide some of the highest-quality evidence available but are challenging to conduct without a practicing faculty member to provide a patient cohort, often require extensive funding, and may involve complex statistical analyses beyond the expertise of most students or residents. Additionally, they may take years to complete, often extending beyond residency or fellowship application deadlines.

Most medical applicants likely hold at least some hesitation in churning out vast amounts of low-quality research merely to boost their publication count for the match process. Ideally, those who pursue scholarly activity should be driven by a genuine desire to contribute meaningfully to the medical literature. One particularly valuable avenue for trainees wishing to engage in research is the systematic review, which aims to identify, evaluate, and summarize the findings of all relevant individual studies regarding a research topic and answer a focused question. If performed thoughtfully, a systematic review can meaningfully contribute to the medical literature without requiring access to a prospectively followed cohort of patients or the constant supervision of a faculty mentor. Sure, systematic reviews may not be as robust as prospective cohort clinical trials, but they often provide comprehensive insights and are considered valuable contributions to evidence-based medicine. With the help of co-residents or medical students, a medical reference librarian, and a statistician—along with a working understanding of universally accepted quality measures—a resident physician and their team can produce a systematic review that ultimately may merit publication in a top-tier medical journal.

The remainder of this column will outline a streamlined approach to the systematic review writing process, specifically tailored for medical residents who may not have affiliations to a prolific research department or established relationships with faculty mentors in their field of interest. The aim is to offer a basic framework to help residents navigate the complexities of conducting and writing a high-quality, impactful systematic review. It is important to emphasize that resident research should always be conducted under the guidance of a faculty mentor, and this approach is not intended to encourage independent research and publication by residents. Instead, it provides steps that can be undertaken with a foundational understanding of accepted principles, allowing residents to compile a working draft of a manuscript in collaboration with a trusted faculty mentor.

The Systematic Review: A Simple Approach

Step 1: Choose a Topic—Once a resident has decided to embark on conducting a systematic review, the first step is to choose a topic, which requires consideration of several factors to ensure relevance, feasibility, and impact. Begin by identifying areas of clinical uncertainty or controversy in which a comprehensive synthesis of the literature could provide valuable insights. Often, such a topic can be gleaned from the conclusion section of other primary studies; statements such as “further study is needed to determine the efficacy of X” or “systematic reviews would be beneficial to ascertaining the impact of Y” may be a great place to start.

Next, ensure that sufficient primary studies exist to support a robust review or meta-analysis by conducting a preliminary literature search, which will confirm that the chosen topic is both researchable and relevant. A narrow, focused, well-defined topic likely will prove more feasible to review than a broad, ill-defined one. Once a topic is selected, it is advisable to discuss it with a faculty mentor before starting the literature search to ensure the topic’s feasibility and clinical relevance, helping to guide your research in a meaningful direction.

When deciding between a systematic review and a meta-analysis, the nature of the research question is an influential factor. A systematic review is particularly suitable for addressing broad questions or topics when the aim is to summarize and synthesize all relevant research studies; for example, a systematic review may investigate the various treatment options for atopic dermatitis and their efficacy, which allows for a comprehensive overview of the available treatments—both the interventions and the outcomes. In contrast, a meta-analysis is ideal for collecting and statistically combining quantitative data from multiple primary studies, provided there are enough relevant studies available in the literature.

Step 2: Build a Team—Recruiting a skilled librarian to assist with Medical Subject Headings (MeSH) terms and retrieving relevant papers is crucial for conducting a high-quality systematic review or meta-analysis. Medical librarians specializing in health sciences enhance the efficiency, comprehensiveness, and reliability of your literature search, substantially boosting your work’s credibility. These librarians are well versed in medical databases such as PubMed and Embase. Begin by contacting your institution’s library services, as there often are valuable resources and personnel available to assist you. Personally, I was surprised to find a librarian at my institution specifically dedicated to helping medical residents with such projects! These professionals are eager to help, and if provided with the scope and goal of your project, they can deliver literature search results in a digestible format. Similarly, seeking the expertise of a medical statistician is crucial to the accuracy and legitimacy of your study. In your final paper, it is important to recognize the contributions of the librarian and statistician, either as co-authors or in the acknowledgments section.

In addition, recruiting colleagues or medical students can be an effective strategy to make the project more feasible and offer collaborative benefits for all parties involved. Given the growing emphasis on research for residency and fellowship admissions, there usually is no shortage of motivated volunteers.

Next, identify the software tool you will use for your systematic review. Options range from simple spreadsheets such as Microsoft Excel to reference managers such as EndNote or Mendeley or dedicated systematic review tools. Academic institutions may subscribe to paid services such as Covidence (https://www.covidence.org), or you can utilize free alternatives such as Rayyan (https://www.rayyan.ai). Investing time in learning to navigate dedicated systematic review software can greatly enhance efficiency and reduce frustrations compared to more basic methods. Ultimately, staying organized, thorough, and committed is key.

Step 3: Conduct the Literature Review—At this point, your research topic has been decided, a medical reference librarian has provided the results of a comprehensive literature search, and a software tool has been chosen. The next task is to read hundreds or thousands of papers—easy, right? With your dedicated team assembled, the workload can be divided and conquered. The first step involves screening out duplicate and irrelevant studies based on titles and abstracts. Next, review the remaining papers in more detail. Those that pass this preliminary screen should be read in their entirety, and only the papers relevant to the research topic should be included in the final synthesis. If there are uncertainties about a study’s relevance, consulting a faculty mentor is advisable. To ensure the systematic review is as thorough as possible, pay special attention to the references section of each paper, as cited references can reveal relevant studies that may have been missed in the literature search.

Once all relevant papers are compiled and read, the relevant data points should be extracted and imputed into a data sheet. Collaborating with a medical statistician is crucial at this stage, as they can provide guidance on the most effective ways to structure and input data. After all studies are included, the relevant statistical analyses on the resultant dataset can be run.

Step 4: Write the Paper—In 2020, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was developed to ensure transparent and complete reporting of systematic reviews. A full discussion of PRISMA guidelines is beyond the scope of this paper; Page et al¹⁴ provided a summary, checklist, and flow diagram that is available online (https://www.prisma-statement.org). Following the PRISMA checklist and guidelines ensures a high-quality, transparent, and reliable systematic review. These guidelines not only help streamline and simplify the writing process but also enhance its efficiency and effectiveness. Discovering the PRISMA checklist can be transformative, providing a valuable roadmap that guides the author through each step of the reporting process, helping to avoid common pitfalls. This structured approach ultimately leads to a more comprehensive and trustworthy review.

Step 5: Make Finishing Touches—At this stage in the systematic review process, the studies have been compiled and thoroughly analyzed and the statistical analysis has been conducted. The results have been organized within a structured framework following the PRISMA checklist. With these steps completed, the next task is to finalize the manuscript and seek a final review from the senior author or faculty mentor. To streamline this process, it is beneficial to adhere to the formatting guidelines of the specific medical journal you intend to submit to. Check the author guidelines on the journal’s website and review recent systematic reviews published there as a reference. Even if you have not chosen a journal yet, formatting your manuscript according to a prestigious journal’s general style provides a strong foundation that can be easily adapted to fit another journal’s requirements if necessary.

Final Thoughts

Designing and conducting a systematic review is no easy task, but it can be a valuable skill for dermatology residents aiming to contribute meaningfully to the medical literature. The process of compiling a systematic review offers an opportunity for developing critical research skills, from formulating a research question to synthesizing evidence and presenting findings in a clear methodical way. Engaging in systematic review writing not only enhances the resident’s understanding of a particular topic but also demonstrates a commitment to scholarly activity—a key factor in an increasingly competitive residency and fellowship application environment.

The basic steps outlined in this article are just one way in which residents can begin to navigate the complexities of medical research, specifically the systematic review process. By assembling a supportive team, utilizing available resources, and adhering to established guidelines such as PRISMA, one can produce a high-quality, impactful review. Ultimately, the systematic review process is not just about publication—it is about fostering a habit of inquiry, improving patient care, and contributing to the ever-evolving field of medicine. With dedication and collaboration, even the most challenging aspects of research can be tackled, paving the way for future opportunities and professional growth. In this way, perhaps one day the spirit of the “research race” can shift from a frantic sprint to a graceful marathon, where each mile is run with heart and every step is filled with purpose.

Dermatology remains one of the most competitive specialties in the residency match, with successful applicants demonstrating a well-rounded application reflecting not only their academic excellence but also their dedication to research, community service, and hands-on clinical experience.¹ A growing emphasis on scholarly activities has made it crucial for applicants to stand out, with an increasing number opting to take gap years to engage in focused research endeavors.² In highly competitive specialties such as dermatology, successful applicants now report more than 20 research items on average.^3,4 This trend also is evident in primary care specialties, which have seen a 2- to 3-fold increase in reported research activities. The average unmatched applicant today lists more research items than the average matched applicant did a decade ago, underscoring the growing emphasis on scholarly activity.³

Ideally, graduate medical education should foster an environment of inquiry and scholarship, where residents develop new knowledge, evaluate research findings, and cultivate lifelong habits of inquiry. The Accreditation Council for Graduate Medical Education requires residents to engage in scholarship, such as case reports, research reviews, and original research.⁵ Research during residency has been linked to several benefits, including enhanced patient care through improved critical appraisal skills, clinical reasoning, and lifelong learning.^6,7 Additionally, students and residents who publish research are more likely to achieve higher rank during residency and pursue careers in academic medicine, potentially helping to address the decline in clinician investigators.^8,9 Publishing and presenting research also can enhance a residency program’s reputation, making it more attractive to competitive applicants, and may be beneficial for residents seeking jobs or fellowships.⁶

Dermatology residency programs vary in their structure and support for resident research. One survey revealed that many programs lack the necessary support, structure, and resources to effectively promote and maintain research training.¹ Additionally, residents have less exposure to researchers who could serve as mentors due to the growing demands placed on attending physicians in teaching hospitals.¹⁰

The Research Arms Race

The growing emphasis on scholarly activity for residency and fellowship applicants coupled with the use of research productivity to differentiate candidates has led some to declare a “research arms race” in residency selection.³ As one author stated, “We need less research, better research, and research done for the right reasons.”¹¹ Indeed, most articles authored by medical students are short reviews or case reports, with the majority (59% [207/350]) being cited zero times, according to one analysis.¹² Given the variable research infrastructure between programs and the decreasing availability of research mentors despite the growing emphasis on scholarly activity, applicants face an unfortunate dilemma. Until the system changes, those who protest this research arms race by not engaging in substantial scholarly activity are less likely to match into competitive specialties. Thus, the race continues.

The Value of Mentorship

Resident research success is impacted by having an effective faculty research mentor.¹³ Although all medical research at the student or resident levels should be conducted with a faculty mentor to oversee it, finding a mentor can be challenging. If a resident’s program boasts a strong research infrastructure or prolific faculty, building relationships with potential mentors is a logical first step for residents wishing to engage in research; however, if suitable mentors are lacking, efforts should be made by residents to establish these connections elsewhere, such as attending society meetings to network with potential mentors and applying to formal mentorship programs (eg, the American Society for Dermatologic Surgery’s Preceptor Program, the Women’s Dermatologic Society’s Mentorship Award). Unsolicited email inquiries asking, “Hi Dr. X, my name is Y, and I was wondering if you have any research projects I could help with?” often go unanswered. Instead, consider emailing or approaching potential mentors with a more developed proposition, such as the following example:

Hello Dr. X, my name is Y. I have enjoyed reading your publications on A, which inspired me to think about B. I reviewed the literature and noticed a potential to enhance our current understanding on the topic. My team and I conducted a systematic review of the available literature and drafted a manuscript summarizing our findings. Given your expertise in this field, would you be willing to collaborate on this paper? We would be grateful for your critical eye, suggestions for improvement, and overall thoughts.

This approach demonstrates initiative, provides a clear plan, and shows respect for the mentor’s expertise, increasing the likelihood of a positive response and fruitful collaboration. Assuming the resident’s working draft meets the potential mentor’s basic expectations, such a display of initiative is likely to impress them, and they may then offer opportunities to engage in meaningful research projects in the future. Everyone benefits! These efforts to establish connections with mentors can pave the way to further collaboration and meaningful research opportunities for dermatology residents.

The Systematic Review: An Attractive Option For Residents

There are several potential avenues for students or residents interested in pursuing research. Case reports and case series are relatively easy to compile, can be completed quickly, and often require minimal guidance from a faculty mentor; however, case reports rank low in the research hierarchy. Conversely, prospective blinded clinical trials provide some of the highest-quality evidence available but are challenging to conduct without a practicing faculty member to provide a patient cohort, often require extensive funding, and may involve complex statistical analyses beyond the expertise of most students or residents. Additionally, they may take years to complete, often extending beyond residency or fellowship application deadlines.

Most medical applicants likely hold at least some hesitation in churning out vast amounts of low-quality research merely to boost their publication count for the match process. Ideally, those who pursue scholarly activity should be driven by a genuine desire to contribute meaningfully to the medical literature. One particularly valuable avenue for trainees wishing to engage in research is the systematic review, which aims to identify, evaluate, and summarize the findings of all relevant individual studies regarding a research topic and answer a focused question. If performed thoughtfully, a systematic review can meaningfully contribute to the medical literature without requiring access to a prospectively followed cohort of patients or the constant supervision of a faculty mentor. Sure, systematic reviews may not be as robust as prospective cohort clinical trials, but they often provide comprehensive insights and are considered valuable contributions to evidence-based medicine. With the help of co-residents or medical students, a medical reference librarian, and a statistician—along with a working understanding of universally accepted quality measures—a resident physician and their team can produce a systematic review that ultimately may merit publication in a top-tier medical journal.

The remainder of this column will outline a streamlined approach to the systematic review writing process, specifically tailored for medical residents who may not have affiliations to a prolific research department or established relationships with faculty mentors in their field of interest. The aim is to offer a basic framework to help residents navigate the complexities of conducting and writing a high-quality, impactful systematic review. It is important to emphasize that resident research should always be conducted under the guidance of a faculty mentor, and this approach is not intended to encourage independent research and publication by residents. Instead, it provides steps that can be undertaken with a foundational understanding of accepted principles, allowing residents to compile a working draft of a manuscript in collaboration with a trusted faculty mentor.

The Systematic Review: A Simple Approach

Step 1: Choose a Topic—Once a resident has decided to embark on conducting a systematic review, the first step is to choose a topic, which requires consideration of several factors to ensure relevance, feasibility, and impact. Begin by identifying areas of clinical uncertainty or controversy in which a comprehensive synthesis of the literature could provide valuable insights. Often, such a topic can be gleaned from the conclusion section of other primary studies; statements such as “further study is needed to determine the efficacy of X” or “systematic reviews would be beneficial to ascertaining the impact of Y” may be a great place to start.

Next, ensure that sufficient primary studies exist to support a robust review or meta-analysis by conducting a preliminary literature search, which will confirm that the chosen topic is both researchable and relevant. A narrow, focused, well-defined topic likely will prove more feasible to review than a broad, ill-defined one. Once a topic is selected, it is advisable to discuss it with a faculty mentor before starting the literature search to ensure the topic’s feasibility and clinical relevance, helping to guide your research in a meaningful direction.

When deciding between a systematic review and a meta-analysis, the nature of the research question is an influential factor. A systematic review is particularly suitable for addressing broad questions or topics when the aim is to summarize and synthesize all relevant research studies; for example, a systematic review may investigate the various treatment options for atopic dermatitis and their efficacy, which allows for a comprehensive overview of the available treatments—both the interventions and the outcomes. In contrast, a meta-analysis is ideal for collecting and statistically combining quantitative data from multiple primary studies, provided there are enough relevant studies available in the literature.

Step 2: Build a Team—Recruiting a skilled librarian to assist with Medical Subject Headings (MeSH) terms and retrieving relevant papers is crucial for conducting a high-quality systematic review or meta-analysis. Medical librarians specializing in health sciences enhance the efficiency, comprehensiveness, and reliability of your literature search, substantially boosting your work’s credibility. These librarians are well versed in medical databases such as PubMed and Embase. Begin by contacting your institution’s library services, as there often are valuable resources and personnel available to assist you. Personally, I was surprised to find a librarian at my institution specifically dedicated to helping medical residents with such projects! These professionals are eager to help, and if provided with the scope and goal of your project, they can deliver literature search results in a digestible format. Similarly, seeking the expertise of a medical statistician is crucial to the accuracy and legitimacy of your study. In your final paper, it is important to recognize the contributions of the librarian and statistician, either as co-authors or in the acknowledgments section.

In addition, recruiting colleagues or medical students can be an effective strategy to make the project more feasible and offer collaborative benefits for all parties involved. Given the growing emphasis on research for residency and fellowship admissions, there usually is no shortage of motivated volunteers.

Next, identify the software tool you will use for your systematic review. Options range from simple spreadsheets such as Microsoft Excel to reference managers such as EndNote or Mendeley or dedicated systematic review tools. Academic institutions may subscribe to paid services such as Covidence (https://www.covidence.org), or you can utilize free alternatives such as Rayyan (https://www.rayyan.ai). Investing time in learning to navigate dedicated systematic review software can greatly enhance efficiency and reduce frustrations compared to more basic methods. Ultimately, staying organized, thorough, and committed is key.

Step 3: Conduct the Literature Review—At this point, your research topic has been decided, a medical reference librarian has provided the results of a comprehensive literature search, and a software tool has been chosen. The next task is to read hundreds or thousands of papers—easy, right? With your dedicated team assembled, the workload can be divided and conquered. The first step involves screening out duplicate and irrelevant studies based on titles and abstracts. Next, review the remaining papers in more detail. Those that pass this preliminary screen should be read in their entirety, and only the papers relevant to the research topic should be included in the final synthesis. If there are uncertainties about a study’s relevance, consulting a faculty mentor is advisable. To ensure the systematic review is as thorough as possible, pay special attention to the references section of each paper, as cited references can reveal relevant studies that may have been missed in the literature search.

Once all relevant papers are compiled and read, the relevant data points should be extracted and imputed into a data sheet. Collaborating with a medical statistician is crucial at this stage, as they can provide guidance on the most effective ways to structure and input data. After all studies are included, the relevant statistical analyses on the resultant dataset can be run.

Step 4: Write the Paper—In 2020, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was developed to ensure transparent and complete reporting of systematic reviews. A full discussion of PRISMA guidelines is beyond the scope of this paper; Page et al¹⁴ provided a summary, checklist, and flow diagram that is available online (https://www.prisma-statement.org). Following the PRISMA checklist and guidelines ensures a high-quality, transparent, and reliable systematic review. These guidelines not only help streamline and simplify the writing process but also enhance its efficiency and effectiveness. Discovering the PRISMA checklist can be transformative, providing a valuable roadmap that guides the author through each step of the reporting process, helping to avoid common pitfalls. This structured approach ultimately leads to a more comprehensive and trustworthy review.

Step 5: Make Finishing Touches—At this stage in the systematic review process, the studies have been compiled and thoroughly analyzed and the statistical analysis has been conducted. The results have been organized within a structured framework following the PRISMA checklist. With these steps completed, the next task is to finalize the manuscript and seek a final review from the senior author or faculty mentor. To streamline this process, it is beneficial to adhere to the formatting guidelines of the specific medical journal you intend to submit to. Check the author guidelines on the journal’s website and review recent systematic reviews published there as a reference. Even if you have not chosen a journal yet, formatting your manuscript according to a prestigious journal’s general style provides a strong foundation that can be easily adapted to fit another journal’s requirements if necessary.

Final Thoughts

Designing and conducting a systematic review is no easy task, but it can be a valuable skill for dermatology residents aiming to contribute meaningfully to the medical literature. The process of compiling a systematic review offers an opportunity for developing critical research skills, from formulating a research question to synthesizing evidence and presenting findings in a clear methodical way. Engaging in systematic review writing not only enhances the resident’s understanding of a particular topic but also demonstrates a commitment to scholarly activity—a key factor in an increasingly competitive residency and fellowship application environment.

The basic steps outlined in this article are just one way in which residents can begin to navigate the complexities of medical research, specifically the systematic review process. By assembling a supportive team, utilizing available resources, and adhering to established guidelines such as PRISMA, one can produce a high-quality, impactful review. Ultimately, the systematic review process is not just about publication—it is about fostering a habit of inquiry, improving patient care, and contributing to the ever-evolving field of medicine. With dedication and collaboration, even the most challenging aspects of research can be tackled, paving the way for future opportunities and professional growth. In this way, perhaps one day the spirit of the “research race” can shift from a frantic sprint to a graceful marathon, where each mile is run with heart and every step is filled with purpose.

Financial relationships between physicians and industry are prevalent and complex and may have implications for patient care. A 2007 study reported that 94% of 3167 physicians surveyed had established some form of paid relationship with companies in the pharmaceutical industry.¹ To facilitate increased transparency around these relationships, lawmakers passed the Physician Payments Sunshine Act in 2010, which requires pharmaceutical companies and device manufacturers to report all payments made to physicians.² Mandatory disclosures include meals, honoraria, travel expenses, grants, and ownership or investment interests greater than $10. The information is displayed publicly in the Open Payments database (OPD)(https://openpayments-data.cms.gov/), a platform run by the Centers for Medicare and Medicaid Services.

The OPD allows for in-depth analyses of industry payments made to physicians. Many medical specialties—including orthopedics,^3-5 plastic surgery,^6,7 ophthalmology,⁸ and gastroenterology⁹—have published extensive literature characterizing the nature of these payments and disparities in the distribution of payments based on sex, geographic distribution, and other factors. After the first full year of OPD data collection for dermatology in 2014, Feng et al¹⁰ examined the number, amount, and nature of industry payments to dermatologists, as well as their geographic distribution for that year. As a follow-up to this initial research, Schlager et al¹¹ characterized payments made to dermatologists for the year 2016 and found an increase in the total payments, mean payments, and number of dermatologists receiving payments compared with the 2014 data.

Our study aimed to characterize the last 5 years of available OPD data—from January 1, 2017, to December 31, 2021—to further explore trends in industry payments made to dermatologists. In particular, we examined the effects of the COVID-19 pandemic on payments as well as sex disparities and the distribution of industry payments.

Methods

We performed a retrospective analysis of the OPD for the general payment datasets from January 1, 2017, to December 31, 2021. The results were filtered to include only payments made to dermatologists, excluding physicians from other specialties, physician assistants, and other types of practitioners. Data for each physician were grouped by National Provider Identifier (NPI) for providers included in the set, allowing for analysis at the individual level. Data on sex were extracted from the National Plan & Provider Enumeration System’s monthly data dissemination for NPIs for July 2023 (when the study was conducted) and were joined to the OPD data using the NPI number reported for each physician. All data were extracted, transformed, and analyzed using R software (version 4.2.1). Figures and visualizations were produced using Microsoft Excel 2016.

Results

In 2017, a total of 358,884 payments were made by industry to dermatologists, accounting for nearly $58.0 million. The mean total value of payments received per dermatologist was $5231.74, and the mean payment amount was $161.49. In 2018, the total number of payments increased year-over-year by 5.5% (378,509 payments), the total value of payments received increased by 7.5% (approximately $62.3 million), and the mean total value of payments received per dermatologist increased by 5.3% ($5508.98). In 2019, the total number of payments increased by 3.0% (389,670 total payments), the total value of payments recieved increased by 13.2% (approximately $70.5 million), and the mean total value of payments received per dermatologist increased by 11.3% ($6133.45). All of these values decreased in 2020, likely due to COVID-19–related restrictions on travel and meetings (total number of payments, 208,470 [−46.5%]; total value of payments received, approximately $37.5 million [−46.9%], mean total value of payments received per dermatologist, $3757.27 [−38.7%]), but the mean payment amount remained stable at $179.47. In 2021, the total number of payments (295,808 [+41.9%]), total value of payments received (approximately $50.3 million [+34.4%]), and mean total value of payments received per dermatologist ($4707.88 [+25.3%]) all rebounded, but not to pre-2020 levels (Table 1). When looking at the geographic distribution of payments, the top 5 states receiving the highest total value of payments during the study period included California ($41.51 million), New York ($32.26 million), Florida ($21.38 million), Texas ($19.93 million), and Pennsylvania ($11.69 million).

For each year from 2017 to 2021, more than 80% of payments made to dermatologists were less than $50. The majority (60.7%–75.8%) were in the $10 to $50 range. Between 4% and 5% of payments were more than $1000 for each year. Fewer than 10% of dermatologists received more than $5000 in total payments per year. Most dermatologists (33.3%–36.9%) received $100 to $500 per year. The distribution of payments stratified by number of payments made by amount and payment amount per dermatologist is further delineated in Table 2.

Comment

Benefits of Physician Relationships With Industry—The Physician Payments Sunshine Act increased transparency of industry payments to physicians by creating the OPD through which these relationships can be reported.¹² The effects of these relationships on treatment practices have been the subject of many studies in recent years. Some have suggested that industry ties may impact prescription patterns of endorsed medications.¹³ It also has been reported that the chance of a research study identifying a positive outcome for a particular treatment is higher when the study is funded by a pharmaceutical company compared to other sponsors.¹⁴ On the other hand, some researchers have argued that, when established and maintained in an ethical manner, industry-physician relationships may help practitioners stay updated on the newest treatment paradigms and benefit patient care.¹⁵ Industry relationships may help drive innovation of new products with direct input from frontline physicians who take care of the patients these products aim to help.

Limitations of the OPD—Critics of the OPD have argued that the reported data lack sufficient context and are not easily interpretable by most patients.¹⁶ In addition, many patients might not know about the existence of the database. Indeed, one national survey-based study showed that only 12% of 3542 respondents knew that this information was publicly available, and only 5% knew whether their own physician had received industry payments.¹⁷

Increased Payments From Industry—Our analysis builds on previously reported data in dermatology from 2014 to 2016.^10,11 We found that the trends of increasing numbers and dollar amounts of payments made by industry to dermatologists continued from 2017 to 2019, which may reflect the intended effects of the Physician Payments Sunshine Act, as more payments are being reported in a transparent manner. It also shows that relationships between industry and dermatologists have become more commonplace over time.

It is important to consider these trends in the context of overall Medicare expenditures and prescription volumes. Between 2008 and 2021, prescription volumes have been increasing at a rate of 1% to 4% per year, with 2020 being an exception as the volume decreased slightly from the year prior due to COVID-19 (−3%). Similarly, total Medicare and Medicaid expenditures have been growing at a rate of almost 5% per year.¹⁸ Based on our study results, it appears the total value of payments made between 2017 and 2021 increased at a rate that outpaced prescription volume and expenditures; however, it is difficult to draw conclusions about the relationship between payments made to dermatologists and spending without examining prescriptions specific to dermatologists in the OPD dataset. This relationship could be further explored in future studies.

COVID-19 Restrictions Impacted Payments in 2021—We hypothesize that COVID-19–related restrictions on traveling and in-person meetings led to a decrease in the number of payments, total payment amount, and mean total value of payments received per dermatologist. Notably, compensation for services other than consulting, including speaking fees, had the most precipitous decrease in total payment amount. On the other hand, honoraria and consulting fees were least impacted, as many dermatologists were still able to maintain relationships with industry on an advisory basis without traveling. From 2020 to 2021, the number of total payments and dollar amounts increased with easing of COVID-19 restrictions; however, they had not yet rebounded to 2019 levels during the study period. It will be interesting to continue monitoring these trends once data from future years become available.

Top-Compensated Dermatologists—Our study results also show that for all years from 2017 through 2021, the majority of industry payments were made to a small concentrated percentage of top-compensated dermatologists, which may reflect larger and more frequent payments to those identified by pharmaceutical companies as thought leaders and key opinion leaders in the field or those who are more willing to establish extensive ties with industry. Similarly skewed distributions in payments have been shown in other medical subspecialties including neurosurgery, plastic surgery, otolaryngology, and orthopedics.^4,6,19,20 It also is apparent that the majority of compensated dermatologists in the OPD maintain relatively small ties with industry. For every year from 2017 to 2021, more than half of compensated dermatologists received total payments of less than $500 per year, most of which stemmed from the food and beverage category. Interestingly, a prior study showed that patient perceptions of industry-physician ties may be more strongly impacted by the payment category than the amount.²¹ For example, respondents viewed payments for meals and lodging more negatively, as they were seen more as personal gifts without direct benefit to patients. Conversely, respondents held more positive views of physicians who received free drug samples, which were perceived as benefiting patients, as well as those receiving consulting fees, which were perceived as a signal of physician expertise. Notably, in the same study, physicians who received no payments from industry were seen as honest but also were viewed by some respondents as being inexperienced or uninformed about new treatments.²¹

The contribution and public perception of dermatologists who conduct investigator-initiated research utilizing other types of funding (eg, government grants) also are important to consider but were not directly assessed within the scope of the current study.

Sex Disparities in Compensation—Multiple studies in the literature have demonstrated that sex inequities exist across medical specialties.^22,23 In dermatology, although women make up slightly more than 50% of board-certified dermatologists, they continue to be underrepresented compared with men in leadership positions, academic rank, research funding, and lectureships at national meetings.^24-27 In survey-based studies specifically examining gender-based physician compensation, male dermatologists were found to earn higher salaries than their female counterparts in both private practice and academic settings, even after adjusting for work hours, practice characteristics, and academic rank.^28,29

Our study contributes to the growing body of evidence suggesting that sex inequities also may exist with regard to financial payments from industry. Our results showed that, although the number of male and female dermatologists with industry relationships was similar each year, the number of payments made and total payment amount were both significantly (P<.001) higher for male dermatologists from 2017 through 2021. In 2021, the mean payment amount ($201.57 for male dermatologists; $117.73 for female dermatologists) and mean total amount of payments received ($6172.89 and $2957.79, respectively) also were significantly higher for male compared with female dermatologists (P<.001). The cause of this disparity likely is multifactorial and warrants additional studies in the future. One hypothesis in the existing literature is that male physicians may be more inclined to seek out relationships with industry; it also is possible that disparities in research funding, academic rank, and speaking opportunities at national conferences detailed previously may contribute to inequities in industry payments as companies seek out perceived leaders in the field.³⁰

Limitations and Future Directions—Several important limitations of our study warrant further consideration. As with any database study, the accuracy of the results presented and the conclusions drawn are highly dependent on the precision of the available data, which is reliant on transparent documentation by pharmaceutical companies and physicians. There are no independent methods of verifying the information reported. There have been reports in the literature questioning the utility of the OPD data and risk for misinterpretation.^16,31 Furthermore, the OPD only includes companies whose products are covered by government-sponsored programs, such as Medicare and Medicaid, and therefore does not encompass the totality of industry-dermatologist relationships. We also focused specifically on board-certified dermatologists and did not analyze the extent of industry relationships involving residents, nurses, physician assistants, and other critical members of health care teams that may impact patient care. Differences between academic and private practice payments also could not be examined using the OPD but could present an interesting area for future studies.

Despite these limitations, our study was extensive, using the publicly available OPD to analyze trends and disparities in financial relationships between dermatologists and industry partners from 2017 through 2021. Notably, these findings are not intended to provide judgment or seek to tease out financial relationships that are beneficial for patient care from those that are not; rather, they are intended only to lend additional transparency, provoke thought, and encourage future studies and discussion surrounding this important topic.

Conclusion

Financial relationships between dermatologists and industry are complex and are becoming more prevalent, as shown in our study. These relationships may be critical to facilitate novel patient-centered research and growth in the field of dermatology; however, they also have the potential to be seen as bias in patient care. Transparent reporting of these relationships is an important step in future research regarding the effects of different payment types and serves as the basis for further understanding industry-dermatologist relationships as well as any inequities that exist in the distribution of payments. We encourage all dermatologists to review their public profiles in the OPD. Physicians have the opportunity to review all payment data reported by companies and challenge the accuracy of the data if necessary.

Financial relationships between physicians and industry are prevalent and complex and may have implications for patient care. A 2007 study reported that 94% of 3167 physicians surveyed had established some form of paid relationship with companies in the pharmaceutical industry.¹ To facilitate increased transparency around these relationships, lawmakers passed the Physician Payments Sunshine Act in 2010, which requires pharmaceutical companies and device manufacturers to report all payments made to physicians.² Mandatory disclosures include meals, honoraria, travel expenses, grants, and ownership or investment interests greater than $10. The information is displayed publicly in the Open Payments database (OPD)(https://openpayments-data.cms.gov/), a platform run by the Centers for Medicare and Medicaid Services.

The OPD allows for in-depth analyses of industry payments made to physicians. Many medical specialties—including orthopedics,^3-5 plastic surgery,^6,7 ophthalmology,⁸ and gastroenterology⁹—have published extensive literature characterizing the nature of these payments and disparities in the distribution of payments based on sex, geographic distribution, and other factors. After the first full year of OPD data collection for dermatology in 2014, Feng et al¹⁰ examined the number, amount, and nature of industry payments to dermatologists, as well as their geographic distribution for that year. As a follow-up to this initial research, Schlager et al¹¹ characterized payments made to dermatologists for the year 2016 and found an increase in the total payments, mean payments, and number of dermatologists receiving payments compared with the 2014 data.

Our study aimed to characterize the last 5 years of available OPD data—from January 1, 2017, to December 31, 2021—to further explore trends in industry payments made to dermatologists. In particular, we examined the effects of the COVID-19 pandemic on payments as well as sex disparities and the distribution of industry payments.

Methods

We performed a retrospective analysis of the OPD for the general payment datasets from January 1, 2017, to December 31, 2021. The results were filtered to include only payments made to dermatologists, excluding physicians from other specialties, physician assistants, and other types of practitioners. Data for each physician were grouped by National Provider Identifier (NPI) for providers included in the set, allowing for analysis at the individual level. Data on sex were extracted from the National Plan & Provider Enumeration System’s monthly data dissemination for NPIs for July 2023 (when the study was conducted) and were joined to the OPD data using the NPI number reported for each physician. All data were extracted, transformed, and analyzed using R software (version 4.2.1). Figures and visualizations were produced using Microsoft Excel 2016.

Results

In 2017, a total of 358,884 payments were made by industry to dermatologists, accounting for nearly $58.0 million. The mean total value of payments received per dermatologist was $5231.74, and the mean payment amount was $161.49. In 2018, the total number of payments increased year-over-year by 5.5% (378,509 payments), the total value of payments received increased by 7.5% (approximately $62.3 million), and the mean total value of payments received per dermatologist increased by 5.3% ($5508.98). In 2019, the total number of payments increased by 3.0% (389,670 total payments), the total value of payments recieved increased by 13.2% (approximately $70.5 million), and the mean total value of payments received per dermatologist increased by 11.3% ($6133.45). All of these values decreased in 2020, likely due to COVID-19–related restrictions on travel and meetings (total number of payments, 208,470 [−46.5%]; total value of payments received, approximately $37.5 million [−46.9%], mean total value of payments received per dermatologist, $3757.27 [−38.7%]), but the mean payment amount remained stable at $179.47. In 2021, the total number of payments (295,808 [+41.9%]), total value of payments received (approximately $50.3 million [+34.4%]), and mean total value of payments received per dermatologist ($4707.88 [+25.3%]) all rebounded, but not to pre-2020 levels (Table 1). When looking at the geographic distribution of payments, the top 5 states receiving the highest total value of payments during the study period included California ($41.51 million), New York ($32.26 million), Florida ($21.38 million), Texas ($19.93 million), and Pennsylvania ($11.69 million).

For each year from 2017 to 2021, more than 80% of payments made to dermatologists were less than $50. The majority (60.7%–75.8%) were in the $10 to $50 range. Between 4% and 5% of payments were more than $1000 for each year. Fewer than 10% of dermatologists received more than $5000 in total payments per year. Most dermatologists (33.3%–36.9%) received $100 to $500 per year. The distribution of payments stratified by number of payments made by amount and payment amount per dermatologist is further delineated in Table 2.

Comment

Benefits of Physician Relationships With Industry—The Physician Payments Sunshine Act increased transparency of industry payments to physicians by creating the OPD through which these relationships can be reported.¹² The effects of these relationships on treatment practices have been the subject of many studies in recent years. Some have suggested that industry ties may impact prescription patterns of endorsed medications.¹³ It also has been reported that the chance of a research study identifying a positive outcome for a particular treatment is higher when the study is funded by a pharmaceutical company compared to other sponsors.¹⁴ On the other hand, some researchers have argued that, when established and maintained in an ethical manner, industry-physician relationships may help practitioners stay updated on the newest treatment paradigms and benefit patient care.¹⁵ Industry relationships may help drive innovation of new products with direct input from frontline physicians who take care of the patients these products aim to help.

Limitations of the OPD—Critics of the OPD have argued that the reported data lack sufficient context and are not easily interpretable by most patients.¹⁶ In addition, many patients might not know about the existence of the database. Indeed, one national survey-based study showed that only 12% of 3542 respondents knew that this information was publicly available, and only 5% knew whether their own physician had received industry payments.¹⁷

Increased Payments From Industry—Our analysis builds on previously reported data in dermatology from 2014 to 2016.^10,11 We found that the trends of increasing numbers and dollar amounts of payments made by industry to dermatologists continued from 2017 to 2019, which may reflect the intended effects of the Physician Payments Sunshine Act, as more payments are being reported in a transparent manner. It also shows that relationships between industry and dermatologists have become more commonplace over time.

It is important to consider these trends in the context of overall Medicare expenditures and prescription volumes. Between 2008 and 2021, prescription volumes have been increasing at a rate of 1% to 4% per year, with 2020 being an exception as the volume decreased slightly from the year prior due to COVID-19 (−3%). Similarly, total Medicare and Medicaid expenditures have been growing at a rate of almost 5% per year.¹⁸ Based on our study results, it appears the total value of payments made between 2017 and 2021 increased at a rate that outpaced prescription volume and expenditures; however, it is difficult to draw conclusions about the relationship between payments made to dermatologists and spending without examining prescriptions specific to dermatologists in the OPD dataset. This relationship could be further explored in future studies.

COVID-19 Restrictions Impacted Payments in 2021—We hypothesize that COVID-19–related restrictions on traveling and in-person meetings led to a decrease in the number of payments, total payment amount, and mean total value of payments received per dermatologist. Notably, compensation for services other than consulting, including speaking fees, had the most precipitous decrease in total payment amount. On the other hand, honoraria and consulting fees were least impacted, as many dermatologists were still able to maintain relationships with industry on an advisory basis without traveling. From 2020 to 2021, the number of total payments and dollar amounts increased with easing of COVID-19 restrictions; however, they had not yet rebounded to 2019 levels during the study period. It will be interesting to continue monitoring these trends once data from future years become available.

Top-Compensated Dermatologists—Our study results also show that for all years from 2017 through 2021, the majority of industry payments were made to a small concentrated percentage of top-compensated dermatologists, which may reflect larger and more frequent payments to those identified by pharmaceutical companies as thought leaders and key opinion leaders in the field or those who are more willing to establish extensive ties with industry. Similarly skewed distributions in payments have been shown in other medical subspecialties including neurosurgery, plastic surgery, otolaryngology, and orthopedics.^4,6,19,20 It also is apparent that the majority of compensated dermatologists in the OPD maintain relatively small ties with industry. For every year from 2017 to 2021, more than half of compensated dermatologists received total payments of less than $500 per year, most of which stemmed from the food and beverage category. Interestingly, a prior study showed that patient perceptions of industry-physician ties may be more strongly impacted by the payment category than the amount.²¹ For example, respondents viewed payments for meals and lodging more negatively, as they were seen more as personal gifts without direct benefit to patients. Conversely, respondents held more positive views of physicians who received free drug samples, which were perceived as benefiting patients, as well as those receiving consulting fees, which were perceived as a signal of physician expertise. Notably, in the same study, physicians who received no payments from industry were seen as honest but also were viewed by some respondents as being inexperienced or uninformed about new treatments.²¹

The contribution and public perception of dermatologists who conduct investigator-initiated research utilizing other types of funding (eg, government grants) also are important to consider but were not directly assessed within the scope of the current study.

Sex Disparities in Compensation—Multiple studies in the literature have demonstrated that sex inequities exist across medical specialties.^22,23 In dermatology, although women make up slightly more than 50% of board-certified dermatologists, they continue to be underrepresented compared with men in leadership positions, academic rank, research funding, and lectureships at national meetings.^24-27 In survey-based studies specifically examining gender-based physician compensation, male dermatologists were found to earn higher salaries than their female counterparts in both private practice and academic settings, even after adjusting for work hours, practice characteristics, and academic rank.^28,29

Our study contributes to the growing body of evidence suggesting that sex inequities also may exist with regard to financial payments from industry. Our results showed that, although the number of male and female dermatologists with industry relationships was similar each year, the number of payments made and total payment amount were both significantly (P<.001) higher for male dermatologists from 2017 through 2021. In 2021, the mean payment amount ($201.57 for male dermatologists; $117.73 for female dermatologists) and mean total amount of payments received ($6172.89 and $2957.79, respectively) also were significantly higher for male compared with female dermatologists (P<.001). The cause of this disparity likely is multifactorial and warrants additional studies in the future. One hypothesis in the existing literature is that male physicians may be more inclined to seek out relationships with industry; it also is possible that disparities in research funding, academic rank, and speaking opportunities at national conferences detailed previously may contribute to inequities in industry payments as companies seek out perceived leaders in the field.³⁰

Limitations and Future Directions—Several important limitations of our study warrant further consideration. As with any database study, the accuracy of the results presented and the conclusions drawn are highly dependent on the precision of the available data, which is reliant on transparent documentation by pharmaceutical companies and physicians. There are no independent methods of verifying the information reported. There have been reports in the literature questioning the utility of the OPD data and risk for misinterpretation.^16,31 Furthermore, the OPD only includes companies whose products are covered by government-sponsored programs, such as Medicare and Medicaid, and therefore does not encompass the totality of industry-dermatologist relationships. We also focused specifically on board-certified dermatologists and did not analyze the extent of industry relationships involving residents, nurses, physician assistants, and other critical members of health care teams that may impact patient care. Differences between academic and private practice payments also could not be examined using the OPD but could present an interesting area for future studies.

Despite these limitations, our study was extensive, using the publicly available OPD to analyze trends and disparities in financial relationships between dermatologists and industry partners from 2017 through 2021. Notably, these findings are not intended to provide judgment or seek to tease out financial relationships that are beneficial for patient care from those that are not; rather, they are intended only to lend additional transparency, provoke thought, and encourage future studies and discussion surrounding this important topic.

Conclusion

Financial relationships between dermatologists and industry are complex and are becoming more prevalent, as shown in our study. These relationships may be critical to facilitate novel patient-centered research and growth in the field of dermatology; however, they also have the potential to be seen as bias in patient care. Transparent reporting of these relationships is an important step in future research regarding the effects of different payment types and serves as the basis for further understanding industry-dermatologist relationships as well as any inequities that exist in the distribution of payments. We encourage all dermatologists to review their public profiles in the OPD. Physicians have the opportunity to review all payment data reported by companies and challenge the accuracy of the data if necessary.

Financial relationships between physicians and industry are prevalent and complex and may have implications for patient care. A 2007 study reported that 94% of 3167 physicians surveyed had established some form of paid relationship with companies in the pharmaceutical industry.¹ To facilitate increased transparency around these relationships, lawmakers passed the Physician Payments Sunshine Act in 2010, which requires pharmaceutical companies and device manufacturers to report all payments made to physicians.² Mandatory disclosures include meals, honoraria, travel expenses, grants, and ownership or investment interests greater than $10. The information is displayed publicly in the Open Payments database (OPD)(https://openpayments-data.cms.gov/), a platform run by the Centers for Medicare and Medicaid Services.

The OPD allows for in-depth analyses of industry payments made to physicians. Many medical specialties—including orthopedics,^3-5 plastic surgery,^6,7 ophthalmology,⁸ and gastroenterology⁹—have published extensive literature characterizing the nature of these payments and disparities in the distribution of payments based on sex, geographic distribution, and other factors. After the first full year of OPD data collection for dermatology in 2014, Feng et al¹⁰ examined the number, amount, and nature of industry payments to dermatologists, as well as their geographic distribution for that year. As a follow-up to this initial research, Schlager et al¹¹ characterized payments made to dermatologists for the year 2016 and found an increase in the total payments, mean payments, and number of dermatologists receiving payments compared with the 2014 data.

Our study aimed to characterize the last 5 years of available OPD data—from January 1, 2017, to December 31, 2021—to further explore trends in industry payments made to dermatologists. In particular, we examined the effects of the COVID-19 pandemic on payments as well as sex disparities and the distribution of industry payments.

Methods

We performed a retrospective analysis of the OPD for the general payment datasets from January 1, 2017, to December 31, 2021. The results were filtered to include only payments made to dermatologists, excluding physicians from other specialties, physician assistants, and other types of practitioners. Data for each physician were grouped by National Provider Identifier (NPI) for providers included in the set, allowing for analysis at the individual level. Data on sex were extracted from the National Plan & Provider Enumeration System’s monthly data dissemination for NPIs for July 2023 (when the study was conducted) and were joined to the OPD data using the NPI number reported for each physician. All data were extracted, transformed, and analyzed using R software (version 4.2.1). Figures and visualizations were produced using Microsoft Excel 2016.

Results

In 2017, a total of 358,884 payments were made by industry to dermatologists, accounting for nearly $58.0 million. The mean total value of payments received per dermatologist was $5231.74, and the mean payment amount was $161.49. In 2018, the total number of payments increased year-over-year by 5.5% (378,509 payments), the total value of payments received increased by 7.5% (approximately $62.3 million), and the mean total value of payments received per dermatologist increased by 5.3% ($5508.98). In 2019, the total number of payments increased by 3.0% (389,670 total payments), the total value of payments recieved increased by 13.2% (approximately $70.5 million), and the mean total value of payments received per dermatologist increased by 11.3% ($6133.45). All of these values decreased in 2020, likely due to COVID-19–related restrictions on travel and meetings (total number of payments, 208,470 [−46.5%]; total value of payments received, approximately $37.5 million [−46.9%], mean total value of payments received per dermatologist, $3757.27 [−38.7%]), but the mean payment amount remained stable at $179.47. In 2021, the total number of payments (295,808 [+41.9%]), total value of payments received (approximately $50.3 million [+34.4%]), and mean total value of payments received per dermatologist ($4707.88 [+25.3%]) all rebounded, but not to pre-2020 levels (Table 1). When looking at the geographic distribution of payments, the top 5 states receiving the highest total value of payments during the study period included California ($41.51 million), New York ($32.26 million), Florida ($21.38 million), Texas ($19.93 million), and Pennsylvania ($11.69 million).

For each year from 2017 to 2021, more than 80% of payments made to dermatologists were less than $50. The majority (60.7%–75.8%) were in the $10 to $50 range. Between 4% and 5% of payments were more than $1000 for each year. Fewer than 10% of dermatologists received more than $5000 in total payments per year. Most dermatologists (33.3%–36.9%) received $100 to $500 per year. The distribution of payments stratified by number of payments made by amount and payment amount per dermatologist is further delineated in Table 2.

Comment

Benefits of Physician Relationships With Industry—The Physician Payments Sunshine Act increased transparency of industry payments to physicians by creating the OPD through which these relationships can be reported.¹² The effects of these relationships on treatment practices have been the subject of many studies in recent years. Some have suggested that industry ties may impact prescription patterns of endorsed medications.¹³ It also has been reported that the chance of a research study identifying a positive outcome for a particular treatment is higher when the study is funded by a pharmaceutical company compared to other sponsors.¹⁴ On the other hand, some researchers have argued that, when established and maintained in an ethical manner, industry-physician relationships may help practitioners stay updated on the newest treatment paradigms and benefit patient care.¹⁵ Industry relationships may help drive innovation of new products with direct input from frontline physicians who take care of the patients these products aim to help.

Limitations of the OPD—Critics of the OPD have argued that the reported data lack sufficient context and are not easily interpretable by most patients.¹⁶ In addition, many patients might not know about the existence of the database. Indeed, one national survey-based study showed that only 12% of 3542 respondents knew that this information was publicly available, and only 5% knew whether their own physician had received industry payments.¹⁷

Increased Payments From Industry—Our analysis builds on previously reported data in dermatology from 2014 to 2016.^10,11 We found that the trends of increasing numbers and dollar amounts of payments made by industry to dermatologists continued from 2017 to 2019, which may reflect the intended effects of the Physician Payments Sunshine Act, as more payments are being reported in a transparent manner. It also shows that relationships between industry and dermatologists have become more commonplace over time.

It is important to consider these trends in the context of overall Medicare expenditures and prescription volumes. Between 2008 and 2021, prescription volumes have been increasing at a rate of 1% to 4% per year, with 2020 being an exception as the volume decreased slightly from the year prior due to COVID-19 (−3%). Similarly, total Medicare and Medicaid expenditures have been growing at a rate of almost 5% per year.¹⁸ Based on our study results, it appears the total value of payments made between 2017 and 2021 increased at a rate that outpaced prescription volume and expenditures; however, it is difficult to draw conclusions about the relationship between payments made to dermatologists and spending without examining prescriptions specific to dermatologists in the OPD dataset. This relationship could be further explored in future studies.

COVID-19 Restrictions Impacted Payments in 2021—We hypothesize that COVID-19–related restrictions on traveling and in-person meetings led to a decrease in the number of payments, total payment amount, and mean total value of payments received per dermatologist. Notably, compensation for services other than consulting, including speaking fees, had the most precipitous decrease in total payment amount. On the other hand, honoraria and consulting fees were least impacted, as many dermatologists were still able to maintain relationships with industry on an advisory basis without traveling. From 2020 to 2021, the number of total payments and dollar amounts increased with easing of COVID-19 restrictions; however, they had not yet rebounded to 2019 levels during the study period. It will be interesting to continue monitoring these trends once data from future years become available.

Top-Compensated Dermatologists—Our study results also show that for all years from 2017 through 2021, the majority of industry payments were made to a small concentrated percentage of top-compensated dermatologists, which may reflect larger and more frequent payments to those identified by pharmaceutical companies as thought leaders and key opinion leaders in the field or those who are more willing to establish extensive ties with industry. Similarly skewed distributions in payments have been shown in other medical subspecialties including neurosurgery, plastic surgery, otolaryngology, and orthopedics.^4,6,19,20 It also is apparent that the majority of compensated dermatologists in the OPD maintain relatively small ties with industry. For every year from 2017 to 2021, more than half of compensated dermatologists received total payments of less than $500 per year, most of which stemmed from the food and beverage category. Interestingly, a prior study showed that patient perceptions of industry-physician ties may be more strongly impacted by the payment category than the amount.²¹ For example, respondents viewed payments for meals and lodging more negatively, as they were seen more as personal gifts without direct benefit to patients. Conversely, respondents held more positive views of physicians who received free drug samples, which were perceived as benefiting patients, as well as those receiving consulting fees, which were perceived as a signal of physician expertise. Notably, in the same study, physicians who received no payments from industry were seen as honest but also were viewed by some respondents as being inexperienced or uninformed about new treatments.²¹

The contribution and public perception of dermatologists who conduct investigator-initiated research utilizing other types of funding (eg, government grants) also are important to consider but were not directly assessed within the scope of the current study.

Sex Disparities in Compensation—Multiple studies in the literature have demonstrated that sex inequities exist across medical specialties.^22,23 In dermatology, although women make up slightly more than 50% of board-certified dermatologists, they continue to be underrepresented compared with men in leadership positions, academic rank, research funding, and lectureships at national meetings.^24-27 In survey-based studies specifically examining gender-based physician compensation, male dermatologists were found to earn higher salaries than their female counterparts in both private practice and academic settings, even after adjusting for work hours, practice characteristics, and academic rank.^28,29

Our study contributes to the growing body of evidence suggesting that sex inequities also may exist with regard to financial payments from industry. Our results showed that, although the number of male and female dermatologists with industry relationships was similar each year, the number of payments made and total payment amount were both significantly (P<.001) higher for male dermatologists from 2017 through 2021. In 2021, the mean payment amount ($201.57 for male dermatologists; $117.73 for female dermatologists) and mean total amount of payments received ($6172.89 and $2957.79, respectively) also were significantly higher for male compared with female dermatologists (P<.001). The cause of this disparity likely is multifactorial and warrants additional studies in the future. One hypothesis in the existing literature is that male physicians may be more inclined to seek out relationships with industry; it also is possible that disparities in research funding, academic rank, and speaking opportunities at national conferences detailed previously may contribute to inequities in industry payments as companies seek out perceived leaders in the field.³⁰

Limitations and Future Directions—Several important limitations of our study warrant further consideration. As with any database study, the accuracy of the results presented and the conclusions drawn are highly dependent on the precision of the available data, which is reliant on transparent documentation by pharmaceutical companies and physicians. There are no independent methods of verifying the information reported. There have been reports in the literature questioning the utility of the OPD data and risk for misinterpretation.^16,31 Furthermore, the OPD only includes companies whose products are covered by government-sponsored programs, such as Medicare and Medicaid, and therefore does not encompass the totality of industry-dermatologist relationships. We also focused specifically on board-certified dermatologists and did not analyze the extent of industry relationships involving residents, nurses, physician assistants, and other critical members of health care teams that may impact patient care. Differences between academic and private practice payments also could not be examined using the OPD but could present an interesting area for future studies.

Despite these limitations, our study was extensive, using the publicly available OPD to analyze trends and disparities in financial relationships between dermatologists and industry partners from 2017 through 2021. Notably, these findings are not intended to provide judgment or seek to tease out financial relationships that are beneficial for patient care from those that are not; rather, they are intended only to lend additional transparency, provoke thought, and encourage future studies and discussion surrounding this important topic.

Conclusion

Financial relationships between dermatologists and industry are complex and are becoming more prevalent, as shown in our study. These relationships may be critical to facilitate novel patient-centered research and growth in the field of dermatology; however, they also have the potential to be seen as bias in patient care. Transparent reporting of these relationships is an important step in future research regarding the effects of different payment types and serves as the basis for further understanding industry-dermatologist relationships as well as any inequities that exist in the distribution of payments. We encourage all dermatologists to review their public profiles in the OPD. Physicians have the opportunity to review all payment data reported by companies and challenge the accuracy of the data if necessary.

To the Editor:

Chronic cutaneous lupus erythematosus (CCLE) is an inflammatory condition with myriad cutaneous manifestations. Most forms of CCLE have the potential to progress to systemic lupus erythematosus (SLE).¹

Blaschkolinear lupus erythematosus (BLE) is an exceedingly rare subtype of cutaneous lupus erythematosus that usually manifests during childhood as linear plaques along the lines of Blaschko.^2,3 Under normal conditions, Blaschko lines are not noticeable; they correspond to the direction of ectodermal cell migration during cutaneous embryogenesis.^4,5 The embryonic cells travel ventrolaterally, forming a V-shaped pattern on the back, an S-shaped pattern on the trunk, and an hourglass-shaped pattern on the face with several perpendicular intersections near the mouth and nose.⁶ During their migration, the cells are susceptible to somatic mutations and clonal expansion, resulting in a monoclonal population of genetically heterogenous cells. This phenomenon is known as somatic mosaicism and may lead to an increased susceptibility to an array of congenital and inflammatory dermatoses, such as cutaneous lupus erythematosus.⁴ Blaschkolinear entities tend to manifest in a unilateral distribution following exposure to a certain environmental trigger, such as trauma, viral illness, or UV radiation, although a trigger is not always present.⁷ We report a case of BLE manifesting on the head and neck in an adult patient.

A 46-year-old man presented with a pruritic rash of 3 months’ duration on the right cheek that extended inferiorly to the right upper chest. He had a medical history of well-controlled psoriasis, and he denied any antecedent trauma, fevers, chills, arthralgia, or night sweats. There had been no improvement with mometasone ointment 0.1% applied daily for 2 months as prescribed by his primary care provider. Physical examination revealed indurated, red-brown, atrophic plaques in a blaschkolinear distribution around the nose, right upper jaw, right side of the neck, and right upper chest (Figure, A).

To the Editor:

Chronic cutaneous lupus erythematosus (CCLE) is an inflammatory condition with myriad cutaneous manifestations. Most forms of CCLE have the potential to progress to systemic lupus erythematosus (SLE).¹

Blaschkolinear lupus erythematosus (BLE) is an exceedingly rare subtype of cutaneous lupus erythematosus that usually manifests during childhood as linear plaques along the lines of Blaschko.^2,3 Under normal conditions, Blaschko lines are not noticeable; they correspond to the direction of ectodermal cell migration during cutaneous embryogenesis.^4,5 The embryonic cells travel ventrolaterally, forming a V-shaped pattern on the back, an S-shaped pattern on the trunk, and an hourglass-shaped pattern on the face with several perpendicular intersections near the mouth and nose.⁶ During their migration, the cells are susceptible to somatic mutations and clonal expansion, resulting in a monoclonal population of genetically heterogenous cells. This phenomenon is known as somatic mosaicism and may lead to an increased susceptibility to an array of congenital and inflammatory dermatoses, such as cutaneous lupus erythematosus.⁴ Blaschkolinear entities tend to manifest in a unilateral distribution following exposure to a certain environmental trigger, such as trauma, viral illness, or UV radiation, although a trigger is not always present.⁷ We report a case of BLE manifesting on the head and neck in an adult patient.

A 46-year-old man presented with a pruritic rash of 3 months’ duration on the right cheek that extended inferiorly to the right upper chest. He had a medical history of well-controlled psoriasis, and he denied any antecedent trauma, fevers, chills, arthralgia, or night sweats. There had been no improvement with mometasone ointment 0.1% applied daily for 2 months as prescribed by his primary care provider. Physical examination revealed indurated, red-brown, atrophic plaques in a blaschkolinear distribution around the nose, right upper jaw, right side of the neck, and right upper chest (Figure, A).

To the Editor:

Chronic cutaneous lupus erythematosus (CCLE) is an inflammatory condition with myriad cutaneous manifestations. Most forms of CCLE have the potential to progress to systemic lupus erythematosus (SLE).¹

Blaschkolinear lupus erythematosus (BLE) is an exceedingly rare subtype of cutaneous lupus erythematosus that usually manifests during childhood as linear plaques along the lines of Blaschko.^2,3 Under normal conditions, Blaschko lines are not noticeable; they correspond to the direction of ectodermal cell migration during cutaneous embryogenesis.^4,5 The embryonic cells travel ventrolaterally, forming a V-shaped pattern on the back, an S-shaped pattern on the trunk, and an hourglass-shaped pattern on the face with several perpendicular intersections near the mouth and nose.⁶ During their migration, the cells are susceptible to somatic mutations and clonal expansion, resulting in a monoclonal population of genetically heterogenous cells. This phenomenon is known as somatic mosaicism and may lead to an increased susceptibility to an array of congenital and inflammatory dermatoses, such as cutaneous lupus erythematosus.⁴ Blaschkolinear entities tend to manifest in a unilateral distribution following exposure to a certain environmental trigger, such as trauma, viral illness, or UV radiation, although a trigger is not always present.⁷ We report a case of BLE manifesting on the head and neck in an adult patient.

A 46-year-old man presented with a pruritic rash of 3 months’ duration on the right cheek that extended inferiorly to the right upper chest. He had a medical history of well-controlled psoriasis, and he denied any antecedent trauma, fevers, chills, arthralgia, or night sweats. There had been no improvement with mometasone ointment 0.1% applied daily for 2 months as prescribed by his primary care provider. Physical examination revealed indurated, red-brown, atrophic plaques in a blaschkolinear distribution around the nose, right upper jaw, right side of the neck, and right upper chest (Figure, A).

The Diagnosis: Pityriasis Lichenoides et Varioliformis Acuta

Sectioned punch biopsies were performed on the patient’s right arm. Histopathology showed acanthosis and parakeratosis in the epidermis, with vacuolar degeneration and dyskeratosis in the basal layer. Dermal changes included extravasated red blood cells in the papillary dermis as well as perivascular lymphocytic infiltrates in both the papillary and reticular dermis (Figure). Direct immunofluorescence of a perilesional biopsy using anti–human IgG, IgM, IgA, C3, and fibrin conjugates showed no findings of immune deposition. Biopsy results were consistent with pityriasis lichenoides et varioliformis acuta (PLEVA), and the patient was treated with a 5-day course of oral azithromycin, triamcinolone ointment 0.1% twice daily, and phototherapy with narrowband UVB ³ times weekly. Rapid improvement was noted at 2-month follow-up.

Pityriasis lichenoides et varioliformis acuta is a form of pityriasis lichenoides, a group of inflammatory dermatoses that are characterized clinically by successive crops of morphologically diverse lesions. Epidemiologic studies have shown a slight male predominance. It primarily affects children and young adults, with peak ages of 8 and 32 years in pediatric and adult populations, respectively.¹

The pathogenesis of PLEVA remains unclear. An abnormal immune response to Toxoplasma, Epstein-Barr virus, HIV, and other pathogens has been suggested based on serologic evidence of concurrent disease activity with the onset of lesions as well as cutaneous improvement in some patients after treatment of the infection.¹ A T-cell lymphoproliferative etiology also has been considered based on histopathologic similarities between PLEVA and lymphomatoid papulosis (LyP) as well as findings of clonality in T-cell receptor gene rearrangement in many patients.^1,2 Some clinicians consider LyP and PLEVA as separate entities on one disease spectrum.

Eruptions of PLEVA tend to favor the trunk and proximal extremities. Lesions may begin as macules measuring 2 to 3 mm in diameter that quickly evolve into papules with fine scale that remains attached centrally. Ulcerations with hemorrhagic crusts also may be noted as the lesions progress in stage. The rash may persist for weeks to years, and overlapping crops of macules and papules at varying stages of development may be seen in the same patient.¹

Histopathologic findings of PLEVA include spongiosis, dyskeratosis, parakeratosis, and focal keratinocyte necrosis within the epidermis, as well as vacuolar degeneration of the basal layer. Lymphocyte and erythrocyte extravasation may extend into the epidermis. Dermal findings may include edema and wedge-shaped perivascular lymphocytic infiltrates extending into the reticular dermis.¹

Important differential diagnoses to consider include LyP, mycosis fungoides (MF), pemphigus foliaceus, and varicella. Lymphomatoid papulosis is a benign CD30+ lymphoproliferative disorder that is characterized by an indolent course of recurrent, often self-resolving papules that occur most frequently on the trunk, arms, and legs of older patients. There are several histologic subtypes of LyP, but the most common (type A) may manifest with wedge-shaped perivascular lymphocytic infiltrates in the dermis, similar to PLEVA. T-cell receptor gene rearrangement studies characteristically reveal clonality in LyP, and clonality has been reported in PLEVA. However, LyP demonstrates a higher cytologic grade and lacks the characteristic parakeratotic scale and superficial dermal microhemorrhage of PLEVA.³

Mycosis fungoides is a malignant lymphoproliferative disorder that is characterized by an indolent clinical course of persistent patches, plaques, or tumors of various sizes that often manifest in non–sun-exposed areas of the skin. Early stages of MF are difficult to detect histologically, but biopsies may show atypical lymphocytes with hyperchromatic, irregularly contoured nuclei arranged along the basal layer of the epidermis. Epidermal aggregates of atypical lymphocytes (also known as Pautrier microabscesses) are considered highly specific for MF. T-cell receptor and immunopathologic studies also are important adjuncts in the diagnosis of MF.⁴

Pemphigus foliaceus is an autoimmune blistering disease caused by antibodies directed against desmoglein 1, which is found in the granular layer of the epidermis. It manifests with a subtle onset of scattered crusted lesions in the seborrheic areas, such as the scalp, face, chest, and upper back. Histopathologic findings of early blisters may include acantholysis and dyskeratosis in the stratum granulosum as well as vacuolization of the granular layer. The blisters may coalesce into superficial bullae containing fibrin and neutrophils. Immunofluorescence studies that demonstrate intraepidermal C3 and IgG deposition are key to the diagnosis of pemphigus.⁵

Varicella (also known as chickenpox) manifests with crops of vesicles on an erythematous base in a centripetal distribution favoring the trunk and proximal extremities. It often is preceded by prodromal fever, malaise, and myalgia. Histopathologic evaluation of varicella is uncommon but may reveal acantholysis, multinucleation, and nuclear margination of keratinocytes. Viral culture or nucleic acid amplification testing of lesions can be used to verify the diagnosis.⁶

Most cases of PLEVA resolve without intervention.7 Treatment is directed at speeding recovery, providing symptomatic relief, and limiting permanent sequelae. Topical steroids often are used to alleviate inflammation and pruritus. Systemic antibiotics such as doxycycline, minocycline, and erythromycin have been used for their anti-inflammatory properties. Phototherapy of various wavelengths, including broadband and narrowband UVB as well as psoralen plus UVA, have led to improvements in affected patients. Refractory disease may warrant consideration of therapy with methotrexate, acitretin, dapsone, or cyclosporine.⁷

There have been rare reports of PLEVA evolving into its potentially lethal variant, febrile ulceronecrotic Mucha-Habermann disease, which is differentiated by the presence of systemic manifestations, including high fever, sore throat, diarrhea, central nervous system symptoms, abdominal pain, interstitial pneumonitis, splenomegaly, arthritis, sepsis, megaloblastic anemia, or conjunctival ulcers. The orogenital mucosa may be affected. Cutaneous lesions may rapidly progress to large, generalized, coalescent ulcers with necrotic crusts and vasculitic features on biopsy.8 Malignant transformation of PLEVA into LyP or MF rarely may occur and warrants continued follow-up of unresolved lesions.⁹

The Diagnosis: Pityriasis Lichenoides et Varioliformis Acuta

Sectioned punch biopsies were performed on the patient’s right arm. Histopathology showed acanthosis and parakeratosis in the epidermis, with vacuolar degeneration and dyskeratosis in the basal layer. Dermal changes included extravasated red blood cells in the papillary dermis as well as perivascular lymphocytic infiltrates in both the papillary and reticular dermis (Figure). Direct immunofluorescence of a perilesional biopsy using anti–human IgG, IgM, IgA, C3, and fibrin conjugates showed no findings of immune deposition. Biopsy results were consistent with pityriasis lichenoides et varioliformis acuta (PLEVA), and the patient was treated with a 5-day course of oral azithromycin, triamcinolone ointment 0.1% twice daily, and phototherapy with narrowband UVB ³ times weekly. Rapid improvement was noted at 2-month follow-up.

Pityriasis lichenoides et varioliformis acuta is a form of pityriasis lichenoides, a group of inflammatory dermatoses that are characterized clinically by successive crops of morphologically diverse lesions. Epidemiologic studies have shown a slight male predominance. It primarily affects children and young adults, with peak ages of 8 and 32 years in pediatric and adult populations, respectively.¹

The pathogenesis of PLEVA remains unclear. An abnormal immune response to Toxoplasma, Epstein-Barr virus, HIV, and other pathogens has been suggested based on serologic evidence of concurrent disease activity with the onset of lesions as well as cutaneous improvement in some patients after treatment of the infection.¹ A T-cell lymphoproliferative etiology also has been considered based on histopathologic similarities between PLEVA and lymphomatoid papulosis (LyP) as well as findings of clonality in T-cell receptor gene rearrangement in many patients.^1,2 Some clinicians consider LyP and PLEVA as separate entities on one disease spectrum.

Eruptions of PLEVA tend to favor the trunk and proximal extremities. Lesions may begin as macules measuring 2 to 3 mm in diameter that quickly evolve into papules with fine scale that remains attached centrally. Ulcerations with hemorrhagic crusts also may be noted as the lesions progress in stage. The rash may persist for weeks to years, and overlapping crops of macules and papules at varying stages of development may be seen in the same patient.¹

Histopathologic findings of PLEVA include spongiosis, dyskeratosis, parakeratosis, and focal keratinocyte necrosis within the epidermis, as well as vacuolar degeneration of the basal layer. Lymphocyte and erythrocyte extravasation may extend into the epidermis. Dermal findings may include edema and wedge-shaped perivascular lymphocytic infiltrates extending into the reticular dermis.¹

Important differential diagnoses to consider include LyP, mycosis fungoides (MF), pemphigus foliaceus, and varicella. Lymphomatoid papulosis is a benign CD30+ lymphoproliferative disorder that is characterized by an indolent course of recurrent, often self-resolving papules that occur most frequently on the trunk, arms, and legs of older patients. There are several histologic subtypes of LyP, but the most common (type A) may manifest with wedge-shaped perivascular lymphocytic infiltrates in the dermis, similar to PLEVA. T-cell receptor gene rearrangement studies characteristically reveal clonality in LyP, and clonality has been reported in PLEVA. However, LyP demonstrates a higher cytologic grade and lacks the characteristic parakeratotic scale and superficial dermal microhemorrhage of PLEVA.³

Mycosis fungoides is a malignant lymphoproliferative disorder that is characterized by an indolent clinical course of persistent patches, plaques, or tumors of various sizes that often manifest in non–sun-exposed areas of the skin. Early stages of MF are difficult to detect histologically, but biopsies may show atypical lymphocytes with hyperchromatic, irregularly contoured nuclei arranged along the basal layer of the epidermis. Epidermal aggregates of atypical lymphocytes (also known as Pautrier microabscesses) are considered highly specific for MF. T-cell receptor and immunopathologic studies also are important adjuncts in the diagnosis of MF.⁴

Pemphigus foliaceus is an autoimmune blistering disease caused by antibodies directed against desmoglein 1, which is found in the granular layer of the epidermis. It manifests with a subtle onset of scattered crusted lesions in the seborrheic areas, such as the scalp, face, chest, and upper back. Histopathologic findings of early blisters may include acantholysis and dyskeratosis in the stratum granulosum as well as vacuolization of the granular layer. The blisters may coalesce into superficial bullae containing fibrin and neutrophils. Immunofluorescence studies that demonstrate intraepidermal C3 and IgG deposition are key to the diagnosis of pemphigus.⁵

Varicella (also known as chickenpox) manifests with crops of vesicles on an erythematous base in a centripetal distribution favoring the trunk and proximal extremities. It often is preceded by prodromal fever, malaise, and myalgia. Histopathologic evaluation of varicella is uncommon but may reveal acantholysis, multinucleation, and nuclear margination of keratinocytes. Viral culture or nucleic acid amplification testing of lesions can be used to verify the diagnosis.⁶

Most cases of PLEVA resolve without intervention.7 Treatment is directed at speeding recovery, providing symptomatic relief, and limiting permanent sequelae. Topical steroids often are used to alleviate inflammation and pruritus. Systemic antibiotics such as doxycycline, minocycline, and erythromycin have been used for their anti-inflammatory properties. Phototherapy of various wavelengths, including broadband and narrowband UVB as well as psoralen plus UVA, have led to improvements in affected patients. Refractory disease may warrant consideration of therapy with methotrexate, acitretin, dapsone, or cyclosporine.⁷

There have been rare reports of PLEVA evolving into its potentially lethal variant, febrile ulceronecrotic Mucha-Habermann disease, which is differentiated by the presence of systemic manifestations, including high fever, sore throat, diarrhea, central nervous system symptoms, abdominal pain, interstitial pneumonitis, splenomegaly, arthritis, sepsis, megaloblastic anemia, or conjunctival ulcers. The orogenital mucosa may be affected. Cutaneous lesions may rapidly progress to large, generalized, coalescent ulcers with necrotic crusts and vasculitic features on biopsy.8 Malignant transformation of PLEVA into LyP or MF rarely may occur and warrants continued follow-up of unresolved lesions.⁹

The Diagnosis: Pityriasis Lichenoides et Varioliformis Acuta

Sectioned punch biopsies were performed on the patient’s right arm. Histopathology showed acanthosis and parakeratosis in the epidermis, with vacuolar degeneration and dyskeratosis in the basal layer. Dermal changes included extravasated red blood cells in the papillary dermis as well as perivascular lymphocytic infiltrates in both the papillary and reticular dermis (Figure). Direct immunofluorescence of a perilesional biopsy using anti–human IgG, IgM, IgA, C3, and fibrin conjugates showed no findings of immune deposition. Biopsy results were consistent with pityriasis lichenoides et varioliformis acuta (PLEVA), and the patient was treated with a 5-day course of oral azithromycin, triamcinolone ointment 0.1% twice daily, and phototherapy with narrowband UVB ³ times weekly. Rapid improvement was noted at 2-month follow-up.

Pityriasis lichenoides et varioliformis acuta is a form of pityriasis lichenoides, a group of inflammatory dermatoses that are characterized clinically by successive crops of morphologically diverse lesions. Epidemiologic studies have shown a slight male predominance. It primarily affects children and young adults, with peak ages of 8 and 32 years in pediatric and adult populations, respectively.¹

The pathogenesis of PLEVA remains unclear. An abnormal immune response to Toxoplasma, Epstein-Barr virus, HIV, and other pathogens has been suggested based on serologic evidence of concurrent disease activity with the onset of lesions as well as cutaneous improvement in some patients after treatment of the infection.¹ A T-cell lymphoproliferative etiology also has been considered based on histopathologic similarities between PLEVA and lymphomatoid papulosis (LyP) as well as findings of clonality in T-cell receptor gene rearrangement in many patients.^1,2 Some clinicians consider LyP and PLEVA as separate entities on one disease spectrum.

Eruptions of PLEVA tend to favor the trunk and proximal extremities. Lesions may begin as macules measuring 2 to 3 mm in diameter that quickly evolve into papules with fine scale that remains attached centrally. Ulcerations with hemorrhagic crusts also may be noted as the lesions progress in stage. The rash may persist for weeks to years, and overlapping crops of macules and papules at varying stages of development may be seen in the same patient.¹

Histopathologic findings of PLEVA include spongiosis, dyskeratosis, parakeratosis, and focal keratinocyte necrosis within the epidermis, as well as vacuolar degeneration of the basal layer. Lymphocyte and erythrocyte extravasation may extend into the epidermis. Dermal findings may include edema and wedge-shaped perivascular lymphocytic infiltrates extending into the reticular dermis.¹

Important differential diagnoses to consider include LyP, mycosis fungoides (MF), pemphigus foliaceus, and varicella. Lymphomatoid papulosis is a benign CD30+ lymphoproliferative disorder that is characterized by an indolent course of recurrent, often self-resolving papules that occur most frequently on the trunk, arms, and legs of older patients. There are several histologic subtypes of LyP, but the most common (type A) may manifest with wedge-shaped perivascular lymphocytic infiltrates in the dermis, similar to PLEVA. T-cell receptor gene rearrangement studies characteristically reveal clonality in LyP, and clonality has been reported in PLEVA. However, LyP demonstrates a higher cytologic grade and lacks the characteristic parakeratotic scale and superficial dermal microhemorrhage of PLEVA.³

Mycosis fungoides is a malignant lymphoproliferative disorder that is characterized by an indolent clinical course of persistent patches, plaques, or tumors of various sizes that often manifest in non–sun-exposed areas of the skin. Early stages of MF are difficult to detect histologically, but biopsies may show atypical lymphocytes with hyperchromatic, irregularly contoured nuclei arranged along the basal layer of the epidermis. Epidermal aggregates of atypical lymphocytes (also known as Pautrier microabscesses) are considered highly specific for MF. T-cell receptor and immunopathologic studies also are important adjuncts in the diagnosis of MF.⁴

Pemphigus foliaceus is an autoimmune blistering disease caused by antibodies directed against desmoglein 1, which is found in the granular layer of the epidermis. It manifests with a subtle onset of scattered crusted lesions in the seborrheic areas, such as the scalp, face, chest, and upper back. Histopathologic findings of early blisters may include acantholysis and dyskeratosis in the stratum granulosum as well as vacuolization of the granular layer. The blisters may coalesce into superficial bullae containing fibrin and neutrophils. Immunofluorescence studies that demonstrate intraepidermal C3 and IgG deposition are key to the diagnosis of pemphigus.⁵

Varicella (also known as chickenpox) manifests with crops of vesicles on an erythematous base in a centripetal distribution favoring the trunk and proximal extremities. It often is preceded by prodromal fever, malaise, and myalgia. Histopathologic evaluation of varicella is uncommon but may reveal acantholysis, multinucleation, and nuclear margination of keratinocytes. Viral culture or nucleic acid amplification testing of lesions can be used to verify the diagnosis.⁶

Most cases of PLEVA resolve without intervention.7 Treatment is directed at speeding recovery, providing symptomatic relief, and limiting permanent sequelae. Topical steroids often are used to alleviate inflammation and pruritus. Systemic antibiotics such as doxycycline, minocycline, and erythromycin have been used for their anti-inflammatory properties. Phototherapy of various wavelengths, including broadband and narrowband UVB as well as psoralen plus UVA, have led to improvements in affected patients. Refractory disease may warrant consideration of therapy with methotrexate, acitretin, dapsone, or cyclosporine.⁷

There have been rare reports of PLEVA evolving into its potentially lethal variant, febrile ulceronecrotic Mucha-Habermann disease, which is differentiated by the presence of systemic manifestations, including high fever, sore throat, diarrhea, central nervous system symptoms, abdominal pain, interstitial pneumonitis, splenomegaly, arthritis, sepsis, megaloblastic anemia, or conjunctival ulcers. The orogenital mucosa may be affected. Cutaneous lesions may rapidly progress to large, generalized, coalescent ulcers with necrotic crusts and vasculitic features on biopsy.8 Malignant transformation of PLEVA into LyP or MF rarely may occur and warrants continued follow-up of unresolved lesions.⁹

The Cutis Editorial Board is now accepting applications for the 2025 Resident Corner column. The Editorial Board will select 2 to 3 residents to serve as the Resident Corner columnists for 1 year. Articles are posted online only at www.mdedge.com/dermatology but will be referenced in Index Medicus. All applicants must be current residents and will be in residency throughout 2025.

For consideration, send your curriculum vitae along with a brief (not to exceed 500 words) statement of why you enjoy Cutis and what you can offer your fellow residents in contributing a monthly column.

A signed letter of recommendation from the Director of the dermatology residency program also should be supplied.

All materials should be submitted via email to Alicia Sonners ([email protected]) by November 1. The residents who are selected to write the column for the upcoming year will be notified by November 15.

We look forward to continuing to educate dermatology residents on topics that are most important to them!

The Cutis Editorial Board is now accepting applications for the 2025 Resident Corner column. The Editorial Board will select 2 to 3 residents to serve as the Resident Corner columnists for 1 year. Articles are posted online only at www.mdedge.com/dermatology but will be referenced in Index Medicus. All applicants must be current residents and will be in residency throughout 2025.

For consideration, send your curriculum vitae along with a brief (not to exceed 500 words) statement of why you enjoy Cutis and what you can offer your fellow residents in contributing a monthly column.

A signed letter of recommendation from the Director of the dermatology residency program also should be supplied.

All materials should be submitted via email to Alicia Sonners ([email protected]) by November 1. The residents who are selected to write the column for the upcoming year will be notified by November 15.

We look forward to continuing to educate dermatology residents on topics that are most important to them!

The Cutis Editorial Board is now accepting applications for the 2025 Resident Corner column. The Editorial Board will select 2 to 3 residents to serve as the Resident Corner columnists for 1 year. Articles are posted online only at www.mdedge.com/dermatology but will be referenced in Index Medicus. All applicants must be current residents and will be in residency throughout 2025.

For consideration, send your curriculum vitae along with a brief (not to exceed 500 words) statement of why you enjoy Cutis and what you can offer your fellow residents in contributing a monthly column.

A signed letter of recommendation from the Director of the dermatology residency program also should be supplied.

All materials should be submitted via email to Alicia Sonners ([email protected]) by November 1. The residents who are selected to write the column for the upcoming year will be notified by November 15.

We look forward to continuing to educate dermatology residents on topics that are most important to them!

To the Editor:
Crusted scabies (formerly known as Norwegian scabies) is a rare and highly contagious variant of scabies, in which the skin is infested with thousands to millions of Sarcoptes scabiei var hominis mites. We present a case of skin changes that were misdiagnosed as atopic dermatitis, seborrhea, xerosis, and drug eruption on initial presentation, which prompted treatment with a corticosteroid that inadvertently caused progression to crusted scabies.

A 79-year-old woman who uses a wheelchair presented to the clinic with skin changes that consisted of diffuse, severely pruritic, erythematous plaques on the head, neck, trunk, face, and extremities of 2 years’ duration. She had a medical history of hyperlipidemia, hypertension, and hyperglycemia, as well as a stroke that required hospitalization 2 years prior to the onset of the skin changes. She had no history of allergies.

Prior clinical diagnoses by primary care and dermatology included xerosis, atopic dermatitis, seborrhea, and drug eruption. She was treated with a mid-potency topical corticosteroid (triamcinolone acetonide cream 0.1%) twice daily and prednisone 40 mg once daily for 2- to 4-week courses over an 8-month period without reduction in symptoms.

Physical examination at the current presentation revealed golden, crusted, fine, powdery but slightly sticky flakes that spread diffusely across the entire body and came off in crumbles with a simple touch. These widespread crusts were easily visible on clothing. There was underlying diffuse erythema beneath the flaking skin on the trunk and proximal extremities. The scale and shedding skin laid in piles on the patient’s lap and resembled brown sugar (Figure 1). The patient also reported decreased hand function and dexterity due to the yellowbrown, thick, crusty plaques that had developed on both the palmar and dorsal sides of the hands (Figure 2). Erythematous plaques on the scalp, forehead, and inner ears resembled seborrhea (Figure 3). Pruritus severity was rated by the patient as 10 of 10, and she scratched her skin the entire time she was in the clinic. The patient was emotional and stated that she had not been able to sleep due to the discomfort. We suspected scabies, and the patient was reassured to learn that it could be confirmed with a simple skin scrape test.

The crusted lesions on the patient's hands were scraped with a #15-blade scalpel, and a routine potassium hydroxide mount was performed. The skin scrapings were placed on a slide with a drop of 10% potassium hydroxide and observed under low-power (×10) and high-power (×40) microscopy, which revealed thousands of mites and eggs (along with previously hatched eggs) (Figure 4) and quickly confirmed a diagnosis of crusted scabies.an extremely contagious form of scabies seen in older patients with compromised immune systems, malnutrition, or disabilities. The patient was prescribed oral ivermectin (3 mg dosed at 200 μg/kg of body weight) and topical permethrin 5%, neither of which she took, as she died of a COVID-19 infection complication 3 days after this diagnostic clinic visit.

Classic and crusted scabies are both caused by infestation of the Sarcoptes scabiei var hominis mite. Classic scabies is a result of an infestation of a small number of mites (commonly 5–15 mites), while crusted scabies is due to hyperinfestation by as many as millions of mites, the latter often requiring more aggressive treatment. The mites are first transmitted to humans by either skin-toskin contact or fomites on bedding and clothing. The scabies mite undergoes 4 life cycle stages: egg, larvae, nymph, and adult. Once female mites are transmitted, they burrow under the skin and lay 2 to 3 eggs per day. The eggs hatch within 3 to 4 days, after which the larvae migrate to the skin surface. The larval stage lasts for 3 to 4 days, during which the larvae burrow into the stratum corneum to create molting pouches, until they molt into slightly larger nymphs. Nymphs can be found in hair follicles or molting pouches until they further molt within 3 to 4 days into adults, which are round, saclike mites. The adult male and female mites then mate, leaving the female fertile for the rest of her 1- to 2-month lifespan. Impregnated female mites traverse the skin surface in search of a burrow site, using the pulvilli on the anterior aspect of 2 legs to hold onto the skin. Once burrowed, the female mite continues to lay eggs for the rest of her life, with approximately 10% of her eggs resulting in adult mites. Male mites feed in shallow pits of the skin until they find a female burrow site for mating.¹ This continuous life cycle of the scabies mite gives rise to highly transmissible, pruritic skin excoriations, as demonstrated in our patient.

The skin has a relatively late inflammatory and adaptive immune response to scabies, typically occurring 4 to 6 weeks after the initial infestation.² This delayed inflammatory response and onset of symptoms may be due to the scabies mite’s ability to alter aspects of the host’s immune response, which differs in classic vs crusted scabies. In classic scabies, there is a predominance of CD4+ T cells in the dermis and minimal CD8+ T cells. The opposite is true in crusted scabies— there is an overwhelming infiltration of CD8+ T cells and minimal CD4+ T cells.³ The CD8+ T-cell predominance in crusted scabies is hypothesized to be the cause of keratinocyte apoptosis, resulting in epidermal hyperproliferation. Keratinocyte apoptosis also secretes cytokines, which may lead to the immunologic targeting of healthy skin cells. The damage of healthy dermal cells contributes to the inability of the skin’s immune system to mount an effective response, allowing the parasite to grow uncontrollably in patients with crusted scabies.⁴

This ineffective immune response is further exacerbated by corticosteroids, which are commonly prescribed for pruritus experienced by patients with scabies infestations. The mechanism of action of corticosteroids is the production of anti-inflammatory, antimitotic, and immunosuppressive effects.⁵ Because the integumentary immune system is imbalanced during crusted scabies infestation, the immunosuppressive mechanism of oral and topical corticosteroids further reduces the cellular immune response to scabies. The flourishing of the scabies mites along with keratinocyte apoptosis⁴ results in the development of hyperkeratotic skin crusting, most frequently on the palms, soles, arms, and legs. Risk factors for crusted scabies include immunosuppression, hospitalization, crowded living conditions, and poor hygiene, though no known risk factors were documented in up to 42% (33/78) of patients with crusted scabies in one study.⁶

Patients with crusted scabies typically present with generalized, poorly defined, erythematous, fissured plaques covered by scaling and crusts. Plaques on bony prominences such as finger articulations and elbows may have a thick verrucous aspect.¹ Skin flaking that resembles brown sugar—a mixture of white sugar and molasses—is a clue to the diagnosis of crusted scabies. Brown sugar has a slightly sandy and sticky texture that ranges in color from very light brown to very dark brown. When present, flakes always appears slightly lighter than the patient’s skin tone. Although skin burrows are pathognomonic and clinically recognizable features of scabies, these burrows can be disguised by lesions, such as the hyperkeratotic plaques seen in our patient. The lesions may or may not be associated with pruritus, which may occur only at night, and bacterial superinfection has been reported in severe cases of crusted scabies,⁷ as scratching can cause sores, which may lead to infection. In severe cases, the constant scratching could lead to sepsis if the infection enters the bloodstream.⁸ Another symptom of scabies is a rash that causes small bumps that tend to form in a line, resembling small bites, hives, or pimples, and scaly plaques can lead to misdiagnosis as atopic dermatitis.

Treatment often is delayed due to misdiagnosis, as seen in our patient. Common misdiagnoses include atopic dermatitis, pityriasis rosea, systemic lupus erythematosus, bullous pemphigoid, lichen planus, pediculosis corporis, seborrheic scalp dermatitis, and adverse drug reactions.⁹ Patients with extensive infestations of crusted scabies should be treated with a 4-week course of permethrin cream 5% daily for 1 week, then twice per week until resolved, and oral ivermectin 200 μg/kg dosed 1 week apart for up to 4 weeks, if needed.¹ Topical permethrin works by producing a selective neurotoxic effect on invertebrates such as scabies mites, which disrupts the function of voltage-gated sodium channels, thereby paralyzing the adult mites to halt the spread of infestation. However, treatment with topical medications can be difficult due to the thick crusts that have formed, which make it more challenging for the skin to properly absorb the treatment. Additionally, surgical debridement as an adjunct procedure has been done to improve the effectiveness of topical medications by removing all the mites in skin.¹⁰ On the other hand, the mechanism in which ivermectin treats scabies infestations is poorly understood. Current research suggests that ivermectin works by causing persistent opening of pH-gated chloride channels in scabies mites.¹¹ There is emerging concern for drug resistance to these scabicides,¹² revealing a need for further research of treatment options.

Patients with crusted scabies can have an extremely large number of mites (up to 2 million), making them more infectious than patients with classic scabies.¹³ As a result, it is imperative to reduce environmental transmission and risk for reinfection with mites during treatment. Because crusted scabies is transmitted by prolonged skinto- skin contact or by contact with personal items of an infected person (eg, bedding, clothing), treatment guidelines require all clothing, bedding, and towels of a patient with scabies to be machine-washed and dried with hot water and hot dryer cycles. If an item cannot be washed, it should be stored in a sealed plastic bag for 1 week, as scabies mites cannot survive more than 2 to 3 days away from their host of human skin.¹³ Treatment of close contacts of patients with scabies is recommended, as well as for those in endemic areas or closed communities, such as nursing homes or jails.

To the Editor:
Crusted scabies (formerly known as Norwegian scabies) is a rare and highly contagious variant of scabies, in which the skin is infested with thousands to millions of Sarcoptes scabiei var hominis mites. We present a case of skin changes that were misdiagnosed as atopic dermatitis, seborrhea, xerosis, and drug eruption on initial presentation, which prompted treatment with a corticosteroid that inadvertently caused progression to crusted scabies.

A 79-year-old woman who uses a wheelchair presented to the clinic with skin changes that consisted of diffuse, severely pruritic, erythematous plaques on the head, neck, trunk, face, and extremities of 2 years’ duration. She had a medical history of hyperlipidemia, hypertension, and hyperglycemia, as well as a stroke that required hospitalization 2 years prior to the onset of the skin changes. She had no history of allergies.

Prior clinical diagnoses by primary care and dermatology included xerosis, atopic dermatitis, seborrhea, and drug eruption. She was treated with a mid-potency topical corticosteroid (triamcinolone acetonide cream 0.1%) twice daily and prednisone 40 mg once daily for 2- to 4-week courses over an 8-month period without reduction in symptoms.

Physical examination at the current presentation revealed golden, crusted, fine, powdery but slightly sticky flakes that spread diffusely across the entire body and came off in crumbles with a simple touch. These widespread crusts were easily visible on clothing. There was underlying diffuse erythema beneath the flaking skin on the trunk and proximal extremities. The scale and shedding skin laid in piles on the patient’s lap and resembled brown sugar (Figure 1). The patient also reported decreased hand function and dexterity due to the yellowbrown, thick, crusty plaques that had developed on both the palmar and dorsal sides of the hands (Figure 2). Erythematous plaques on the scalp, forehead, and inner ears resembled seborrhea (Figure 3). Pruritus severity was rated by the patient as 10 of 10, and she scratched her skin the entire time she was in the clinic. The patient was emotional and stated that she had not been able to sleep due to the discomfort. We suspected scabies, and the patient was reassured to learn that it could be confirmed with a simple skin scrape test.

The crusted lesions on the patient's hands were scraped with a #15-blade scalpel, and a routine potassium hydroxide mount was performed. The skin scrapings were placed on a slide with a drop of 10% potassium hydroxide and observed under low-power (×10) and high-power (×40) microscopy, which revealed thousands of mites and eggs (along with previously hatched eggs) (Figure 4) and quickly confirmed a diagnosis of crusted scabies.an extremely contagious form of scabies seen in older patients with compromised immune systems, malnutrition, or disabilities. The patient was prescribed oral ivermectin (3 mg dosed at 200 μg/kg of body weight) and topical permethrin 5%, neither of which she took, as she died of a COVID-19 infection complication 3 days after this diagnostic clinic visit.

Classic and crusted scabies are both caused by infestation of the Sarcoptes scabiei var hominis mite. Classic scabies is a result of an infestation of a small number of mites (commonly 5–15 mites), while crusted scabies is due to hyperinfestation by as many as millions of mites, the latter often requiring more aggressive treatment. The mites are first transmitted to humans by either skin-toskin contact or fomites on bedding and clothing. The scabies mite undergoes 4 life cycle stages: egg, larvae, nymph, and adult. Once female mites are transmitted, they burrow under the skin and lay 2 to 3 eggs per day. The eggs hatch within 3 to 4 days, after which the larvae migrate to the skin surface. The larval stage lasts for 3 to 4 days, during which the larvae burrow into the stratum corneum to create molting pouches, until they molt into slightly larger nymphs. Nymphs can be found in hair follicles or molting pouches until they further molt within 3 to 4 days into adults, which are round, saclike mites. The adult male and female mites then mate, leaving the female fertile for the rest of her 1- to 2-month lifespan. Impregnated female mites traverse the skin surface in search of a burrow site, using the pulvilli on the anterior aspect of 2 legs to hold onto the skin. Once burrowed, the female mite continues to lay eggs for the rest of her life, with approximately 10% of her eggs resulting in adult mites. Male mites feed in shallow pits of the skin until they find a female burrow site for mating.¹ This continuous life cycle of the scabies mite gives rise to highly transmissible, pruritic skin excoriations, as demonstrated in our patient.

The skin has a relatively late inflammatory and adaptive immune response to scabies, typically occurring 4 to 6 weeks after the initial infestation.² This delayed inflammatory response and onset of symptoms may be due to the scabies mite’s ability to alter aspects of the host’s immune response, which differs in classic vs crusted scabies. In classic scabies, there is a predominance of CD4+ T cells in the dermis and minimal CD8+ T cells. The opposite is true in crusted scabies— there is an overwhelming infiltration of CD8+ T cells and minimal CD4+ T cells.³ The CD8+ T-cell predominance in crusted scabies is hypothesized to be the cause of keratinocyte apoptosis, resulting in epidermal hyperproliferation. Keratinocyte apoptosis also secretes cytokines, which may lead to the immunologic targeting of healthy skin cells. The damage of healthy dermal cells contributes to the inability of the skin’s immune system to mount an effective response, allowing the parasite to grow uncontrollably in patients with crusted scabies.⁴

This ineffective immune response is further exacerbated by corticosteroids, which are commonly prescribed for pruritus experienced by patients with scabies infestations. The mechanism of action of corticosteroids is the production of anti-inflammatory, antimitotic, and immunosuppressive effects.⁵ Because the integumentary immune system is imbalanced during crusted scabies infestation, the immunosuppressive mechanism of oral and topical corticosteroids further reduces the cellular immune response to scabies. The flourishing of the scabies mites along with keratinocyte apoptosis⁴ results in the development of hyperkeratotic skin crusting, most frequently on the palms, soles, arms, and legs. Risk factors for crusted scabies include immunosuppression, hospitalization, crowded living conditions, and poor hygiene, though no known risk factors were documented in up to 42% (33/78) of patients with crusted scabies in one study.⁶

Patients with crusted scabies typically present with generalized, poorly defined, erythematous, fissured plaques covered by scaling and crusts. Plaques on bony prominences such as finger articulations and elbows may have a thick verrucous aspect.¹ Skin flaking that resembles brown sugar—a mixture of white sugar and molasses—is a clue to the diagnosis of crusted scabies. Brown sugar has a slightly sandy and sticky texture that ranges in color from very light brown to very dark brown. When present, flakes always appears slightly lighter than the patient’s skin tone. Although skin burrows are pathognomonic and clinically recognizable features of scabies, these burrows can be disguised by lesions, such as the hyperkeratotic plaques seen in our patient. The lesions may or may not be associated with pruritus, which may occur only at night, and bacterial superinfection has been reported in severe cases of crusted scabies,⁷ as scratching can cause sores, which may lead to infection. In severe cases, the constant scratching could lead to sepsis if the infection enters the bloodstream.⁸ Another symptom of scabies is a rash that causes small bumps that tend to form in a line, resembling small bites, hives, or pimples, and scaly plaques can lead to misdiagnosis as atopic dermatitis.

Treatment often is delayed due to misdiagnosis, as seen in our patient. Common misdiagnoses include atopic dermatitis, pityriasis rosea, systemic lupus erythematosus, bullous pemphigoid, lichen planus, pediculosis corporis, seborrheic scalp dermatitis, and adverse drug reactions.⁹ Patients with extensive infestations of crusted scabies should be treated with a 4-week course of permethrin cream 5% daily for 1 week, then twice per week until resolved, and oral ivermectin 200 μg/kg dosed 1 week apart for up to 4 weeks, if needed.¹ Topical permethrin works by producing a selective neurotoxic effect on invertebrates such as scabies mites, which disrupts the function of voltage-gated sodium channels, thereby paralyzing the adult mites to halt the spread of infestation. However, treatment with topical medications can be difficult due to the thick crusts that have formed, which make it more challenging for the skin to properly absorb the treatment. Additionally, surgical debridement as an adjunct procedure has been done to improve the effectiveness of topical medications by removing all the mites in skin.¹⁰ On the other hand, the mechanism in which ivermectin treats scabies infestations is poorly understood. Current research suggests that ivermectin works by causing persistent opening of pH-gated chloride channels in scabies mites.¹¹ There is emerging concern for drug resistance to these scabicides,¹² revealing a need for further research of treatment options.

Patients with crusted scabies can have an extremely large number of mites (up to 2 million), making them more infectious than patients with classic scabies.¹³ As a result, it is imperative to reduce environmental transmission and risk for reinfection with mites during treatment. Because crusted scabies is transmitted by prolonged skinto- skin contact or by contact with personal items of an infected person (eg, bedding, clothing), treatment guidelines require all clothing, bedding, and towels of a patient with scabies to be machine-washed and dried with hot water and hot dryer cycles. If an item cannot be washed, it should be stored in a sealed plastic bag for 1 week, as scabies mites cannot survive more than 2 to 3 days away from their host of human skin.¹³ Treatment of close contacts of patients with scabies is recommended, as well as for those in endemic areas or closed communities, such as nursing homes or jails.

To the Editor:
Crusted scabies (formerly known as Norwegian scabies) is a rare and highly contagious variant of scabies, in which the skin is infested with thousands to millions of Sarcoptes scabiei var hominis mites. We present a case of skin changes that were misdiagnosed as atopic dermatitis, seborrhea, xerosis, and drug eruption on initial presentation, which prompted treatment with a corticosteroid that inadvertently caused progression to crusted scabies.

A 79-year-old woman who uses a wheelchair presented to the clinic with skin changes that consisted of diffuse, severely pruritic, erythematous plaques on the head, neck, trunk, face, and extremities of 2 years’ duration. She had a medical history of hyperlipidemia, hypertension, and hyperglycemia, as well as a stroke that required hospitalization 2 years prior to the onset of the skin changes. She had no history of allergies.

Prior clinical diagnoses by primary care and dermatology included xerosis, atopic dermatitis, seborrhea, and drug eruption. She was treated with a mid-potency topical corticosteroid (triamcinolone acetonide cream 0.1%) twice daily and prednisone 40 mg once daily for 2- to 4-week courses over an 8-month period without reduction in symptoms.

Physical examination at the current presentation revealed golden, crusted, fine, powdery but slightly sticky flakes that spread diffusely across the entire body and came off in crumbles with a simple touch. These widespread crusts were easily visible on clothing. There was underlying diffuse erythema beneath the flaking skin on the trunk and proximal extremities. The scale and shedding skin laid in piles on the patient’s lap and resembled brown sugar (Figure 1). The patient also reported decreased hand function and dexterity due to the yellowbrown, thick, crusty plaques that had developed on both the palmar and dorsal sides of the hands (Figure 2). Erythematous plaques on the scalp, forehead, and inner ears resembled seborrhea (Figure 3). Pruritus severity was rated by the patient as 10 of 10, and she scratched her skin the entire time she was in the clinic. The patient was emotional and stated that she had not been able to sleep due to the discomfort. We suspected scabies, and the patient was reassured to learn that it could be confirmed with a simple skin scrape test.

The crusted lesions on the patient's hands were scraped with a #15-blade scalpel, and a routine potassium hydroxide mount was performed. The skin scrapings were placed on a slide with a drop of 10% potassium hydroxide and observed under low-power (×10) and high-power (×40) microscopy, which revealed thousands of mites and eggs (along with previously hatched eggs) (Figure 4) and quickly confirmed a diagnosis of crusted scabies.an extremely contagious form of scabies seen in older patients with compromised immune systems, malnutrition, or disabilities. The patient was prescribed oral ivermectin (3 mg dosed at 200 μg/kg of body weight) and topical permethrin 5%, neither of which she took, as she died of a COVID-19 infection complication 3 days after this diagnostic clinic visit.

Classic and crusted scabies are both caused by infestation of the Sarcoptes scabiei var hominis mite. Classic scabies is a result of an infestation of a small number of mites (commonly 5–15 mites), while crusted scabies is due to hyperinfestation by as many as millions of mites, the latter often requiring more aggressive treatment. The mites are first transmitted to humans by either skin-toskin contact or fomites on bedding and clothing. The scabies mite undergoes 4 life cycle stages: egg, larvae, nymph, and adult. Once female mites are transmitted, they burrow under the skin and lay 2 to 3 eggs per day. The eggs hatch within 3 to 4 days, after which the larvae migrate to the skin surface. The larval stage lasts for 3 to 4 days, during which the larvae burrow into the stratum corneum to create molting pouches, until they molt into slightly larger nymphs. Nymphs can be found in hair follicles or molting pouches until they further molt within 3 to 4 days into adults, which are round, saclike mites. The adult male and female mites then mate, leaving the female fertile for the rest of her 1- to 2-month lifespan. Impregnated female mites traverse the skin surface in search of a burrow site, using the pulvilli on the anterior aspect of 2 legs to hold onto the skin. Once burrowed, the female mite continues to lay eggs for the rest of her life, with approximately 10% of her eggs resulting in adult mites. Male mites feed in shallow pits of the skin until they find a female burrow site for mating.¹ This continuous life cycle of the scabies mite gives rise to highly transmissible, pruritic skin excoriations, as demonstrated in our patient.

The skin has a relatively late inflammatory and adaptive immune response to scabies, typically occurring 4 to 6 weeks after the initial infestation.² This delayed inflammatory response and onset of symptoms may be due to the scabies mite’s ability to alter aspects of the host’s immune response, which differs in classic vs crusted scabies. In classic scabies, there is a predominance of CD4+ T cells in the dermis and minimal CD8+ T cells. The opposite is true in crusted scabies— there is an overwhelming infiltration of CD8+ T cells and minimal CD4+ T cells.³ The CD8+ T-cell predominance in crusted scabies is hypothesized to be the cause of keratinocyte apoptosis, resulting in epidermal hyperproliferation. Keratinocyte apoptosis also secretes cytokines, which may lead to the immunologic targeting of healthy skin cells. The damage of healthy dermal cells contributes to the inability of the skin’s immune system to mount an effective response, allowing the parasite to grow uncontrollably in patients with crusted scabies.⁴

This ineffective immune response is further exacerbated by corticosteroids, which are commonly prescribed for pruritus experienced by patients with scabies infestations. The mechanism of action of corticosteroids is the production of anti-inflammatory, antimitotic, and immunosuppressive effects.⁵ Because the integumentary immune system is imbalanced during crusted scabies infestation, the immunosuppressive mechanism of oral and topical corticosteroids further reduces the cellular immune response to scabies. The flourishing of the scabies mites along with keratinocyte apoptosis⁴ results in the development of hyperkeratotic skin crusting, most frequently on the palms, soles, arms, and legs. Risk factors for crusted scabies include immunosuppression, hospitalization, crowded living conditions, and poor hygiene, though no known risk factors were documented in up to 42% (33/78) of patients with crusted scabies in one study.⁶

Patients with crusted scabies typically present with generalized, poorly defined, erythematous, fissured plaques covered by scaling and crusts. Plaques on bony prominences such as finger articulations and elbows may have a thick verrucous aspect.¹ Skin flaking that resembles brown sugar—a mixture of white sugar and molasses—is a clue to the diagnosis of crusted scabies. Brown sugar has a slightly sandy and sticky texture that ranges in color from very light brown to very dark brown. When present, flakes always appears slightly lighter than the patient’s skin tone. Although skin burrows are pathognomonic and clinically recognizable features of scabies, these burrows can be disguised by lesions, such as the hyperkeratotic plaques seen in our patient. The lesions may or may not be associated with pruritus, which may occur only at night, and bacterial superinfection has been reported in severe cases of crusted scabies,⁷ as scratching can cause sores, which may lead to infection. In severe cases, the constant scratching could lead to sepsis if the infection enters the bloodstream.⁸ Another symptom of scabies is a rash that causes small bumps that tend to form in a line, resembling small bites, hives, or pimples, and scaly plaques can lead to misdiagnosis as atopic dermatitis.

Treatment often is delayed due to misdiagnosis, as seen in our patient. Common misdiagnoses include atopic dermatitis, pityriasis rosea, systemic lupus erythematosus, bullous pemphigoid, lichen planus, pediculosis corporis, seborrheic scalp dermatitis, and adverse drug reactions.⁹ Patients with extensive infestations of crusted scabies should be treated with a 4-week course of permethrin cream 5% daily for 1 week, then twice per week until resolved, and oral ivermectin 200 μg/kg dosed 1 week apart for up to 4 weeks, if needed.¹ Topical permethrin works by producing a selective neurotoxic effect on invertebrates such as scabies mites, which disrupts the function of voltage-gated sodium channels, thereby paralyzing the adult mites to halt the spread of infestation. However, treatment with topical medications can be difficult due to the thick crusts that have formed, which make it more challenging for the skin to properly absorb the treatment. Additionally, surgical debridement as an adjunct procedure has been done to improve the effectiveness of topical medications by removing all the mites in skin.¹⁰ On the other hand, the mechanism in which ivermectin treats scabies infestations is poorly understood. Current research suggests that ivermectin works by causing persistent opening of pH-gated chloride channels in scabies mites.¹¹ There is emerging concern for drug resistance to these scabicides,¹² revealing a need for further research of treatment options.

Patients with crusted scabies can have an extremely large number of mites (up to 2 million), making them more infectious than patients with classic scabies.¹³ As a result, it is imperative to reduce environmental transmission and risk for reinfection with mites during treatment. Because crusted scabies is transmitted by prolonged skinto- skin contact or by contact with personal items of an infected person (eg, bedding, clothing), treatment guidelines require all clothing, bedding, and towels of a patient with scabies to be machine-washed and dried with hot water and hot dryer cycles. If an item cannot be washed, it should be stored in a sealed plastic bag for 1 week, as scabies mites cannot survive more than 2 to 3 days away from their host of human skin.¹³ Treatment of close contacts of patients with scabies is recommended, as well as for those in endemic areas or closed communities, such as nursing homes or jails.

Melasma (also known as chloasma faciei) is a common chronic skin disorder that results in well-demarcated, hyperpigmented, tan to dark patches that mostly appear in sun-exposed areas such as the face and neck and sometimes the arms. The exact prevalence or incidence is not known but is estimated to be 1% to 50% overall depending on the ethnic population and geographic location.^1,2 Melasma predominantly affects women, but research has shown that approximately 10% to 20% of men are affected by this condition.^3,4 Although melasma can affect patients of all skin types, it primarily affects those with darker skin tones.⁵ The groups most often affected are women of Black, Hispanic, Middle Eastern, and Southeast Asian ethnicity. Although the pathogenesis is complex and not fully understood, multiple pathways and etiologies have been theorized to cause melasma. Potential causes include exposure to UV radiation, oral contraceptives, hormonal changes, medications, thyroid dysfunction, genetics, and pregnancy.^6,7 Cytokines and growth factors, including adipokine and angiopoietin, synthesized by sebaceous glands play a role in the pathogenic mechanism of melasma. Cytokines and growth factors are hypothesized to modulate the function of melanocytes.⁸ Both melanocytes and sebocytes are controlled by α–melanocyte-stimulating hormone. Therefore, overexpression of α–melanocyte-stimulating hormone will result in overproduction of these 2 cell types, resulting in melasma. Melasma can be classified into 4 subtypes using Wood lamp examination: epidermal, dermal, mixed, or indeterminate.³ Furthermore, melasma is divided into subgroups based on the location: malar region, mandibular region, and centrofacial patch pattern.^9,10 The involvement of sebaceous glands in the pathogenesis of melasma may explain the predilection for the centrofacial region, which is the most common pattern.

The severity of melasma can be assessed using the melasma area and severity index (MASI), which is calculated by subjective assessment of 3 main factors: (1) facial area of involvement; (2) darkness of affected region; and (3) homogeneity, with the extent of melasma indicated by a score ranging from 0 to 48.¹¹ The modified MASI (mMASI) subsequently was introduced to assist with assessing the severity of melasma and creating distinct ranges for mild, moderate, and severe cases, ranging from 0 (mild) to 24 (severe).¹² Both indices are used in research to assess the improvement of melasma with treatment.

Patients with melasma report a decrease in quality of life, increased emotional stress, and lower self-esteem due to cosmesis.¹³ Treatment of melasma can be highly challenging and often is complicated by relapsing. Historically, the treatment of melasma has included the use of chemical lightening agents. Additional treatment options include the use of lasers and complex chemical peels,^9,10 but these interventions may result in adverse outcomes for individuals with darker skin tones. The current gold-standard treatment is topical hydroquinone and broad-spectrum sunscreen. Although hydroquinone is effective in the treatment of melasma, relapse is common. The goal of melasma management is not only to treat acute hyperpigmentation but also to prevent relapse. Other therapies that currently are being explored for the clinically sustained treatment of melasma include tranexamic acid (TXA)(trans-4-[aminomethyl]cyclohexanecarboxylic acid),^9,10 an antifibrinolytic agent routinely used to prevent blood loss during surgery and in the management of menorrhagia. It is a synthetic derivative of lysine and serves as a potent plasmin inhibitor by blocking the lysine-binding sites of plasminogen molecules, thus preventing the conversion of plasminogen to plasmin. It also prevents fibrinolysis and blood loss.

In addition to its hemostatic properties, TXA has been found to have hypopigmentation properties.^14,15 Plasminogen also can be found in human epidermal basal cells and human keratinocytes, and it is postulated that TXA’s interaction with these cells explains its hypopigmentation properties. Both UV radiation and hormones activate plasminogen into plasmin, resulting in the activation of tyrosinase and melanogenesis.^14,15 Tranexamic acid is postulated to inhibit the keratinocyte-plasminogen pathway, thus leading to the inhibition of UV-induced and hormone-induced pigmentation. Also, TXA serves as a competitive inhibitor for tyrosinase due to its structural similarity to tyrosine.¹⁵ The combination of these 2 mechanisms contributes to the skin-lightening effects of TXA, making it a potential treatment for melasma.

Furthermore, the use of microneedling is being explored as a treatment option for melasma. Microneedling creates microscopic punctures in the skin using tiny needles, resulting in a wound-healing response and skin resurfacing. The microneedling technique is utilized to create small holes in the skin, with needle depths that can be adjusted from 0.5 to 3.5 mm to target different layers of the dermis and allow for discreet application of TXA.¹⁶ We sought to look at the current literature on the use and effectiveness of microneedling in combination with TXA to treat melasma and prevent relapse.

Methods

A systematic review was performed of PubMed articles indexed for MEDLINE and Embase in November 2021 to compile available articles that studied TXA and microneedling as a treatment for melasma. The PubMed search terms were (melasma) AND (microneedling* OR ‘tranexamic acid’ OR TXA or TA). The Embase search terms were (cholasma OR melasma) AND (tranexamic acid OR TXA) AND (microneedling)(Figure). The search was then limited to ”randomized controlled trial” and ”clinical trial” in English-language journals. Duplicates were excluded. After thorough evaluation, articles that discussed the use of TXA in combination with treatment options other than microneedling also were excluded.

Results

The literature search yielded a total of 12 articles that assessed the effectiveness of TXA and microneedling for the treatment of melasma (Table).^17-28 Several articles concluded that TXA was equally effective at reducing melasma lesions when compared with the standard treatment of hydroquinone. Some of the reviewed articles also demonstrated the effectiveness of microneedling in improving melasma lesions as a stand-alone treatment. These studies highlighted the enhanced efficacy of the combined treatment of TXA and microneedling compared with their individual uses.^17-28

Comment

Melasma is a common chronic hyperpigmentation disorder, making its treatment clinically challenging. Many patients experience symptom relapses, and limited effective treatment options make achieving complete clearance difficult, underscoring the need for improved therapeutic approaches. Recently, researchers have explored alternative treatments to address the challenges of melasma management. Tranexamic acid is an antifibrinolytic used to prevent blood loss and has emerged as a potential treatment for melasma. Similarly, microneedling—a technique in which multiple punctures are made in the skin to activate and stimulate wound healing and skin rejuvenation—shows promise for melasma.

Oral TXA for Melasma—Oral TXA has been shown to reduce melasma lesions. Del Rosario et al¹⁷ recruited 44 women (39 of whom completed the study) with moderate to severe melasma and randomized them into 2 groups: oral TXA and placebo. This study demonstrated a 49% reduction in the mMASI score in all participants taking oral TXA (250 mg twice daily [BID]) compared with an 18% reduction in the control group (placebo capsule BID) after 3 months of treatment. In patients with moderate and severe melasma, 45% and 51% mMASI score reductions were reported in the treatment group, respectively, vs 16% and 19% score reductions in placebo group, respectively. These researchers concluded that oral TXA may be effective at treating moderate to severe melasma. Although patients with severe melasma had a better response to treatment, their improvement was not sustained compared with patients with moderate melasma after a 3-month posttreatment follow-up.¹⁷

Microneedling Plus TXA for Melasma—Microneedling alone has been shown to be effective for melasma. El Attar et al¹⁸ conducted a split-face study of microneedling (1.5-mm depth) plus topical TXA (0.5 mL)(right side of the face[treatment arm]) compared with microneedling (1.5-mm depth) plus topical vitamin C (0.5 mL)(left side of the face [control group]) in 20 women with melasma. The sessions were repeated every 2 weeks for a total of 6 sessions. Although researchers found no statistically significant differences between the 2 treatment sides, microneedling plus TXA showed a slight advantage over microneedling plus vitamin C in dermoscopic examination. Both sides showed improvement in pigmented lesions, but vitamin C–treated lesions did not show an improvement in vascularity vs TXA.¹⁸

Saleh et al¹⁹ further showed that combination treatment with microneedling and TXA may improve clinical outcomes better than microneedling alone. Their study demonstrated a reduction in MASI score that was significantly higher in the combination treatment group compared with the microneedling alone group (P=.001). There was a significant reduction in melanoma antigen recognized by T cells 1 (MART-1)–positive cells in the combination treatment group compared with the microneedling alone group (P=.001). Lastly, combined therapy improved melasma patches better than microneedling alone.¹⁹

Xu et al²⁰ conducted a split-face study (N=28) exploring the effectiveness of transdermal application of topical TXA using a microarray pen with microneedles (vibration at 3000×/min) plus topical TXA on one side of the face, while the other side received only topical TXA as a control. After 12 weeks of treatment, combination therapy with microneedling and TXA decreased brown spot scores, lowered melanin index (MI) values, improved blinded physician assessment, and improved patient satisfaction vs TXA therapy alone.²⁰

Kaur et al²¹ conducted a split-face, randomized, controlled trial of microneedling (1-mm depth) with TXA solution 10% vs microneedling (1-mm depth) with distilled water alone for 8 weeks (N=40). They graded participant responses to treatment using reductions in mMASI scores¹² at every 2 weeks of follow-up (no response, minimal or poor response=0%–25%; partial or fair response=26%–50%; good response=51%–75%; and excellent response=>75%). They reported an overall reduction in mMASI scores for both the treatment side and the control side in all participants, showing a 65.92% improvement in mean mMASI scores on the treatment side vs 20.75% improvement on the control side at week 8. Both sides showed statistically significant reductions in mean mMASI scores (P<.05). Clinically, 40% (16/40) of participants showed an excellent response to combined treatment compared with 0% (0/40) to microneedling alone. Overall, patient satisfaction was similar across both groups. This study demonstrated that microneedling alone improves melasma, but a combination of microneedling plus TXA showed a better clinical reduction in melasma. However, the researchers did not follow up with participants posttreatment, so it remains unclear if the improved clinical outcomes were sustained long-term.²¹

Ebrahim et al²² reported that the combination of 0.5 mL TXA (4 mg/mL) and microneedling (0.25- to 1-mm depth) was effective for melasma. Although there was improvement within microneedling and TXA, the study also showed that intradermal injection of TXA was significant in reducing mean mMASI scores and improving melasma (P<.001). The reduction in mMASI scores for the group receiving intradermal injections of TXA (left side; 74.8% reduction in mean mMASI score) vs the group receiving microneedling application of TXA (right side; 73.6% reduction in mean mMASI score) was not statistically significant. These findings suggest that the mode of TXA application may not be critical in determining clinical responses to TXA treatment. Although there was no reported statistically significant difference in clinical outcomes between the 2 treatments, patient satisfaction was higher on the microneedling side. Only 8 of 50 participants (16%) experienced recurrence 3 months posttreatment.²²

Saki et al²³ compared the efficacy of topical hydroquinone (2%) to intradermal TXA injections in treating melasma. They found intradermal TXA injections to be a clinically effective mode of treatment.²³

Sharma et al²⁴ explored the efficacy and safety of oral TXA by randomly assigning 100 Indian patients (20 of whom withdrew before study completion) with melasma into 2 groups: group A received TXA 250 mg twice daily, and group B received intradermal microinjections of TXA (4 mg/mL) every 4 weeks. The MASI scores were assessed at 4-week intervals for a total of 12 weeks. There was a decrease in MASI scores in both groups, and there was no statistically significant difference in mean percentage reduction in MASI scores between the 2 routes of drug administration, further suggesting the effectiveness of TXA independent of administration route. Two patients in group A relapsed at 24 weeks, and there were no relapses in group B, which may suggest a minimal superiority of TXA plus microneedling at providing more sustainable results compared with oral TXA alone. A notable limitation of this study was a high dropout rate as well as lack of long-term follow-up with participants, limiting the generalizability of the conclusions.²⁴

Cassiano et al²⁵ assigned 64 women with melasma to 1 of 3 treatment groups or a control group to compare the effectiveness of microneedling (M group: 1.5 mm; 2 sessions), oral TXA (T group: 250 mg/d twice daily for 60 days), and a combination of microneedling (2 sessions) and oral TXA (MT group: 250 mg/d twice daily for 60 days)with placebo for clinically reducing melasma lesions. The intervention period was 60 days followed by a 60-day maintenance phase for a total study period of 120 days. The researchers evaluated mMASI scores, quality of life, and difference in colorimetric luminosity. All treatment groups showed a reduction in mMASI scores at both 30 days and 60 days, indicating improved melasma severity. The MT and T groups had more significant improvement at 30 days compared with the control group (P<.03), suggesting that microneedling plus TXA and TXA alone promote faster improvement in melasma lesions. By 60 days, the M, T, and MT groups outperformed the control group, with no significant differences between the M, T, and MT groups. However, at the 120-day maintenance follow-up, the T group did not maintain its improvement compared with the control group. The M and MT groups showed no significance difference in effectiveness at 120 days, suggesting that microneedling may promote less frequent relapse and sustained remission compared to TXA alone.²⁵

Hydroquinone for Melasma—Additional studies on the use of TXA treatments show that TXA may be an equally effective alternative to the standard use of hydroquinone treatment. Shamsi Meymandi et al²⁶ did not find a statistically significant difference in treatment with TXA plus microneedling vs the standard regimen of hydroquinone. More importantly, patient and physician satisfaction assessments were similar between the 2 groups. Compared to hydroquinone, nightly treatment is not necessary with microneedling and TXA.²⁶

Xing et al²⁷ supported these conclusions with their study. They compared 3 study arms for a duration of 12 weeks: group A received topical 1.8% liposomal TXA BID, group B received stamp-mode electric microneedling with 5% TXA weekly, and group C applied 2% ­hydroquinone cream nightly. The study concluded that all 3 groups showed a significant reduction in mean MI by the end of the study, but a better MI improvement was observed in groups B and C (both P<.001) compared with group A (P<.01).²⁷

Zaky et al²⁸ showed that both hydroquinone and combination treatment of TXA plus microneedling are effective at improving melasma lesions. Further studies are needed to definitively conclude if combination treatment is more efficacious than hydroquinone; if the combination is more effective, it provides a treatment option for patients with melasma who may not be good candidates for hydroquinone treatment.

Study Limitations—One limitation in all the studies evaluated is the sample size. Because they all had small sample sizes, it is difficult to definitively conclude that the combination TXA and microneedling is an effective and appropriate treatment for patients with melasma. Furthermore, the quality of these studies was mostly dependent on subjectivity of the mMASI scores. Future large randomized controlled trials with a diverse participant population are needed to assess the effectiveness of TXA and microneedling in melasma treatment.

Another limitation is that many of the studies did not follow the patients longitudinally, which did not allow for an evaluation of whether patients had a relapse of melasma. Due to the chronic nature of melasma and frequent disease recurrence, future longitudinal studies are needed to monitor for disease recurrence.

Conclusion

Tranexamic acid and microneedling are potential treatment options for patients with melasma, and combination therapy appears more effective than either TXA or microneedling alone at providing sustained improvement of melasma lesions. Combination therapy appears safe and well tolerated, but its effect on reducing long-term disease recurrence is yet to be established.

Melasma (also known as chloasma faciei) is a common chronic skin disorder that results in well-demarcated, hyperpigmented, tan to dark patches that mostly appear in sun-exposed areas such as the face and neck and sometimes the arms. The exact prevalence or incidence is not known but is estimated to be 1% to 50% overall depending on the ethnic population and geographic location.^1,2 Melasma predominantly affects women, but research has shown that approximately 10% to 20% of men are affected by this condition.^3,4 Although melasma can affect patients of all skin types, it primarily affects those with darker skin tones.⁵ The groups most often affected are women of Black, Hispanic, Middle Eastern, and Southeast Asian ethnicity. Although the pathogenesis is complex and not fully understood, multiple pathways and etiologies have been theorized to cause melasma. Potential causes include exposure to UV radiation, oral contraceptives, hormonal changes, medications, thyroid dysfunction, genetics, and pregnancy.^6,7 Cytokines and growth factors, including adipokine and angiopoietin, synthesized by sebaceous glands play a role in the pathogenic mechanism of melasma. Cytokines and growth factors are hypothesized to modulate the function of melanocytes.⁸ Both melanocytes and sebocytes are controlled by α–melanocyte-stimulating hormone. Therefore, overexpression of α–melanocyte-stimulating hormone will result in overproduction of these 2 cell types, resulting in melasma. Melasma can be classified into 4 subtypes using Wood lamp examination: epidermal, dermal, mixed, or indeterminate.³ Furthermore, melasma is divided into subgroups based on the location: malar region, mandibular region, and centrofacial patch pattern.^9,10 The involvement of sebaceous glands in the pathogenesis of melasma may explain the predilection for the centrofacial region, which is the most common pattern.

The severity of melasma can be assessed using the melasma area and severity index (MASI), which is calculated by subjective assessment of 3 main factors: (1) facial area of involvement; (2) darkness of affected region; and (3) homogeneity, with the extent of melasma indicated by a score ranging from 0 to 48.¹¹ The modified MASI (mMASI) subsequently was introduced to assist with assessing the severity of melasma and creating distinct ranges for mild, moderate, and severe cases, ranging from 0 (mild) to 24 (severe).¹² Both indices are used in research to assess the improvement of melasma with treatment.

Patients with melasma report a decrease in quality of life, increased emotional stress, and lower self-esteem due to cosmesis.¹³ Treatment of melasma can be highly challenging and often is complicated by relapsing. Historically, the treatment of melasma has included the use of chemical lightening agents. Additional treatment options include the use of lasers and complex chemical peels,^9,10 but these interventions may result in adverse outcomes for individuals with darker skin tones. The current gold-standard treatment is topical hydroquinone and broad-spectrum sunscreen. Although hydroquinone is effective in the treatment of melasma, relapse is common. The goal of melasma management is not only to treat acute hyperpigmentation but also to prevent relapse. Other therapies that currently are being explored for the clinically sustained treatment of melasma include tranexamic acid (TXA)(trans-4-[aminomethyl]cyclohexanecarboxylic acid),^9,10 an antifibrinolytic agent routinely used to prevent blood loss during surgery and in the management of menorrhagia. It is a synthetic derivative of lysine and serves as a potent plasmin inhibitor by blocking the lysine-binding sites of plasminogen molecules, thus preventing the conversion of plasminogen to plasmin. It also prevents fibrinolysis and blood loss.

In addition to its hemostatic properties, TXA has been found to have hypopigmentation properties.^14,15 Plasminogen also can be found in human epidermal basal cells and human keratinocytes, and it is postulated that TXA’s interaction with these cells explains its hypopigmentation properties. Both UV radiation and hormones activate plasminogen into plasmin, resulting in the activation of tyrosinase and melanogenesis.^14,15 Tranexamic acid is postulated to inhibit the keratinocyte-plasminogen pathway, thus leading to the inhibition of UV-induced and hormone-induced pigmentation. Also, TXA serves as a competitive inhibitor for tyrosinase due to its structural similarity to tyrosine.¹⁵ The combination of these 2 mechanisms contributes to the skin-lightening effects of TXA, making it a potential treatment for melasma.

Furthermore, the use of microneedling is being explored as a treatment option for melasma. Microneedling creates microscopic punctures in the skin using tiny needles, resulting in a wound-healing response and skin resurfacing. The microneedling technique is utilized to create small holes in the skin, with needle depths that can be adjusted from 0.5 to 3.5 mm to target different layers of the dermis and allow for discreet application of TXA.¹⁶ We sought to look at the current literature on the use and effectiveness of microneedling in combination with TXA to treat melasma and prevent relapse.

Methods

A systematic review was performed of PubMed articles indexed for MEDLINE and Embase in November 2021 to compile available articles that studied TXA and microneedling as a treatment for melasma. The PubMed search terms were (melasma) AND (microneedling* OR ‘tranexamic acid’ OR TXA or TA). The Embase search terms were (cholasma OR melasma) AND (tranexamic acid OR TXA) AND (microneedling)(Figure). The search was then limited to ”randomized controlled trial” and ”clinical trial” in English-language journals. Duplicates were excluded. After thorough evaluation, articles that discussed the use of TXA in combination with treatment options other than microneedling also were excluded.

Results

The literature search yielded a total of 12 articles that assessed the effectiveness of TXA and microneedling for the treatment of melasma (Table).^17-28 Several articles concluded that TXA was equally effective at reducing melasma lesions when compared with the standard treatment of hydroquinone. Some of the reviewed articles also demonstrated the effectiveness of microneedling in improving melasma lesions as a stand-alone treatment. These studies highlighted the enhanced efficacy of the combined treatment of TXA and microneedling compared with their individual uses.^17-28

Comment

Melasma is a common chronic hyperpigmentation disorder, making its treatment clinically challenging. Many patients experience symptom relapses, and limited effective treatment options make achieving complete clearance difficult, underscoring the need for improved therapeutic approaches. Recently, researchers have explored alternative treatments to address the challenges of melasma management. Tranexamic acid is an antifibrinolytic used to prevent blood loss and has emerged as a potential treatment for melasma. Similarly, microneedling—a technique in which multiple punctures are made in the skin to activate and stimulate wound healing and skin rejuvenation—shows promise for melasma.

Oral TXA for Melasma—Oral TXA has been shown to reduce melasma lesions. Del Rosario et al¹⁷ recruited 44 women (39 of whom completed the study) with moderate to severe melasma and randomized them into 2 groups: oral TXA and placebo. This study demonstrated a 49% reduction in the mMASI score in all participants taking oral TXA (250 mg twice daily [BID]) compared with an 18% reduction in the control group (placebo capsule BID) after 3 months of treatment. In patients with moderate and severe melasma, 45% and 51% mMASI score reductions were reported in the treatment group, respectively, vs 16% and 19% score reductions in placebo group, respectively. These researchers concluded that oral TXA may be effective at treating moderate to severe melasma. Although patients with severe melasma had a better response to treatment, their improvement was not sustained compared with patients with moderate melasma after a 3-month posttreatment follow-up.¹⁷

Microneedling Plus TXA for Melasma—Microneedling alone has been shown to be effective for melasma. El Attar et al¹⁸ conducted a split-face study of microneedling (1.5-mm depth) plus topical TXA (0.5 mL)(right side of the face[treatment arm]) compared with microneedling (1.5-mm depth) plus topical vitamin C (0.5 mL)(left side of the face [control group]) in 20 women with melasma. The sessions were repeated every 2 weeks for a total of 6 sessions. Although researchers found no statistically significant differences between the 2 treatment sides, microneedling plus TXA showed a slight advantage over microneedling plus vitamin C in dermoscopic examination. Both sides showed improvement in pigmented lesions, but vitamin C–treated lesions did not show an improvement in vascularity vs TXA.¹⁸

Saleh et al¹⁹ further showed that combination treatment with microneedling and TXA may improve clinical outcomes better than microneedling alone. Their study demonstrated a reduction in MASI score that was significantly higher in the combination treatment group compared with the microneedling alone group (P=.001). There was a significant reduction in melanoma antigen recognized by T cells 1 (MART-1)–positive cells in the combination treatment group compared with the microneedling alone group (P=.001). Lastly, combined therapy improved melasma patches better than microneedling alone.¹⁹

Xu et al²⁰ conducted a split-face study (N=28) exploring the effectiveness of transdermal application of topical TXA using a microarray pen with microneedles (vibration at 3000×/min) plus topical TXA on one side of the face, while the other side received only topical TXA as a control. After 12 weeks of treatment, combination therapy with microneedling and TXA decreased brown spot scores, lowered melanin index (MI) values, improved blinded physician assessment, and improved patient satisfaction vs TXA therapy alone.²⁰

Kaur et al²¹ conducted a split-face, randomized, controlled trial of microneedling (1-mm depth) with TXA solution 10% vs microneedling (1-mm depth) with distilled water alone for 8 weeks (N=40). They graded participant responses to treatment using reductions in mMASI scores¹² at every 2 weeks of follow-up (no response, minimal or poor response=0%–25%; partial or fair response=26%–50%; good response=51%–75%; and excellent response=>75%). They reported an overall reduction in mMASI scores for both the treatment side and the control side in all participants, showing a 65.92% improvement in mean mMASI scores on the treatment side vs 20.75% improvement on the control side at week 8. Both sides showed statistically significant reductions in mean mMASI scores (P<.05). Clinically, 40% (16/40) of participants showed an excellent response to combined treatment compared with 0% (0/40) to microneedling alone. Overall, patient satisfaction was similar across both groups. This study demonstrated that microneedling alone improves melasma, but a combination of microneedling plus TXA showed a better clinical reduction in melasma. However, the researchers did not follow up with participants posttreatment, so it remains unclear if the improved clinical outcomes were sustained long-term.²¹

Ebrahim et al²² reported that the combination of 0.5 mL TXA (4 mg/mL) and microneedling (0.25- to 1-mm depth) was effective for melasma. Although there was improvement within microneedling and TXA, the study also showed that intradermal injection of TXA was significant in reducing mean mMASI scores and improving melasma (P<.001). The reduction in mMASI scores for the group receiving intradermal injections of TXA (left side; 74.8% reduction in mean mMASI score) vs the group receiving microneedling application of TXA (right side; 73.6% reduction in mean mMASI score) was not statistically significant. These findings suggest that the mode of TXA application may not be critical in determining clinical responses to TXA treatment. Although there was no reported statistically significant difference in clinical outcomes between the 2 treatments, patient satisfaction was higher on the microneedling side. Only 8 of 50 participants (16%) experienced recurrence 3 months posttreatment.²²

Saki et al²³ compared the efficacy of topical hydroquinone (2%) to intradermal TXA injections in treating melasma. They found intradermal TXA injections to be a clinically effective mode of treatment.²³

Sharma et al²⁴ explored the efficacy and safety of oral TXA by randomly assigning 100 Indian patients (20 of whom withdrew before study completion) with melasma into 2 groups: group A received TXA 250 mg twice daily, and group B received intradermal microinjections of TXA (4 mg/mL) every 4 weeks. The MASI scores were assessed at 4-week intervals for a total of 12 weeks. There was a decrease in MASI scores in both groups, and there was no statistically significant difference in mean percentage reduction in MASI scores between the 2 routes of drug administration, further suggesting the effectiveness of TXA independent of administration route. Two patients in group A relapsed at 24 weeks, and there were no relapses in group B, which may suggest a minimal superiority of TXA plus microneedling at providing more sustainable results compared with oral TXA alone. A notable limitation of this study was a high dropout rate as well as lack of long-term follow-up with participants, limiting the generalizability of the conclusions.²⁴

Cassiano et al²⁵ assigned 64 women with melasma to 1 of 3 treatment groups or a control group to compare the effectiveness of microneedling (M group: 1.5 mm; 2 sessions), oral TXA (T group: 250 mg/d twice daily for 60 days), and a combination of microneedling (2 sessions) and oral TXA (MT group: 250 mg/d twice daily for 60 days)with placebo for clinically reducing melasma lesions. The intervention period was 60 days followed by a 60-day maintenance phase for a total study period of 120 days. The researchers evaluated mMASI scores, quality of life, and difference in colorimetric luminosity. All treatment groups showed a reduction in mMASI scores at both 30 days and 60 days, indicating improved melasma severity. The MT and T groups had more significant improvement at 30 days compared with the control group (P<.03), suggesting that microneedling plus TXA and TXA alone promote faster improvement in melasma lesions. By 60 days, the M, T, and MT groups outperformed the control group, with no significant differences between the M, T, and MT groups. However, at the 120-day maintenance follow-up, the T group did not maintain its improvement compared with the control group. The M and MT groups showed no significance difference in effectiveness at 120 days, suggesting that microneedling may promote less frequent relapse and sustained remission compared to TXA alone.²⁵

Hydroquinone for Melasma—Additional studies on the use of TXA treatments show that TXA may be an equally effective alternative to the standard use of hydroquinone treatment. Shamsi Meymandi et al²⁶ did not find a statistically significant difference in treatment with TXA plus microneedling vs the standard regimen of hydroquinone. More importantly, patient and physician satisfaction assessments were similar between the 2 groups. Compared to hydroquinone, nightly treatment is not necessary with microneedling and TXA.²⁶

Xing et al²⁷ supported these conclusions with their study. They compared 3 study arms for a duration of 12 weeks: group A received topical 1.8% liposomal TXA BID, group B received stamp-mode electric microneedling with 5% TXA weekly, and group C applied 2% ­hydroquinone cream nightly. The study concluded that all 3 groups showed a significant reduction in mean MI by the end of the study, but a better MI improvement was observed in groups B and C (both P<.001) compared with group A (P<.01).²⁷

Zaky et al²⁸ showed that both hydroquinone and combination treatment of TXA plus microneedling are effective at improving melasma lesions. Further studies are needed to definitively conclude if combination treatment is more efficacious than hydroquinone; if the combination is more effective, it provides a treatment option for patients with melasma who may not be good candidates for hydroquinone treatment.

Study Limitations—One limitation in all the studies evaluated is the sample size. Because they all had small sample sizes, it is difficult to definitively conclude that the combination TXA and microneedling is an effective and appropriate treatment for patients with melasma. Furthermore, the quality of these studies was mostly dependent on subjectivity of the mMASI scores. Future large randomized controlled trials with a diverse participant population are needed to assess the effectiveness of TXA and microneedling in melasma treatment.

Another limitation is that many of the studies did not follow the patients longitudinally, which did not allow for an evaluation of whether patients had a relapse of melasma. Due to the chronic nature of melasma and frequent disease recurrence, future longitudinal studies are needed to monitor for disease recurrence.

Conclusion

Tranexamic acid and microneedling are potential treatment options for patients with melasma, and combination therapy appears more effective than either TXA or microneedling alone at providing sustained improvement of melasma lesions. Combination therapy appears safe and well tolerated, but its effect on reducing long-term disease recurrence is yet to be established.

Melasma (also known as chloasma faciei) is a common chronic skin disorder that results in well-demarcated, hyperpigmented, tan to dark patches that mostly appear in sun-exposed areas such as the face and neck and sometimes the arms. The exact prevalence or incidence is not known but is estimated to be 1% to 50% overall depending on the ethnic population and geographic location.^1,2 Melasma predominantly affects women, but research has shown that approximately 10% to 20% of men are affected by this condition.^3,4 Although melasma can affect patients of all skin types, it primarily affects those with darker skin tones.⁵ The groups most often affected are women of Black, Hispanic, Middle Eastern, and Southeast Asian ethnicity. Although the pathogenesis is complex and not fully understood, multiple pathways and etiologies have been theorized to cause melasma. Potential causes include exposure to UV radiation, oral contraceptives, hormonal changes, medications, thyroid dysfunction, genetics, and pregnancy.^6,7 Cytokines and growth factors, including adipokine and angiopoietin, synthesized by sebaceous glands play a role in the pathogenic mechanism of melasma. Cytokines and growth factors are hypothesized to modulate the function of melanocytes.⁸ Both melanocytes and sebocytes are controlled by α–melanocyte-stimulating hormone. Therefore, overexpression of α–melanocyte-stimulating hormone will result in overproduction of these 2 cell types, resulting in melasma. Melasma can be classified into 4 subtypes using Wood lamp examination: epidermal, dermal, mixed, or indeterminate.³ Furthermore, melasma is divided into subgroups based on the location: malar region, mandibular region, and centrofacial patch pattern.^9,10 The involvement of sebaceous glands in the pathogenesis of melasma may explain the predilection for the centrofacial region, which is the most common pattern.

The severity of melasma can be assessed using the melasma area and severity index (MASI), which is calculated by subjective assessment of 3 main factors: (1) facial area of involvement; (2) darkness of affected region; and (3) homogeneity, with the extent of melasma indicated by a score ranging from 0 to 48.¹¹ The modified MASI (mMASI) subsequently was introduced to assist with assessing the severity of melasma and creating distinct ranges for mild, moderate, and severe cases, ranging from 0 (mild) to 24 (severe).¹² Both indices are used in research to assess the improvement of melasma with treatment.

Patients with melasma report a decrease in quality of life, increased emotional stress, and lower self-esteem due to cosmesis.¹³ Treatment of melasma can be highly challenging and often is complicated by relapsing. Historically, the treatment of melasma has included the use of chemical lightening agents. Additional treatment options include the use of lasers and complex chemical peels,^9,10 but these interventions may result in adverse outcomes for individuals with darker skin tones. The current gold-standard treatment is topical hydroquinone and broad-spectrum sunscreen. Although hydroquinone is effective in the treatment of melasma, relapse is common. The goal of melasma management is not only to treat acute hyperpigmentation but also to prevent relapse. Other therapies that currently are being explored for the clinically sustained treatment of melasma include tranexamic acid (TXA)(trans-4-[aminomethyl]cyclohexanecarboxylic acid),^9,10 an antifibrinolytic agent routinely used to prevent blood loss during surgery and in the management of menorrhagia. It is a synthetic derivative of lysine and serves as a potent plasmin inhibitor by blocking the lysine-binding sites of plasminogen molecules, thus preventing the conversion of plasminogen to plasmin. It also prevents fibrinolysis and blood loss.

In addition to its hemostatic properties, TXA has been found to have hypopigmentation properties.^14,15 Plasminogen also can be found in human epidermal basal cells and human keratinocytes, and it is postulated that TXA’s interaction with these cells explains its hypopigmentation properties. Both UV radiation and hormones activate plasminogen into plasmin, resulting in the activation of tyrosinase and melanogenesis.^14,15 Tranexamic acid is postulated to inhibit the keratinocyte-plasminogen pathway, thus leading to the inhibition of UV-induced and hormone-induced pigmentation. Also, TXA serves as a competitive inhibitor for tyrosinase due to its structural similarity to tyrosine.¹⁵ The combination of these 2 mechanisms contributes to the skin-lightening effects of TXA, making it a potential treatment for melasma.

Furthermore, the use of microneedling is being explored as a treatment option for melasma. Microneedling creates microscopic punctures in the skin using tiny needles, resulting in a wound-healing response and skin resurfacing. The microneedling technique is utilized to create small holes in the skin, with needle depths that can be adjusted from 0.5 to 3.5 mm to target different layers of the dermis and allow for discreet application of TXA.¹⁶ We sought to look at the current literature on the use and effectiveness of microneedling in combination with TXA to treat melasma and prevent relapse.

Methods

A systematic review was performed of PubMed articles indexed for MEDLINE and Embase in November 2021 to compile available articles that studied TXA and microneedling as a treatment for melasma. The PubMed search terms were (melasma) AND (microneedling* OR ‘tranexamic acid’ OR TXA or TA). The Embase search terms were (cholasma OR melasma) AND (tranexamic acid OR TXA) AND (microneedling)(Figure). The search was then limited to ”randomized controlled trial” and ”clinical trial” in English-language journals. Duplicates were excluded. After thorough evaluation, articles that discussed the use of TXA in combination with treatment options other than microneedling also were excluded.

Results

The literature search yielded a total of 12 articles that assessed the effectiveness of TXA and microneedling for the treatment of melasma (Table).^17-28 Several articles concluded that TXA was equally effective at reducing melasma lesions when compared with the standard treatment of hydroquinone. Some of the reviewed articles also demonstrated the effectiveness of microneedling in improving melasma lesions as a stand-alone treatment. These studies highlighted the enhanced efficacy of the combined treatment of TXA and microneedling compared with their individual uses.^17-28

Comment

Melasma is a common chronic hyperpigmentation disorder, making its treatment clinically challenging. Many patients experience symptom relapses, and limited effective treatment options make achieving complete clearance difficult, underscoring the need for improved therapeutic approaches. Recently, researchers have explored alternative treatments to address the challenges of melasma management. Tranexamic acid is an antifibrinolytic used to prevent blood loss and has emerged as a potential treatment for melasma. Similarly, microneedling—a technique in which multiple punctures are made in the skin to activate and stimulate wound healing and skin rejuvenation—shows promise for melasma.

Oral TXA for Melasma—Oral TXA has been shown to reduce melasma lesions. Del Rosario et al¹⁷ recruited 44 women (39 of whom completed the study) with moderate to severe melasma and randomized them into 2 groups: oral TXA and placebo. This study demonstrated a 49% reduction in the mMASI score in all participants taking oral TXA (250 mg twice daily [BID]) compared with an 18% reduction in the control group (placebo capsule BID) after 3 months of treatment. In patients with moderate and severe melasma, 45% and 51% mMASI score reductions were reported in the treatment group, respectively, vs 16% and 19% score reductions in placebo group, respectively. These researchers concluded that oral TXA may be effective at treating moderate to severe melasma. Although patients with severe melasma had a better response to treatment, their improvement was not sustained compared with patients with moderate melasma after a 3-month posttreatment follow-up.¹⁷

Microneedling Plus TXA for Melasma—Microneedling alone has been shown to be effective for melasma. El Attar et al¹⁸ conducted a split-face study of microneedling (1.5-mm depth) plus topical TXA (0.5 mL)(right side of the face[treatment arm]) compared with microneedling (1.5-mm depth) plus topical vitamin C (0.5 mL)(left side of the face [control group]) in 20 women with melasma. The sessions were repeated every 2 weeks for a total of 6 sessions. Although researchers found no statistically significant differences between the 2 treatment sides, microneedling plus TXA showed a slight advantage over microneedling plus vitamin C in dermoscopic examination. Both sides showed improvement in pigmented lesions, but vitamin C–treated lesions did not show an improvement in vascularity vs TXA.¹⁸

Saleh et al¹⁹ further showed that combination treatment with microneedling and TXA may improve clinical outcomes better than microneedling alone. Their study demonstrated a reduction in MASI score that was significantly higher in the combination treatment group compared with the microneedling alone group (P=.001). There was a significant reduction in melanoma antigen recognized by T cells 1 (MART-1)–positive cells in the combination treatment group compared with the microneedling alone group (P=.001). Lastly, combined therapy improved melasma patches better than microneedling alone.¹⁹

Xu et al²⁰ conducted a split-face study (N=28) exploring the effectiveness of transdermal application of topical TXA using a microarray pen with microneedles (vibration at 3000×/min) plus topical TXA on one side of the face, while the other side received only topical TXA as a control. After 12 weeks of treatment, combination therapy with microneedling and TXA decreased brown spot scores, lowered melanin index (MI) values, improved blinded physician assessment, and improved patient satisfaction vs TXA therapy alone.²⁰

Kaur et al²¹ conducted a split-face, randomized, controlled trial of microneedling (1-mm depth) with TXA solution 10% vs microneedling (1-mm depth) with distilled water alone for 8 weeks (N=40). They graded participant responses to treatment using reductions in mMASI scores¹² at every 2 weeks of follow-up (no response, minimal or poor response=0%–25%; partial or fair response=26%–50%; good response=51%–75%; and excellent response=>75%). They reported an overall reduction in mMASI scores for both the treatment side and the control side in all participants, showing a 65.92% improvement in mean mMASI scores on the treatment side vs 20.75% improvement on the control side at week 8. Both sides showed statistically significant reductions in mean mMASI scores (P<.05). Clinically, 40% (16/40) of participants showed an excellent response to combined treatment compared with 0% (0/40) to microneedling alone. Overall, patient satisfaction was similar across both groups. This study demonstrated that microneedling alone improves melasma, but a combination of microneedling plus TXA showed a better clinical reduction in melasma. However, the researchers did not follow up with participants posttreatment, so it remains unclear if the improved clinical outcomes were sustained long-term.²¹

Ebrahim et al²² reported that the combination of 0.5 mL TXA (4 mg/mL) and microneedling (0.25- to 1-mm depth) was effective for melasma. Although there was improvement within microneedling and TXA, the study also showed that intradermal injection of TXA was significant in reducing mean mMASI scores and improving melasma (P<.001). The reduction in mMASI scores for the group receiving intradermal injections of TXA (left side; 74.8% reduction in mean mMASI score) vs the group receiving microneedling application of TXA (right side; 73.6% reduction in mean mMASI score) was not statistically significant. These findings suggest that the mode of TXA application may not be critical in determining clinical responses to TXA treatment. Although there was no reported statistically significant difference in clinical outcomes between the 2 treatments, patient satisfaction was higher on the microneedling side. Only 8 of 50 participants (16%) experienced recurrence 3 months posttreatment.²²

Saki et al²³ compared the efficacy of topical hydroquinone (2%) to intradermal TXA injections in treating melasma. They found intradermal TXA injections to be a clinically effective mode of treatment.²³

Sharma et al²⁴ explored the efficacy and safety of oral TXA by randomly assigning 100 Indian patients (20 of whom withdrew before study completion) with melasma into 2 groups: group A received TXA 250 mg twice daily, and group B received intradermal microinjections of TXA (4 mg/mL) every 4 weeks. The MASI scores were assessed at 4-week intervals for a total of 12 weeks. There was a decrease in MASI scores in both groups, and there was no statistically significant difference in mean percentage reduction in MASI scores between the 2 routes of drug administration, further suggesting the effectiveness of TXA independent of administration route. Two patients in group A relapsed at 24 weeks, and there were no relapses in group B, which may suggest a minimal superiority of TXA plus microneedling at providing more sustainable results compared with oral TXA alone. A notable limitation of this study was a high dropout rate as well as lack of long-term follow-up with participants, limiting the generalizability of the conclusions.²⁴

Cassiano et al²⁵ assigned 64 women with melasma to 1 of 3 treatment groups or a control group to compare the effectiveness of microneedling (M group: 1.5 mm; 2 sessions), oral TXA (T group: 250 mg/d twice daily for 60 days), and a combination of microneedling (2 sessions) and oral TXA (MT group: 250 mg/d twice daily for 60 days)with placebo for clinically reducing melasma lesions. The intervention period was 60 days followed by a 60-day maintenance phase for a total study period of 120 days. The researchers evaluated mMASI scores, quality of life, and difference in colorimetric luminosity. All treatment groups showed a reduction in mMASI scores at both 30 days and 60 days, indicating improved melasma severity. The MT and T groups had more significant improvement at 30 days compared with the control group (P<.03), suggesting that microneedling plus TXA and TXA alone promote faster improvement in melasma lesions. By 60 days, the M, T, and MT groups outperformed the control group, with no significant differences between the M, T, and MT groups. However, at the 120-day maintenance follow-up, the T group did not maintain its improvement compared with the control group. The M and MT groups showed no significance difference in effectiveness at 120 days, suggesting that microneedling may promote less frequent relapse and sustained remission compared to TXA alone.²⁵

Hydroquinone for Melasma—Additional studies on the use of TXA treatments show that TXA may be an equally effective alternative to the standard use of hydroquinone treatment. Shamsi Meymandi et al²⁶ did not find a statistically significant difference in treatment with TXA plus microneedling vs the standard regimen of hydroquinone. More importantly, patient and physician satisfaction assessments were similar between the 2 groups. Compared to hydroquinone, nightly treatment is not necessary with microneedling and TXA.²⁶

Xing et al²⁷ supported these conclusions with their study. They compared 3 study arms for a duration of 12 weeks: group A received topical 1.8% liposomal TXA BID, group B received stamp-mode electric microneedling with 5% TXA weekly, and group C applied 2% ­hydroquinone cream nightly. The study concluded that all 3 groups showed a significant reduction in mean MI by the end of the study, but a better MI improvement was observed in groups B and C (both P<.001) compared with group A (P<.01).²⁷

Zaky et al²⁸ showed that both hydroquinone and combination treatment of TXA plus microneedling are effective at improving melasma lesions. Further studies are needed to definitively conclude if combination treatment is more efficacious than hydroquinone; if the combination is more effective, it provides a treatment option for patients with melasma who may not be good candidates for hydroquinone treatment.

Study Limitations—One limitation in all the studies evaluated is the sample size. Because they all had small sample sizes, it is difficult to definitively conclude that the combination TXA and microneedling is an effective and appropriate treatment for patients with melasma. Furthermore, the quality of these studies was mostly dependent on subjectivity of the mMASI scores. Future large randomized controlled trials with a diverse participant population are needed to assess the effectiveness of TXA and microneedling in melasma treatment.

Another limitation is that many of the studies did not follow the patients longitudinally, which did not allow for an evaluation of whether patients had a relapse of melasma. Due to the chronic nature of melasma and frequent disease recurrence, future longitudinal studies are needed to monitor for disease recurrence.

Conclusion

Tranexamic acid and microneedling are potential treatment options for patients with melasma, and combination therapy appears more effective than either TXA or microneedling alone at providing sustained improvement of melasma lesions. Combination therapy appears safe and well tolerated, but its effect on reducing long-term disease recurrence is yet to be established.

The Diagnosis: Brunsting-Perry Cicatricial Pemphigoid

Physical examination and histopathology are paramount in diagnosing Brunsting-Perry cicatricial pemphigoid (BPCP). In our patient, histopathology showed subepidermal blistering with a mixed superficial dermal inflammatory cell infiltrate. Direct immunofluorescence was positive for linear IgG and C3 antibodies along the basement membrane. The scarring erosions on the scalp combined with the autoantibody findings on direct immunofluorescence were consistent with BPCP. He was started on dapsone 100 mg daily and demonstrated complete resolution of symptoms after 10 months, with the exception of persistent scarring hair loss (Figure).

Brunsting-Perry cicatricial pemphigoid is a rare dermatologic condition. It was first defined in 1957 when Brunsting and Perry¹ examined 7 patients with cicatricial pemphigoid that predominantly affected the head and neck region, with occasional mucous membrane involvement but no mucosal scarring. Characteristically, BPCP manifests as scarring herpetiform plaques with varied blisters, erosions, crusts, and scarring.¹ It primarily affects middle-aged men.²

Historically, BPCP has been considered a variant of cicatricial pemphigoid (now known as mucous membrane pemphigoid), bullous pemphigoid, or epidermolysis bullosa acquisita.³ The antigen target has not been established clearly; however, autoantibodies against laminin 332, collagen VII, and BP180 and BP230 have been proposed.^2,4,5 Jacoby et al6 described BPCP on a spectrum with bullous pemphigoid and cicatricial pemphigoid, with primarily circulating autoantibodies on one end and tissue-fixed autoantibodies on the other.

The differential for BPCP also includes anti-p200 pemphigoid and anti–laminin 332 pemphigoid. Anti-p200 pemphigoid also is known as bullous pemphigoid with antibodies against the 200-kDa protein.⁷ It may clinically manifest similar to bullous pemphigoid and other subepidermal autoimmune blistering diseases; thus, immunopathologic differentiation can be helpful. Anti–laminin 332 pemphigoid (also known as anti–laminin gamma-1 pemphigoid) is characterized by autoantibodies targeting the laminin 332 protein in the basement membrane zone, resulting in blistering and erosions.⁸ Similar to BPCP and epidermolysis bullosa aquisita, anti–laminin 332 pemphigoid may affect cephalic regions and mucous membrane surfaces, resulting in scarring and cicatricial changes. Anti–laminin 332 pemphigoid also has been associated with internal malignancy.⁸ The use of the salt-split skin technique can be utilized to differentiate these entities based on their autoantibody-binding patterns in relation to the lamina densa.

Treatment options for mild BPCP include potent topical or intralesional steroids and dapsone, while more severe cases may require systemic therapy with rituximab, azathioprine, mycophenolate mofetil, or cyclophosphamide.⁴

This case highlights the importance of histopathologic examination of skin lesions with an unusual history or clinical presentation. Dermatologists should consider BPCP when presented with erosions, ulcerations, or blisters of the head and neck in middle-aged male patients.

The Diagnosis: Brunsting-Perry Cicatricial Pemphigoid

Physical examination and histopathology are paramount in diagnosing Brunsting-Perry cicatricial pemphigoid (BPCP). In our patient, histopathology showed subepidermal blistering with a mixed superficial dermal inflammatory cell infiltrate. Direct immunofluorescence was positive for linear IgG and C3 antibodies along the basement membrane. The scarring erosions on the scalp combined with the autoantibody findings on direct immunofluorescence were consistent with BPCP. He was started on dapsone 100 mg daily and demonstrated complete resolution of symptoms after 10 months, with the exception of persistent scarring hair loss (Figure).

Brunsting-Perry cicatricial pemphigoid is a rare dermatologic condition. It was first defined in 1957 when Brunsting and Perry¹ examined 7 patients with cicatricial pemphigoid that predominantly affected the head and neck region, with occasional mucous membrane involvement but no mucosal scarring. Characteristically, BPCP manifests as scarring herpetiform plaques with varied blisters, erosions, crusts, and scarring.¹ It primarily affects middle-aged men.²

Historically, BPCP has been considered a variant of cicatricial pemphigoid (now known as mucous membrane pemphigoid), bullous pemphigoid, or epidermolysis bullosa acquisita.³ The antigen target has not been established clearly; however, autoantibodies against laminin 332, collagen VII, and BP180 and BP230 have been proposed.^2,4,5 Jacoby et al6 described BPCP on a spectrum with bullous pemphigoid and cicatricial pemphigoid, with primarily circulating autoantibodies on one end and tissue-fixed autoantibodies on the other.

The differential for BPCP also includes anti-p200 pemphigoid and anti–laminin 332 pemphigoid. Anti-p200 pemphigoid also is known as bullous pemphigoid with antibodies against the 200-kDa protein.⁷ It may clinically manifest similar to bullous pemphigoid and other subepidermal autoimmune blistering diseases; thus, immunopathologic differentiation can be helpful. Anti–laminin 332 pemphigoid (also known as anti–laminin gamma-1 pemphigoid) is characterized by autoantibodies targeting the laminin 332 protein in the basement membrane zone, resulting in blistering and erosions.⁸ Similar to BPCP and epidermolysis bullosa aquisita, anti–laminin 332 pemphigoid may affect cephalic regions and mucous membrane surfaces, resulting in scarring and cicatricial changes. Anti–laminin 332 pemphigoid also has been associated with internal malignancy.⁸ The use of the salt-split skin technique can be utilized to differentiate these entities based on their autoantibody-binding patterns in relation to the lamina densa.

Treatment options for mild BPCP include potent topical or intralesional steroids and dapsone, while more severe cases may require systemic therapy with rituximab, azathioprine, mycophenolate mofetil, or cyclophosphamide.⁴

This case highlights the importance of histopathologic examination of skin lesions with an unusual history or clinical presentation. Dermatologists should consider BPCP when presented with erosions, ulcerations, or blisters of the head and neck in middle-aged male patients.

The Diagnosis: Brunsting-Perry Cicatricial Pemphigoid

Physical examination and histopathology are paramount in diagnosing Brunsting-Perry cicatricial pemphigoid (BPCP). In our patient, histopathology showed subepidermal blistering with a mixed superficial dermal inflammatory cell infiltrate. Direct immunofluorescence was positive for linear IgG and C3 antibodies along the basement membrane. The scarring erosions on the scalp combined with the autoantibody findings on direct immunofluorescence were consistent with BPCP. He was started on dapsone 100 mg daily and demonstrated complete resolution of symptoms after 10 months, with the exception of persistent scarring hair loss (Figure).

Brunsting-Perry cicatricial pemphigoid is a rare dermatologic condition. It was first defined in 1957 when Brunsting and Perry¹ examined 7 patients with cicatricial pemphigoid that predominantly affected the head and neck region, with occasional mucous membrane involvement but no mucosal scarring. Characteristically, BPCP manifests as scarring herpetiform plaques with varied blisters, erosions, crusts, and scarring.¹ It primarily affects middle-aged men.²

Historically, BPCP has been considered a variant of cicatricial pemphigoid (now known as mucous membrane pemphigoid), bullous pemphigoid, or epidermolysis bullosa acquisita.³ The antigen target has not been established clearly; however, autoantibodies against laminin 332, collagen VII, and BP180 and BP230 have been proposed.^2,4,5 Jacoby et al6 described BPCP on a spectrum with bullous pemphigoid and cicatricial pemphigoid, with primarily circulating autoantibodies on one end and tissue-fixed autoantibodies on the other.

The differential for BPCP also includes anti-p200 pemphigoid and anti–laminin 332 pemphigoid. Anti-p200 pemphigoid also is known as bullous pemphigoid with antibodies against the 200-kDa protein.⁷ It may clinically manifest similar to bullous pemphigoid and other subepidermal autoimmune blistering diseases; thus, immunopathologic differentiation can be helpful. Anti–laminin 332 pemphigoid (also known as anti–laminin gamma-1 pemphigoid) is characterized by autoantibodies targeting the laminin 332 protein in the basement membrane zone, resulting in blistering and erosions.⁸ Similar to BPCP and epidermolysis bullosa aquisita, anti–laminin 332 pemphigoid may affect cephalic regions and mucous membrane surfaces, resulting in scarring and cicatricial changes. Anti–laminin 332 pemphigoid also has been associated with internal malignancy.⁸ The use of the salt-split skin technique can be utilized to differentiate these entities based on their autoantibody-binding patterns in relation to the lamina densa.

Treatment options for mild BPCP include potent topical or intralesional steroids and dapsone, while more severe cases may require systemic therapy with rituximab, azathioprine, mycophenolate mofetil, or cyclophosphamide.⁴

This case highlights the importance of histopathologic examination of skin lesions with an unusual history or clinical presentation. Dermatologists should consider BPCP when presented with erosions, ulcerations, or blisters of the head and neck in middle-aged male patients.

Pruritus, which is defined as an itching sensation that elicits a desire to scratch, is the most common cutaneous condition. Pruritus is considered chronic when it lasts for more than 6 weeks.¹ Etiologies implicated in chronic pruritus include but are not limited to primary skin diseases such as atopic dermatitis, systemic causes, neuropathic disorders, and psychogenic reasons.² In approximately 8% to 35% of patients, the cause of pruritus remains elusive despite intensive investigation.³ The mechanisms of itch are multifaceted and include complex neural pathways.⁴ Although itch and pain share many similarities, they have distinct pathways based on their spinal connections.⁵ Nevertheless, both conditions show a wide overlap of receptors on peripheral nerve endings and activated brain parts.^6,7 Fibromyalgia, the third most common musculoskeletal condition, affects 2% to 3% of the population worldwide and is at least 7 times more common in females.^8,9 Its pathogenesis is not entirely clear but is thought to involve neurogenic inflammation, aberrations in peripheral nerves, and central pain mechanisms. Fibromyalgia is characterized by a plethora of symptoms including chronic widespread pain, autonomic disturbances, persistent fatigue and sleep disturbances, and hyperalgesia, as well as somatic and psychiatric symptoms.¹⁰

Fibromyalgia is accompanied by altered skin features including increased counts of mast cells and excessive degranulation,¹¹ neurogenic inflammation with elevated cytokine expression,¹² disrupted collagen metabolism,¹³ and microcirculation abnormalities.¹⁴ There has been limited research exploring the dermatologic manifestations of fibromyalgia. One retrospective study that included 845 patients with fibromyalgia reported increased occurrence of “neurodermatoses,” including pruritus, neurotic excoriations, prurigo nodules, and lichen simplex chronicus (LSC), among other cutaneous comorbidities.¹⁵ Another small study demonstrated an increased incidence of xerosis and neurotic excoriations in females with fibromyalgia.¹⁶ A paucity of large epidemiologic studies demonstrating the fibromyalgia-pruritus connection may lead to misdiagnosis, misinterpretation, and undertreatment of these patients.

Up to 49% of fibromyalgia patients experience small-fiber neuropathy.¹⁷ Electrophysiologic measurements, quantitative sensory testing, pain-related evoked potentials, and skin biopsies showed that patients with fibromyalgia have compromised small-fiber function, impaired pathways carrying fiber pain signals, and reduced skin innervation and regenerating fibers.^18,19 Accordingly, pruritus that has been reported in fibromyalgia is believed to be of neuropathic origin.¹⁵ Overall, it is suspected that the same mechanism that causes hypersensitivity and pain in fibromyalgia patients also predisposes them to pruritus. Similar systemic treatments (eg, analgesics, antidepressants, anticonvulsants) prescribed for both conditions support this theory.^20-25

Our large cross-sectional study sought to establish the association between fibromyalgia and pruritus as well as related pruritic conditions.

Methods

Study Design and Setting—We conducted a cross-­sectional retrospective study using data-mining techniques to access information from the Clalit Health Services (CHS) database. Clalit Health Services is the largest health maintenance organization in Israel. It encompasses an extensive database with continuous real-time input from medical, administrative, and pharmaceutical computerized operating systems, which helps facilitate data collection for epidemiologic studies. A chronic disease register is gathered from these data sources and continuously updated and validated through logistic checks. The current study was approved by the institutional review board of the CHS (approval #0212-17-com2). Informed consent was not required because the data were de-identified and this was a noninterventional observational study.

Study Population and Covariates—Medical records of CHS enrollees were screened for the diagnosis of fibromyalgia, and data on prevalent cases of fibromyalgia were retrieved. The diagnosis of fibromyalgia was based on the documentation of a fibromyalgia-specific diagnostic code registered by a board-certified rheumatologist. A control group of individuals without fibromyalgia was selected through 1:2 matching based on age, sex, and primary care clinic. The control group was randomly selected from the list of CHS members frequency-matched to cases, excluding case patients with fibromyalgia. Age matching was grounded on the exact year of birth (1-year strata).

Other covariates in the analysis included pruritus-related skin disorders, including prurigo nodularis, neurotic excoriations, and LSC. There were 3 socioeconomic status categories according to patients' poverty index: low, intermediate, and high.²⁶

Statistical Analysis—The distribution of sociodemographic and clinical features was compared between patients with fibromyalgia and controls using the χ² test for sex and socioeconomic status and the t test for age. Conditional logistic regression then was used to calculate adjusted odds ratio (OR) and 95% CI to compare patients with fibromyalgia and controls with respect to the presence of pruritic comorbidities. All statistical analyses were performed using SPSS software (version 26). P<.05 was considered statistically significant in all tests.

Results

Our study population comprised 4971 patients with fibromyalgia and 9896 age- and sex-matched controls. Proportional to the reported female predominance among patients with fibromyalgia,²⁷ 4479 (90.1%) patients with fibromyalgia were females and a similar proportion was documented among controls (P=.99). There was a slightly higher proportion of unmarried patients among those with fibromyalgia compared with controls (41.9% vs 39.4%; P=.004). Socioeconomic status was matched between patients and controls (P=.99). Descriptive characteristics of the study population are presented in Table 1.

We assessed the presence of pruritus as well as 3 other pruritus-related skin disorders—prurigo nodularis, neurotic excoriations, and LSC—among patients with fibromyalgia and controls. Logistic regression was used to evaluate the independent association between fibromyalgia and pruritus. Table 2 presents the results of multivariate logistic regression models and summarizes the adjusted ORs for pruritic conditions in patients with fibromyalgia and different demographic features across the entire study sample. Fibromyalgia demonstrated strong independent associations with pruritus (OR, 1.8; 95% CI, 1.8-2.4; P<.001), prurigo nodularis (OR, 2.9; 95% CI, 1.1-8.4; P=.038), and LSC (OR, 1.5; 95% CI, 1.1-2.1; P=.01); the association with neurotic excoriations was not significant. Female sex significantly increased the risk for pruritus (OR 1.3; 95% CI, 1.0-1.6; P=.039), while age slightly increased the odds for pruritus (OR, 1.0; 95% CI, 1.0-1.04; P<.001), neurotic excoriations (OR, 1.0; 95% CI, 1.0-1.1; P=.046), and LSC (OR, 1.0; 95% CI, 1.01-1.04; P=.006). Finally, socioeconomic status was inversely correlated with pruritus (OR, 1.1; 95% CI, 1.1-1.5; P=.002).

Comment

A wide range of skin manifestations have been associated with fibromyalgia, but the exact mechanisms remain unclear. Nevertheless, it is conceivable that autonomic nervous system dysfunction,^28-31 amplified cutaneous opioid receptor activity,³² and an elevated presence of cutaneous mast cells with excessive degranulation may partially explain the frequent occurrence of pruritus and related skin disorders such as neurotic excoriations, prurigo nodularis, and LSC in individuals with fibromyalgia.^15,16 In line with these findings, our study—which was based on data from the largest health maintenance organization in Israel—demonstrated an increased prevalence of pruritus and related pruritic disorders among individuals diagnosed with fibromyalgia.

This cross-sectional study links pruritus with fibromyalgia. Few preliminary epidemiologic studies have shown an increased occurrence of cutaneous manifestations in patients with fibromyalgia. One chart review that looked at skin findings in patients with fibromyalgia revealed 32 distinct cutaneous manifestations, and pruritus was the major concern in 3.3% of 845 patients.¹⁵

A focused cross-sectional study involving only women (66 with fibromyalgia and 79 healthy controls) discovered 14 skin conditions that were more common in those with fibromyalgia. Notably, xerosis and neurotic excoriations were more prevalent compared to the control group.¹⁶

The brain and the skin—both derivatives of the embryonic ectoderm^33,34—are linked by pruritus. Although itch has its dedicated neurons, there is a wide-ranging overlap of brain-activated areas between pain and itch,⁶ and the neural anatomy of pain and itch are closely related in both the peripheral and central nervous systems^35-37; for example, diseases of the central nervous system are accompanied by pruritus in as many as 15% of cases, while postherpetic neuralgia can result in chronic pain, itching, or a combination of both.^38,39 Other instances include notalgia paresthetica and brachioradial pruritus.³⁸ Additionally, there is a noteworthy psychologic impact associated with both itch and pain,^40,41 with both psychosomatic and psychologic factors implicated in chronic pruritus and in fibromyalgia.⁴² Lastly, the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system are altered in both fibromyalgia and pruritus.^43-45

Tey et al⁴⁵ characterized the itch experienced in fibromyalgia as functional, which is described as pruritus associated with a somatoform disorder. In our study, we found a higher prevalence of pruritus among patients with fibromyalgia, and this association remained significant (P<.05) even when excluding other pruritic skin conditions and systemic diseases that can trigger itching. In addition, our logistic regression analyses revealed independent associations between fibromyalgia and pruritus, prurigo nodularis, and LSC.

According to Twycross et al,⁴⁶ there are 4 clinical categories of itch, which may coexist⁷: pruritoceptive (originating in the skin), neuropathic (originating in pathology located along the afferent pathway), neurogenic (central origin but lacks a neural pathology), and psychogenic.⁴⁷ Skin biopsy findings in patients with fibromyalgia include increased mast cell counts¹¹ and degranulation,⁴⁸ increased expression of δ and κ opioid receptors,³² vasoconstriction within tender points,⁴⁹ and elevated IL-1β, IL-6, or tumor necrosis factor α by reverse transcriptase-polymerase chain reaction.¹² A case recently was presented by Görg et al⁵⁰ involving a female patient with fibromyalgia who had been experiencing chronic pruritus, which the authors attributed to small-fiber neuropathy based on evidence from a skin biopsy indicating a reduced number of intraepidermal nerves and the fact that the itching originated around tender points. Altogether, the observed alterations may work together to make patients with fibromyalgia more susceptible to various skin-related comorbidities in general, especially those related to pruritus. Eventually, it might be the case that several itch categories and related pathomechanisms are involved in the pruritus phenotype of patients with fibromyalgia.

Age-related alterations in nerve fibers, lower immune function, xerosis, polypharmacy, and increased frequency of systemic diseases with age are just a few of the factors that may predispose older individuals to pruritus.^51,52 Indeed, our logistic regression model showed that age was significantly and independently associated with ­pruritus (P<.001), neurotic excoriations (P=.046), and LSC (P=.006). Female sex also was significantly linked with pruritus (P=.039). Intriguingly, high socioeconomic status was significantly associated with the diagnosis of ­pruritus (P=.002), possibly due to easier access to medical care.

There is a considerable overlap between the therapeutic approaches used in pruritus, pruritus-related skin disorders, and fibromyalgia. Antidepressants, anxiolytics, analgesics, and antiepileptics have been used to address both conditions.⁴⁵ The association between these conditions advocates for a multidisciplinary approach in patients with fibromyalgia and potentially supports the rationale for unified therapeutics for both conditions.

Conclusion

Our findings indicate an association between fibromyalgia and pruritus as well as associated pruritic skin disorders. Given the convoluted and largely undiscovered mechanisms underlying fibromyalgia, managing patients with this condition may present substantial challenges.⁵³ The data presented here support the implementation of a multidisciplinary treatment approach for patients with fibromyalgia. This approach should focus on managing fibromyalgia pain as well as addressing its concurrent skin-related conditions. It is advisable to consider treatments such as antiepileptics (eg, pregabalin, gabapentin) that specifically target neuropathic disorders in affected patients. These treatments may hold promise for alleviating fibromyalgia-related pain⁵⁴ and mitigating its related cutaneous comorbidities, especially pruritus.

Pruritus, which is defined as an itching sensation that elicits a desire to scratch, is the most common cutaneous condition. Pruritus is considered chronic when it lasts for more than 6 weeks.¹ Etiologies implicated in chronic pruritus include but are not limited to primary skin diseases such as atopic dermatitis, systemic causes, neuropathic disorders, and psychogenic reasons.² In approximately 8% to 35% of patients, the cause of pruritus remains elusive despite intensive investigation.³ The mechanisms of itch are multifaceted and include complex neural pathways.⁴ Although itch and pain share many similarities, they have distinct pathways based on their spinal connections.⁵ Nevertheless, both conditions show a wide overlap of receptors on peripheral nerve endings and activated brain parts.^6,7 Fibromyalgia, the third most common musculoskeletal condition, affects 2% to 3% of the population worldwide and is at least 7 times more common in females.^8,9 Its pathogenesis is not entirely clear but is thought to involve neurogenic inflammation, aberrations in peripheral nerves, and central pain mechanisms. Fibromyalgia is characterized by a plethora of symptoms including chronic widespread pain, autonomic disturbances, persistent fatigue and sleep disturbances, and hyperalgesia, as well as somatic and psychiatric symptoms.¹⁰

Fibromyalgia is accompanied by altered skin features including increased counts of mast cells and excessive degranulation,¹¹ neurogenic inflammation with elevated cytokine expression,¹² disrupted collagen metabolism,¹³ and microcirculation abnormalities.¹⁴ There has been limited research exploring the dermatologic manifestations of fibromyalgia. One retrospective study that included 845 patients with fibromyalgia reported increased occurrence of “neurodermatoses,” including pruritus, neurotic excoriations, prurigo nodules, and lichen simplex chronicus (LSC), among other cutaneous comorbidities.¹⁵ Another small study demonstrated an increased incidence of xerosis and neurotic excoriations in females with fibromyalgia.¹⁶ A paucity of large epidemiologic studies demonstrating the fibromyalgia-pruritus connection may lead to misdiagnosis, misinterpretation, and undertreatment of these patients.

Up to 49% of fibromyalgia patients experience small-fiber neuropathy.¹⁷ Electrophysiologic measurements, quantitative sensory testing, pain-related evoked potentials, and skin biopsies showed that patients with fibromyalgia have compromised small-fiber function, impaired pathways carrying fiber pain signals, and reduced skin innervation and regenerating fibers.^18,19 Accordingly, pruritus that has been reported in fibromyalgia is believed to be of neuropathic origin.¹⁵ Overall, it is suspected that the same mechanism that causes hypersensitivity and pain in fibromyalgia patients also predisposes them to pruritus. Similar systemic treatments (eg, analgesics, antidepressants, anticonvulsants) prescribed for both conditions support this theory.^20-25

Our large cross-sectional study sought to establish the association between fibromyalgia and pruritus as well as related pruritic conditions.

Methods

Study Design and Setting—We conducted a cross-­sectional retrospective study using data-mining techniques to access information from the Clalit Health Services (CHS) database. Clalit Health Services is the largest health maintenance organization in Israel. It encompasses an extensive database with continuous real-time input from medical, administrative, and pharmaceutical computerized operating systems, which helps facilitate data collection for epidemiologic studies. A chronic disease register is gathered from these data sources and continuously updated and validated through logistic checks. The current study was approved by the institutional review board of the CHS (approval #0212-17-com2). Informed consent was not required because the data were de-identified and this was a noninterventional observational study.

Study Population and Covariates—Medical records of CHS enrollees were screened for the diagnosis of fibromyalgia, and data on prevalent cases of fibromyalgia were retrieved. The diagnosis of fibromyalgia was based on the documentation of a fibromyalgia-specific diagnostic code registered by a board-certified rheumatologist. A control group of individuals without fibromyalgia was selected through 1:2 matching based on age, sex, and primary care clinic. The control group was randomly selected from the list of CHS members frequency-matched to cases, excluding case patients with fibromyalgia. Age matching was grounded on the exact year of birth (1-year strata).

Other covariates in the analysis included pruritus-related skin disorders, including prurigo nodularis, neurotic excoriations, and LSC. There were 3 socioeconomic status categories according to patients' poverty index: low, intermediate, and high.²⁶

Statistical Analysis—The distribution of sociodemographic and clinical features was compared between patients with fibromyalgia and controls using the χ² test for sex and socioeconomic status and the t test for age. Conditional logistic regression then was used to calculate adjusted odds ratio (OR) and 95% CI to compare patients with fibromyalgia and controls with respect to the presence of pruritic comorbidities. All statistical analyses were performed using SPSS software (version 26). P<.05 was considered statistically significant in all tests.

Results

Our study population comprised 4971 patients with fibromyalgia and 9896 age- and sex-matched controls. Proportional to the reported female predominance among patients with fibromyalgia,²⁷ 4479 (90.1%) patients with fibromyalgia were females and a similar proportion was documented among controls (P=.99). There was a slightly higher proportion of unmarried patients among those with fibromyalgia compared with controls (41.9% vs 39.4%; P=.004). Socioeconomic status was matched between patients and controls (P=.99). Descriptive characteristics of the study population are presented in Table 1.

We assessed the presence of pruritus as well as 3 other pruritus-related skin disorders—prurigo nodularis, neurotic excoriations, and LSC—among patients with fibromyalgia and controls. Logistic regression was used to evaluate the independent association between fibromyalgia and pruritus. Table 2 presents the results of multivariate logistic regression models and summarizes the adjusted ORs for pruritic conditions in patients with fibromyalgia and different demographic features across the entire study sample. Fibromyalgia demonstrated strong independent associations with pruritus (OR, 1.8; 95% CI, 1.8-2.4; P<.001), prurigo nodularis (OR, 2.9; 95% CI, 1.1-8.4; P=.038), and LSC (OR, 1.5; 95% CI, 1.1-2.1; P=.01); the association with neurotic excoriations was not significant. Female sex significantly increased the risk for pruritus (OR 1.3; 95% CI, 1.0-1.6; P=.039), while age slightly increased the odds for pruritus (OR, 1.0; 95% CI, 1.0-1.04; P<.001), neurotic excoriations (OR, 1.0; 95% CI, 1.0-1.1; P=.046), and LSC (OR, 1.0; 95% CI, 1.01-1.04; P=.006). Finally, socioeconomic status was inversely correlated with pruritus (OR, 1.1; 95% CI, 1.1-1.5; P=.002).

Comment

A wide range of skin manifestations have been associated with fibromyalgia, but the exact mechanisms remain unclear. Nevertheless, it is conceivable that autonomic nervous system dysfunction,^28-31 amplified cutaneous opioid receptor activity,³² and an elevated presence of cutaneous mast cells with excessive degranulation may partially explain the frequent occurrence of pruritus and related skin disorders such as neurotic excoriations, prurigo nodularis, and LSC in individuals with fibromyalgia.^15,16 In line with these findings, our study—which was based on data from the largest health maintenance organization in Israel—demonstrated an increased prevalence of pruritus and related pruritic disorders among individuals diagnosed with fibromyalgia.

This cross-sectional study links pruritus with fibromyalgia. Few preliminary epidemiologic studies have shown an increased occurrence of cutaneous manifestations in patients with fibromyalgia. One chart review that looked at skin findings in patients with fibromyalgia revealed 32 distinct cutaneous manifestations, and pruritus was the major concern in 3.3% of 845 patients.¹⁵

A focused cross-sectional study involving only women (66 with fibromyalgia and 79 healthy controls) discovered 14 skin conditions that were more common in those with fibromyalgia. Notably, xerosis and neurotic excoriations were more prevalent compared to the control group.¹⁶

The brain and the skin—both derivatives of the embryonic ectoderm^33,34—are linked by pruritus. Although itch has its dedicated neurons, there is a wide-ranging overlap of brain-activated areas between pain and itch,⁶ and the neural anatomy of pain and itch are closely related in both the peripheral and central nervous systems^35-37; for example, diseases of the central nervous system are accompanied by pruritus in as many as 15% of cases, while postherpetic neuralgia can result in chronic pain, itching, or a combination of both.^38,39 Other instances include notalgia paresthetica and brachioradial pruritus.³⁸ Additionally, there is a noteworthy psychologic impact associated with both itch and pain,^40,41 with both psychosomatic and psychologic factors implicated in chronic pruritus and in fibromyalgia.⁴² Lastly, the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system are altered in both fibromyalgia and pruritus.^43-45

Tey et al⁴⁵ characterized the itch experienced in fibromyalgia as functional, which is described as pruritus associated with a somatoform disorder. In our study, we found a higher prevalence of pruritus among patients with fibromyalgia, and this association remained significant (P<.05) even when excluding other pruritic skin conditions and systemic diseases that can trigger itching. In addition, our logistic regression analyses revealed independent associations between fibromyalgia and pruritus, prurigo nodularis, and LSC.

According to Twycross et al,⁴⁶ there are 4 clinical categories of itch, which may coexist⁷: pruritoceptive (originating in the skin), neuropathic (originating in pathology located along the afferent pathway), neurogenic (central origin but lacks a neural pathology), and psychogenic.⁴⁷ Skin biopsy findings in patients with fibromyalgia include increased mast cell counts¹¹ and degranulation,⁴⁸ increased expression of δ and κ opioid receptors,³² vasoconstriction within tender points,⁴⁹ and elevated IL-1β, IL-6, or tumor necrosis factor α by reverse transcriptase-polymerase chain reaction.¹² A case recently was presented by Görg et al⁵⁰ involving a female patient with fibromyalgia who had been experiencing chronic pruritus, which the authors attributed to small-fiber neuropathy based on evidence from a skin biopsy indicating a reduced number of intraepidermal nerves and the fact that the itching originated around tender points. Altogether, the observed alterations may work together to make patients with fibromyalgia more susceptible to various skin-related comorbidities in general, especially those related to pruritus. Eventually, it might be the case that several itch categories and related pathomechanisms are involved in the pruritus phenotype of patients with fibromyalgia.

Age-related alterations in nerve fibers, lower immune function, xerosis, polypharmacy, and increased frequency of systemic diseases with age are just a few of the factors that may predispose older individuals to pruritus.^51,52 Indeed, our logistic regression model showed that age was significantly and independently associated with ­pruritus (P<.001), neurotic excoriations (P=.046), and LSC (P=.006). Female sex also was significantly linked with pruritus (P=.039). Intriguingly, high socioeconomic status was significantly associated with the diagnosis of ­pruritus (P=.002), possibly due to easier access to medical care.

There is a considerable overlap between the therapeutic approaches used in pruritus, pruritus-related skin disorders, and fibromyalgia. Antidepressants, anxiolytics, analgesics, and antiepileptics have been used to address both conditions.⁴⁵ The association between these conditions advocates for a multidisciplinary approach in patients with fibromyalgia and potentially supports the rationale for unified therapeutics for both conditions.

Conclusion

Our findings indicate an association between fibromyalgia and pruritus as well as associated pruritic skin disorders. Given the convoluted and largely undiscovered mechanisms underlying fibromyalgia, managing patients with this condition may present substantial challenges.⁵³ The data presented here support the implementation of a multidisciplinary treatment approach for patients with fibromyalgia. This approach should focus on managing fibromyalgia pain as well as addressing its concurrent skin-related conditions. It is advisable to consider treatments such as antiepileptics (eg, pregabalin, gabapentin) that specifically target neuropathic disorders in affected patients. These treatments may hold promise for alleviating fibromyalgia-related pain⁵⁴ and mitigating its related cutaneous comorbidities, especially pruritus.

Pruritus, which is defined as an itching sensation that elicits a desire to scratch, is the most common cutaneous condition. Pruritus is considered chronic when it lasts for more than 6 weeks.¹ Etiologies implicated in chronic pruritus include but are not limited to primary skin diseases such as atopic dermatitis, systemic causes, neuropathic disorders, and psychogenic reasons.² In approximately 8% to 35% of patients, the cause of pruritus remains elusive despite intensive investigation.³ The mechanisms of itch are multifaceted and include complex neural pathways.⁴ Although itch and pain share many similarities, they have distinct pathways based on their spinal connections.⁵ Nevertheless, both conditions show a wide overlap of receptors on peripheral nerve endings and activated brain parts.^6,7 Fibromyalgia, the third most common musculoskeletal condition, affects 2% to 3% of the population worldwide and is at least 7 times more common in females.^8,9 Its pathogenesis is not entirely clear but is thought to involve neurogenic inflammation, aberrations in peripheral nerves, and central pain mechanisms. Fibromyalgia is characterized by a plethora of symptoms including chronic widespread pain, autonomic disturbances, persistent fatigue and sleep disturbances, and hyperalgesia, as well as somatic and psychiatric symptoms.¹⁰

Fibromyalgia is accompanied by altered skin features including increased counts of mast cells and excessive degranulation,¹¹ neurogenic inflammation with elevated cytokine expression,¹² disrupted collagen metabolism,¹³ and microcirculation abnormalities.¹⁴ There has been limited research exploring the dermatologic manifestations of fibromyalgia. One retrospective study that included 845 patients with fibromyalgia reported increased occurrence of “neurodermatoses,” including pruritus, neurotic excoriations, prurigo nodules, and lichen simplex chronicus (LSC), among other cutaneous comorbidities.¹⁵ Another small study demonstrated an increased incidence of xerosis and neurotic excoriations in females with fibromyalgia.¹⁶ A paucity of large epidemiologic studies demonstrating the fibromyalgia-pruritus connection may lead to misdiagnosis, misinterpretation, and undertreatment of these patients.

Up to 49% of fibromyalgia patients experience small-fiber neuropathy.¹⁷ Electrophysiologic measurements, quantitative sensory testing, pain-related evoked potentials, and skin biopsies showed that patients with fibromyalgia have compromised small-fiber function, impaired pathways carrying fiber pain signals, and reduced skin innervation and regenerating fibers.^18,19 Accordingly, pruritus that has been reported in fibromyalgia is believed to be of neuropathic origin.¹⁵ Overall, it is suspected that the same mechanism that causes hypersensitivity and pain in fibromyalgia patients also predisposes them to pruritus. Similar systemic treatments (eg, analgesics, antidepressants, anticonvulsants) prescribed for both conditions support this theory.^20-25

Our large cross-sectional study sought to establish the association between fibromyalgia and pruritus as well as related pruritic conditions.

Methods

Study Design and Setting—We conducted a cross-­sectional retrospective study using data-mining techniques to access information from the Clalit Health Services (CHS) database. Clalit Health Services is the largest health maintenance organization in Israel. It encompasses an extensive database with continuous real-time input from medical, administrative, and pharmaceutical computerized operating systems, which helps facilitate data collection for epidemiologic studies. A chronic disease register is gathered from these data sources and continuously updated and validated through logistic checks. The current study was approved by the institutional review board of the CHS (approval #0212-17-com2). Informed consent was not required because the data were de-identified and this was a noninterventional observational study.

Study Population and Covariates—Medical records of CHS enrollees were screened for the diagnosis of fibromyalgia, and data on prevalent cases of fibromyalgia were retrieved. The diagnosis of fibromyalgia was based on the documentation of a fibromyalgia-specific diagnostic code registered by a board-certified rheumatologist. A control group of individuals without fibromyalgia was selected through 1:2 matching based on age, sex, and primary care clinic. The control group was randomly selected from the list of CHS members frequency-matched to cases, excluding case patients with fibromyalgia. Age matching was grounded on the exact year of birth (1-year strata).

Other covariates in the analysis included pruritus-related skin disorders, including prurigo nodularis, neurotic excoriations, and LSC. There were 3 socioeconomic status categories according to patients' poverty index: low, intermediate, and high.²⁶

Statistical Analysis—The distribution of sociodemographic and clinical features was compared between patients with fibromyalgia and controls using the χ² test for sex and socioeconomic status and the t test for age. Conditional logistic regression then was used to calculate adjusted odds ratio (OR) and 95% CI to compare patients with fibromyalgia and controls with respect to the presence of pruritic comorbidities. All statistical analyses were performed using SPSS software (version 26). P<.05 was considered statistically significant in all tests.

Results

Our study population comprised 4971 patients with fibromyalgia and 9896 age- and sex-matched controls. Proportional to the reported female predominance among patients with fibromyalgia,²⁷ 4479 (90.1%) patients with fibromyalgia were females and a similar proportion was documented among controls (P=.99). There was a slightly higher proportion of unmarried patients among those with fibromyalgia compared with controls (41.9% vs 39.4%; P=.004). Socioeconomic status was matched between patients and controls (P=.99). Descriptive characteristics of the study population are presented in Table 1.

We assessed the presence of pruritus as well as 3 other pruritus-related skin disorders—prurigo nodularis, neurotic excoriations, and LSC—among patients with fibromyalgia and controls. Logistic regression was used to evaluate the independent association between fibromyalgia and pruritus. Table 2 presents the results of multivariate logistic regression models and summarizes the adjusted ORs for pruritic conditions in patients with fibromyalgia and different demographic features across the entire study sample. Fibromyalgia demonstrated strong independent associations with pruritus (OR, 1.8; 95% CI, 1.8-2.4; P<.001), prurigo nodularis (OR, 2.9; 95% CI, 1.1-8.4; P=.038), and LSC (OR, 1.5; 95% CI, 1.1-2.1; P=.01); the association with neurotic excoriations was not significant. Female sex significantly increased the risk for pruritus (OR 1.3; 95% CI, 1.0-1.6; P=.039), while age slightly increased the odds for pruritus (OR, 1.0; 95% CI, 1.0-1.04; P<.001), neurotic excoriations (OR, 1.0; 95% CI, 1.0-1.1; P=.046), and LSC (OR, 1.0; 95% CI, 1.01-1.04; P=.006). Finally, socioeconomic status was inversely correlated with pruritus (OR, 1.1; 95% CI, 1.1-1.5; P=.002).

Comment

A wide range of skin manifestations have been associated with fibromyalgia, but the exact mechanisms remain unclear. Nevertheless, it is conceivable that autonomic nervous system dysfunction,^28-31 amplified cutaneous opioid receptor activity,³² and an elevated presence of cutaneous mast cells with excessive degranulation may partially explain the frequent occurrence of pruritus and related skin disorders such as neurotic excoriations, prurigo nodularis, and LSC in individuals with fibromyalgia.^15,16 In line with these findings, our study—which was based on data from the largest health maintenance organization in Israel—demonstrated an increased prevalence of pruritus and related pruritic disorders among individuals diagnosed with fibromyalgia.

This cross-sectional study links pruritus with fibromyalgia. Few preliminary epidemiologic studies have shown an increased occurrence of cutaneous manifestations in patients with fibromyalgia. One chart review that looked at skin findings in patients with fibromyalgia revealed 32 distinct cutaneous manifestations, and pruritus was the major concern in 3.3% of 845 patients.¹⁵

A focused cross-sectional study involving only women (66 with fibromyalgia and 79 healthy controls) discovered 14 skin conditions that were more common in those with fibromyalgia. Notably, xerosis and neurotic excoriations were more prevalent compared to the control group.¹⁶

The brain and the skin—both derivatives of the embryonic ectoderm^33,34—are linked by pruritus. Although itch has its dedicated neurons, there is a wide-ranging overlap of brain-activated areas between pain and itch,⁶ and the neural anatomy of pain and itch are closely related in both the peripheral and central nervous systems^35-37; for example, diseases of the central nervous system are accompanied by pruritus in as many as 15% of cases, while postherpetic neuralgia can result in chronic pain, itching, or a combination of both.^38,39 Other instances include notalgia paresthetica and brachioradial pruritus.³⁸ Additionally, there is a noteworthy psychologic impact associated with both itch and pain,^40,41 with both psychosomatic and psychologic factors implicated in chronic pruritus and in fibromyalgia.⁴² Lastly, the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system are altered in both fibromyalgia and pruritus.^43-45

Tey et al⁴⁵ characterized the itch experienced in fibromyalgia as functional, which is described as pruritus associated with a somatoform disorder. In our study, we found a higher prevalence of pruritus among patients with fibromyalgia, and this association remained significant (P<.05) even when excluding other pruritic skin conditions and systemic diseases that can trigger itching. In addition, our logistic regression analyses revealed independent associations between fibromyalgia and pruritus, prurigo nodularis, and LSC.

According to Twycross et al,⁴⁶ there are 4 clinical categories of itch, which may coexist⁷: pruritoceptive (originating in the skin), neuropathic (originating in pathology located along the afferent pathway), neurogenic (central origin but lacks a neural pathology), and psychogenic.⁴⁷ Skin biopsy findings in patients with fibromyalgia include increased mast cell counts¹¹ and degranulation,⁴⁸ increased expression of δ and κ opioid receptors,³² vasoconstriction within tender points,⁴⁹ and elevated IL-1β, IL-6, or tumor necrosis factor α by reverse transcriptase-polymerase chain reaction.¹² A case recently was presented by Görg et al⁵⁰ involving a female patient with fibromyalgia who had been experiencing chronic pruritus, which the authors attributed to small-fiber neuropathy based on evidence from a skin biopsy indicating a reduced number of intraepidermal nerves and the fact that the itching originated around tender points. Altogether, the observed alterations may work together to make patients with fibromyalgia more susceptible to various skin-related comorbidities in general, especially those related to pruritus. Eventually, it might be the case that several itch categories and related pathomechanisms are involved in the pruritus phenotype of patients with fibromyalgia.

Age-related alterations in nerve fibers, lower immune function, xerosis, polypharmacy, and increased frequency of systemic diseases with age are just a few of the factors that may predispose older individuals to pruritus.^51,52 Indeed, our logistic regression model showed that age was significantly and independently associated with ­pruritus (P<.001), neurotic excoriations (P=.046), and LSC (P=.006). Female sex also was significantly linked with pruritus (P=.039). Intriguingly, high socioeconomic status was significantly associated with the diagnosis of ­pruritus (P=.002), possibly due to easier access to medical care.

There is a considerable overlap between the therapeutic approaches used in pruritus, pruritus-related skin disorders, and fibromyalgia. Antidepressants, anxiolytics, analgesics, and antiepileptics have been used to address both conditions.⁴⁵ The association between these conditions advocates for a multidisciplinary approach in patients with fibromyalgia and potentially supports the rationale for unified therapeutics for both conditions.

Conclusion

Our findings indicate an association between fibromyalgia and pruritus as well as associated pruritic skin disorders. Given the convoluted and largely undiscovered mechanisms underlying fibromyalgia, managing patients with this condition may present substantial challenges.⁵³ The data presented here support the implementation of a multidisciplinary treatment approach for patients with fibromyalgia. This approach should focus on managing fibromyalgia pain as well as addressing its concurrent skin-related conditions. It is advisable to consider treatments such as antiepileptics (eg, pregabalin, gabapentin) that specifically target neuropathic disorders in affected patients. These treatments may hold promise for alleviating fibromyalgia-related pain⁵⁴ and mitigating its related cutaneous comorbidities, especially pruritus.