Commentary

A 66-year-old woman is discharged from the hospital after an MI. Her discharge medications include atorvastatin 40 mg, lisinopril 20 mg, acetylsalicylic acid 81 mg, and clopidogrel 75 mg. At this patient’s follow-up appointment, she mentions that she has muscle pain and stiffness in both legs and her back. Her labs include thyroid-stimulating hormone of 2.0 and vitamin D of 40. She stops the atorvastatin for 2 weeks with resolution of her symptoms.

Which treatment recommendation would you make for this patient?

A. Restart atorvastatin

B. Start rosuvastatin twice a week

C. Start ezetimibe

D. Start a PCSK9 inhibitor

We often see high-risk cardiovascular disease patients who are concerned about muscle side effects brought on by statins. I think we all can agree that this patient needs aggressive medical therapy for prevention of secondary cardiovascular events. I would restart her atorvastatin.

Neilsen and Nordestgaard found that early statin discontinuation rates increased from 6% in 1995 to 18% in 2010.¹

Early statin discontinuation correlated with negative statin-related news stories, their paper states. This suggests either an increased awareness of side effects or a possible nocebo effect.
 

Statin rechallenge results

Joy and colleagues reported the results on eight patients who had developed myalgias within 3 weeks of starting a statin. These patients, who received placebo or statin, completed an N-of-1 trial with three double-blind, crossover comparisons separated by 3-week washout periods.

Patients were evaluated pain on a visual analog scale (VAS). For each N-of-1 trial there was no statistically significant difference in pain or myalgia score between those who took statin and placebo. Five of the eight patients chose to continue on statins at the end of the trial.

Herrett and colleagues performed a more extensive series of N-of-1 trials involving 200 patients who had stopped or were considering stopping statins because of muscle symptoms.³ Participants either received 2 months of atorvastatin 20 mg or placebo for 2-month blocks six times. They rated their muscle symptoms on a VAS at the end of each block. There was no difference in muscle symptom scores between the statin and placebo periods.

Wood and colleagues took it a step further, when they studied an N-of-1 trial that included statin, placebo, and no treatment.⁴ Each participant received four bottles of atorvastatin 20 mg, four bottles of placebo, and four empty bottles. Each month they used treatment from the bottles based on random sequence and reported daily symptom scores. The mean symptom intensity was 8.0 during no-tablet months, 15.4 during placebo months (P < .001, compared with no-tablet months), and 16.3 during statin months (P < .001, compared with no-tablet months; P = .39, compared with placebo).

Taylor and colleagues studied 120 patients who had prior statin-associated muscle complaints.⁵ Each patient received either simvastatin 20 mg or placebo for 4 weeks, and then were switched for an additional 4 weeks. A total of 43 patients (36%) had pain on simvastatin but not placebo, 21 (17%) had no pain with either treatment, 21 (17%) reported pain with both treatments, and 35 (29%) had pain with placebo but not simvastatin. These studies support the concept of nocebo effect in patients who have muscle symptoms on statins.

So what should be done? Brennan and Roy did a retrospective study of 118 patients referred to a lipid clinic as being statin intolerant to two or more statins.⁶ Most of the patients were able to tolerate a statin: 71% tolerated same statin rechallenge, 53% tolerated statin switch, and 57% tolerated a nonstatin therapy.

In the Prosisa study, only 27% of patients who reported statin-associated muscle symptoms had reappearance of muscle symptoms after rechallenge with a statin.7
 

Research implications

Rechallenge with the same statin seems to be a reasonable first step, followed by switching to a different statin. I also share the concept of nocebo effect with my patients, and tell them I believe they have an excellent chance of tolerating the statin.

Pearl: The majority of patients with muscle symptoms while taking a statin likely have a nocebo effect, and are likely to tolerate rechallenge with the same statin.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.

References

1. Nielsen SF and Nordestgaard BG. Eur Heart J. 2016;37:908-16.

2. Joy TR et al. Ann Intern Med. 2014;160:301-10.

3. Herrett E et al. BMJ. 2021 Feb 24;372:n135.

4. Wood FA et al. N Engl J Med 2020;383:2182-4.

5. Taylor BA et al. Atherosclerosis. 2017;256:100-4.

6. Brennen ET and Roy TR. Can J Card. 2017;33(5):666-73.

7. Bonaiti Fet al. Atherosclerosis. 2020;315:E13-4.

A 66-year-old woman is discharged from the hospital after an MI. Her discharge medications include atorvastatin 40 mg, lisinopril 20 mg, acetylsalicylic acid 81 mg, and clopidogrel 75 mg. At this patient’s follow-up appointment, she mentions that she has muscle pain and stiffness in both legs and her back. Her labs include thyroid-stimulating hormone of 2.0 and vitamin D of 40. She stops the atorvastatin for 2 weeks with resolution of her symptoms.

Which treatment recommendation would you make for this patient?

A. Restart atorvastatin

B. Start rosuvastatin twice a week

C. Start ezetimibe

D. Start a PCSK9 inhibitor

We often see high-risk cardiovascular disease patients who are concerned about muscle side effects brought on by statins. I think we all can agree that this patient needs aggressive medical therapy for prevention of secondary cardiovascular events. I would restart her atorvastatin.

Neilsen and Nordestgaard found that early statin discontinuation rates increased from 6% in 1995 to 18% in 2010.¹

Early statin discontinuation correlated with negative statin-related news stories, their paper states. This suggests either an increased awareness of side effects or a possible nocebo effect.
 

Statin rechallenge results

Joy and colleagues reported the results on eight patients who had developed myalgias within 3 weeks of starting a statin. These patients, who received placebo or statin, completed an N-of-1 trial with three double-blind, crossover comparisons separated by 3-week washout periods.

Patients were evaluated pain on a visual analog scale (VAS). For each N-of-1 trial there was no statistically significant difference in pain or myalgia score between those who took statin and placebo. Five of the eight patients chose to continue on statins at the end of the trial.

Herrett and colleagues performed a more extensive series of N-of-1 trials involving 200 patients who had stopped or were considering stopping statins because of muscle symptoms.³ Participants either received 2 months of atorvastatin 20 mg or placebo for 2-month blocks six times. They rated their muscle symptoms on a VAS at the end of each block. There was no difference in muscle symptom scores between the statin and placebo periods.

Wood and colleagues took it a step further, when they studied an N-of-1 trial that included statin, placebo, and no treatment.⁴ Each participant received four bottles of atorvastatin 20 mg, four bottles of placebo, and four empty bottles. Each month they used treatment from the bottles based on random sequence and reported daily symptom scores. The mean symptom intensity was 8.0 during no-tablet months, 15.4 during placebo months (P < .001, compared with no-tablet months), and 16.3 during statin months (P < .001, compared with no-tablet months; P = .39, compared with placebo).

Taylor and colleagues studied 120 patients who had prior statin-associated muscle complaints.⁵ Each patient received either simvastatin 20 mg or placebo for 4 weeks, and then were switched for an additional 4 weeks. A total of 43 patients (36%) had pain on simvastatin but not placebo, 21 (17%) had no pain with either treatment, 21 (17%) reported pain with both treatments, and 35 (29%) had pain with placebo but not simvastatin. These studies support the concept of nocebo effect in patients who have muscle symptoms on statins.

So what should be done? Brennan and Roy did a retrospective study of 118 patients referred to a lipid clinic as being statin intolerant to two or more statins.⁶ Most of the patients were able to tolerate a statin: 71% tolerated same statin rechallenge, 53% tolerated statin switch, and 57% tolerated a nonstatin therapy.

In the Prosisa study, only 27% of patients who reported statin-associated muscle symptoms had reappearance of muscle symptoms after rechallenge with a statin.7
 

Research implications

Rechallenge with the same statin seems to be a reasonable first step, followed by switching to a different statin. I also share the concept of nocebo effect with my patients, and tell them I believe they have an excellent chance of tolerating the statin.

Pearl: The majority of patients with muscle symptoms while taking a statin likely have a nocebo effect, and are likely to tolerate rechallenge with the same statin.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.

References

1. Nielsen SF and Nordestgaard BG. Eur Heart J. 2016;37:908-16.

2. Joy TR et al. Ann Intern Med. 2014;160:301-10.

3. Herrett E et al. BMJ. 2021 Feb 24;372:n135.

4. Wood FA et al. N Engl J Med 2020;383:2182-4.

5. Taylor BA et al. Atherosclerosis. 2017;256:100-4.

6. Brennen ET and Roy TR. Can J Card. 2017;33(5):666-73.

7. Bonaiti Fet al. Atherosclerosis. 2020;315:E13-4.

A 66-year-old woman is discharged from the hospital after an MI. Her discharge medications include atorvastatin 40 mg, lisinopril 20 mg, acetylsalicylic acid 81 mg, and clopidogrel 75 mg. At this patient’s follow-up appointment, she mentions that she has muscle pain and stiffness in both legs and her back. Her labs include thyroid-stimulating hormone of 2.0 and vitamin D of 40. She stops the atorvastatin for 2 weeks with resolution of her symptoms.

Which treatment recommendation would you make for this patient?

A. Restart atorvastatin

B. Start rosuvastatin twice a week

C. Start ezetimibe

D. Start a PCSK9 inhibitor

We often see high-risk cardiovascular disease patients who are concerned about muscle side effects brought on by statins. I think we all can agree that this patient needs aggressive medical therapy for prevention of secondary cardiovascular events. I would restart her atorvastatin.

Neilsen and Nordestgaard found that early statin discontinuation rates increased from 6% in 1995 to 18% in 2010.¹

Early statin discontinuation correlated with negative statin-related news stories, their paper states. This suggests either an increased awareness of side effects or a possible nocebo effect.
 

Statin rechallenge results

Joy and colleagues reported the results on eight patients who had developed myalgias within 3 weeks of starting a statin. These patients, who received placebo or statin, completed an N-of-1 trial with three double-blind, crossover comparisons separated by 3-week washout periods.

Patients were evaluated pain on a visual analog scale (VAS). For each N-of-1 trial there was no statistically significant difference in pain or myalgia score between those who took statin and placebo. Five of the eight patients chose to continue on statins at the end of the trial.

Herrett and colleagues performed a more extensive series of N-of-1 trials involving 200 patients who had stopped or were considering stopping statins because of muscle symptoms.³ Participants either received 2 months of atorvastatin 20 mg or placebo for 2-month blocks six times. They rated their muscle symptoms on a VAS at the end of each block. There was no difference in muscle symptom scores between the statin and placebo periods.

Wood and colleagues took it a step further, when they studied an N-of-1 trial that included statin, placebo, and no treatment.⁴ Each participant received four bottles of atorvastatin 20 mg, four bottles of placebo, and four empty bottles. Each month they used treatment from the bottles based on random sequence and reported daily symptom scores. The mean symptom intensity was 8.0 during no-tablet months, 15.4 during placebo months (P < .001, compared with no-tablet months), and 16.3 during statin months (P < .001, compared with no-tablet months; P = .39, compared with placebo).

Taylor and colleagues studied 120 patients who had prior statin-associated muscle complaints.⁵ Each patient received either simvastatin 20 mg or placebo for 4 weeks, and then were switched for an additional 4 weeks. A total of 43 patients (36%) had pain on simvastatin but not placebo, 21 (17%) had no pain with either treatment, 21 (17%) reported pain with both treatments, and 35 (29%) had pain with placebo but not simvastatin. These studies support the concept of nocebo effect in patients who have muscle symptoms on statins.

So what should be done? Brennan and Roy did a retrospective study of 118 patients referred to a lipid clinic as being statin intolerant to two or more statins.⁶ Most of the patients were able to tolerate a statin: 71% tolerated same statin rechallenge, 53% tolerated statin switch, and 57% tolerated a nonstatin therapy.

In the Prosisa study, only 27% of patients who reported statin-associated muscle symptoms had reappearance of muscle symptoms after rechallenge with a statin.7
 

Research implications

Rechallenge with the same statin seems to be a reasonable first step, followed by switching to a different statin. I also share the concept of nocebo effect with my patients, and tell them I believe they have an excellent chance of tolerating the statin.

Pearl: The majority of patients with muscle symptoms while taking a statin likely have a nocebo effect, and are likely to tolerate rechallenge with the same statin.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.

References

1. Nielsen SF and Nordestgaard BG. Eur Heart J. 2016;37:908-16.

2. Joy TR et al. Ann Intern Med. 2014;160:301-10.

3. Herrett E et al. BMJ. 2021 Feb 24;372:n135.

4. Wood FA et al. N Engl J Med 2020;383:2182-4.

5. Taylor BA et al. Atherosclerosis. 2017;256:100-4.

6. Brennen ET and Roy TR. Can J Card. 2017;33(5):666-73.

7. Bonaiti Fet al. Atherosclerosis. 2020;315:E13-4.

The US population is becoming more diverse. By 2044, it is predicted that there will be a majority minority population in the United States.¹ Therefore, it is imperative to continue to develop educational mechanisms for all dermatologists to increase and maintain competency in skin of color dermatology, which will contribute to the achievement of health equity for patients with all skin tones and hair types.

Not only is clinical skin of color education necessary, but diversity, equity, and inclusion (DEI) education for dermatologists also is critical. Clinical examination,² diagnosis, and treatment of skin and hair disorders across the skin of color spectrum with cultural humility is essential to achieve health equity. If trainees, dermatologists, other specialists, and primary care clinicians are not frequently exposed to patients with darker skin tones and coily hair, the nuances in diagnosing and treating these patients must be learned in alternate ways.

To ready the nation’s physicians and clinicians to care for the growing diverse population, exposure to more images of dermatologic diseases in those with darker skin tones in journal articles, textbooks, conference lectures, and online dermatology image libraries is necessary to help close the skin of color training and practice gap.^3,4 The following initiatives demonstrate how Cutis has sought to address these educational gaps and remains committed to improving DEI education in dermatology.

Collaboration With the Skin of Color Society

The Skin of Color Society (SOCS), which was founded in 2004 by Dr. Susan C. Taylor, is a dermatologic organization with more than 800 members representing 32 countries. Its mission includes promoting awareness and excellence within skin of color dermatology through research, education, and mentorship. The SOCS has utilized strategic partnerships with national and international dermatologists, as well as professional medical organizations and community, industry, and corporate groups, to ultimately ensure that patients with skin of color receive the expert care they deserve.⁵ In 2017, Cutis published the inaugural article in its collaboration with the SOCS,⁶ and more articles, which undergo regular peer review, continue to be published quarterly (https://www.mdedge.com/dermatology/skin-color).

Increase Number of Journal Articles on Skin of Color Topics

Increasing the number of journal articles on skin of color–related topics needs to be intentional, as it is a tool that has been identified as a necessary part of enhancing awareness and subsequently improving patient care. Wilson et al⁷ used stringent criteria to review all articles published from January 2018 to October 2020 in 52 dermatology journals for inclusion of topics on skin of color, hair in patients with skin of color, diversity and inclusion, and socioeconomic and health care disparities in the skin of color population. The journals they reviewed included publications based on continents with majority skin of color populations, such as Asia, as well as those with minority skin of color populations, such as Europe. During the study period, the percentage of articles covering skin of color ranged from 2.04% to 61.8%, with an average of 16.8%.⁷

The total number of Cutis articles published during the study period was 709, with 132 (18.62%) meeting the investigators’ criteria for articles on skin of color; these included case reports in which at least 1 patient with skin of color was featured.⁷ Overall, Cutis ranked 16th of the 52 journals for inclusion of skin of color content. Cutis was one of only a few journals based in North America, a non–skin-of-color–predominant continent, to make the top 16 in this study.⁷

Some of the 132 skin of color articles published in Cutis were the result of the journal’s collaboration with the SOCS. Through this collaboration, articles were published on a variety of skin of color topics, including DEI (6), alopecia and hair care (5), dermoscopy/optical coherence tomography imaging (1), atopic dermatitis (1), cosmetics (1), hidradenitis suppurativa (1), pigmentation (1), rosacea (1), and skin cancer (2). These articles also resulted in a number of podcast discussions (https://www.mdedge.com/podcasts/dermatology-weekly), including one on dealing with DEI, one on pigmentation, and one on dermoscopy/optical coherence tomography imaging. The latter featured the SOCS Scientific Symposium poster winners in 2020.

The number of articles published specifically through Cutis’s collaboration with the SOCS accounted for only a small part of the journal’s 132 skin of color articles identified in the study by Wilson et al.⁷ We speculate that Cutis’s display of intentional commitment to supporting the inclusion of skin of color articles in the journal may in turn encourage its broader readership to submit more skin of color–focused articles for peer review.

Wilson et al⁷ specifically remarked that “Cutis’s [Skin of Color] section in each issue is a promising idea.” They also highlighted Clinics in Dermatology for committing an entire issue to skin of color; however, despite this initiative, Clinics in Dermatology still ranked 35th of 52 journals with regard to the overall percentage of skin of color articles published.⁷ This suggests that a journal publishing one special issue on skin of color annually is a helpful addition to the literature, but increasing the number of articles related to skin of color in each journal issue, similar to Cutis, will ultimately result in a higher overall number of skin of color articles in the dermatology literature.

Both Amuzie et al⁴ and Wilson et al⁷ concluded that the higher a journal’s impact factor, the lower the number of skin of color articles published.However, skin of color articles published in high-impact journals received a higher number of citations than those in other lower-impact journals.⁴ High-impact journals may use Cutis as a model for increasing the number of skin of color articles they publish, which will have a notable impact on increasing skin of color knowledge and educating dermatologists.

Coverage of Diversity, Equity, and Inclusion

In another study, Bray et al⁸ conducted a PubMed search of articles indexed for MEDLINE from January 2008 to July 2019 to quantify the number of articles specifically focused on DEI in a variety of medical specialties. The field of dermatology had the highest number of articles published on DEI (25) compared to the other specialties, including family medicine (23), orthopedic surgery (12), internal medicine (9), general surgery (7), radiology (6), ophthalmology (2), and anesthesiology (2).⁸ However, Wilson et al⁷ found that, out of all the categories of skin of color articles published in dermatology journals during their study period, those focused on DEI made up less than 1% of the total number of articles. Dermatology is off to a great start compared to other specialties, but there is still more work to do in dermatology for DEI. Cutis’s collaboration with the SOCS has resulted in 6 DEI articles published since 2017.

Think Beyond Dermatology Education

The collaboration between Cutis and the SOCS was established to create a series of articles dedicated to increasing the skin of color dermatology knowledge base of the Cutis readership and beyond; however, increased readership and more citations are needed to amplify the reach of the articles published by these skin of color experts. Cutis’s collaboration with SOCS is one mechanism to increase the skin of color literature, but skin of color and DEI articles outside of this collaboration should continue to be published in each issue of Cutis.

The collaboration between SOCS and Cutis was and continues to be a forward-thinking step toward improving skin of color dermatology education, but there is still work to be done across the medical literature with regard to increasing intentional publication of skin of color articles. Nondermatologist clinicians in the Cutis readership benefit from knowledge of skin of color, as all specialties and primary care will see increased patient diversity in their examination rooms.

To further ensure that primary care is not left behind, Cutis has partnered with The Journal of Family Practice to produce a new column called Dx Across the Skin of Color Spectrum (https://www.mdedge.com/dermatology/dx-across-skin-color-spectrum), which is co-published in both journals.^9,10 These one-page fact sheets highlight images of dermatologic conditions in skin of color as well as images of the same condition in lighter skin, a concept suggested by Cutis Associate Editor, Dr. Candrice R. Heath. The goal of this new column is to increase the accurate diagnosis of dermatologic conditions in skin of color and to highlight health disparities related to a particular condition in an easy-to-understand format. Uniquely, Dr. Heath co-authors this content with family physician Dr. Richard P. Usatine.

Final Thoughts

The entire community of medical journals should continue to develop creative ways to educate their readership. Medical professionals stay up-to-date on best practices through journal articles, textbooks, conferences, and even podcasts. Therefore, it is best to incorporate skin of color knowledge throughout all educational programming, particularly through enduring materials such as journal articles. Wilson et al⁷ suggested that a minimum of 16.8% of a dermatology journal’s articles in each issue should focus on skin of color in addition to special focus issues, as this will work toward more equitable dermatologic care.

Knowledge is only part of the equation; compassionate care with cultural humility is the other part. Publishing scientific facts about biology and structure, diagnosis, and treatment selection in skin of color, as well as committing to lifelong learning about the differences in our patients despite the absence of shared life or cultural experiences, may be the key to truly impacting health equity.¹¹ We believe that together we will get there one journal article and one citation at a time.

The US population is becoming more diverse. By 2044, it is predicted that there will be a majority minority population in the United States.¹ Therefore, it is imperative to continue to develop educational mechanisms for all dermatologists to increase and maintain competency in skin of color dermatology, which will contribute to the achievement of health equity for patients with all skin tones and hair types.

Not only is clinical skin of color education necessary, but diversity, equity, and inclusion (DEI) education for dermatologists also is critical. Clinical examination,² diagnosis, and treatment of skin and hair disorders across the skin of color spectrum with cultural humility is essential to achieve health equity. If trainees, dermatologists, other specialists, and primary care clinicians are not frequently exposed to patients with darker skin tones and coily hair, the nuances in diagnosing and treating these patients must be learned in alternate ways.

To ready the nation’s physicians and clinicians to care for the growing diverse population, exposure to more images of dermatologic diseases in those with darker skin tones in journal articles, textbooks, conference lectures, and online dermatology image libraries is necessary to help close the skin of color training and practice gap.^3,4 The following initiatives demonstrate how Cutis has sought to address these educational gaps and remains committed to improving DEI education in dermatology.

Collaboration With the Skin of Color Society

The Skin of Color Society (SOCS), which was founded in 2004 by Dr. Susan C. Taylor, is a dermatologic organization with more than 800 members representing 32 countries. Its mission includes promoting awareness and excellence within skin of color dermatology through research, education, and mentorship. The SOCS has utilized strategic partnerships with national and international dermatologists, as well as professional medical organizations and community, industry, and corporate groups, to ultimately ensure that patients with skin of color receive the expert care they deserve.⁵ In 2017, Cutis published the inaugural article in its collaboration with the SOCS,⁶ and more articles, which undergo regular peer review, continue to be published quarterly (https://www.mdedge.com/dermatology/skin-color).

Increase Number of Journal Articles on Skin of Color Topics

Increasing the number of journal articles on skin of color–related topics needs to be intentional, as it is a tool that has been identified as a necessary part of enhancing awareness and subsequently improving patient care. Wilson et al⁷ used stringent criteria to review all articles published from January 2018 to October 2020 in 52 dermatology journals for inclusion of topics on skin of color, hair in patients with skin of color, diversity and inclusion, and socioeconomic and health care disparities in the skin of color population. The journals they reviewed included publications based on continents with majority skin of color populations, such as Asia, as well as those with minority skin of color populations, such as Europe. During the study period, the percentage of articles covering skin of color ranged from 2.04% to 61.8%, with an average of 16.8%.⁷

The total number of Cutis articles published during the study period was 709, with 132 (18.62%) meeting the investigators’ criteria for articles on skin of color; these included case reports in which at least 1 patient with skin of color was featured.⁷ Overall, Cutis ranked 16th of the 52 journals for inclusion of skin of color content. Cutis was one of only a few journals based in North America, a non–skin-of-color–predominant continent, to make the top 16 in this study.⁷

Some of the 132 skin of color articles published in Cutis were the result of the journal’s collaboration with the SOCS. Through this collaboration, articles were published on a variety of skin of color topics, including DEI (6), alopecia and hair care (5), dermoscopy/optical coherence tomography imaging (1), atopic dermatitis (1), cosmetics (1), hidradenitis suppurativa (1), pigmentation (1), rosacea (1), and skin cancer (2). These articles also resulted in a number of podcast discussions (https://www.mdedge.com/podcasts/dermatology-weekly), including one on dealing with DEI, one on pigmentation, and one on dermoscopy/optical coherence tomography imaging. The latter featured the SOCS Scientific Symposium poster winners in 2020.

The number of articles published specifically through Cutis’s collaboration with the SOCS accounted for only a small part of the journal’s 132 skin of color articles identified in the study by Wilson et al.⁷ We speculate that Cutis’s display of intentional commitment to supporting the inclusion of skin of color articles in the journal may in turn encourage its broader readership to submit more skin of color–focused articles for peer review.

Wilson et al⁷ specifically remarked that “Cutis’s [Skin of Color] section in each issue is a promising idea.” They also highlighted Clinics in Dermatology for committing an entire issue to skin of color; however, despite this initiative, Clinics in Dermatology still ranked 35th of 52 journals with regard to the overall percentage of skin of color articles published.⁷ This suggests that a journal publishing one special issue on skin of color annually is a helpful addition to the literature, but increasing the number of articles related to skin of color in each journal issue, similar to Cutis, will ultimately result in a higher overall number of skin of color articles in the dermatology literature.

Both Amuzie et al⁴ and Wilson et al⁷ concluded that the higher a journal’s impact factor, the lower the number of skin of color articles published.However, skin of color articles published in high-impact journals received a higher number of citations than those in other lower-impact journals.⁴ High-impact journals may use Cutis as a model for increasing the number of skin of color articles they publish, which will have a notable impact on increasing skin of color knowledge and educating dermatologists.

Coverage of Diversity, Equity, and Inclusion

In another study, Bray et al⁸ conducted a PubMed search of articles indexed for MEDLINE from January 2008 to July 2019 to quantify the number of articles specifically focused on DEI in a variety of medical specialties. The field of dermatology had the highest number of articles published on DEI (25) compared to the other specialties, including family medicine (23), orthopedic surgery (12), internal medicine (9), general surgery (7), radiology (6), ophthalmology (2), and anesthesiology (2).⁸ However, Wilson et al⁷ found that, out of all the categories of skin of color articles published in dermatology journals during their study period, those focused on DEI made up less than 1% of the total number of articles. Dermatology is off to a great start compared to other specialties, but there is still more work to do in dermatology for DEI. Cutis’s collaboration with the SOCS has resulted in 6 DEI articles published since 2017.

Think Beyond Dermatology Education

The collaboration between Cutis and the SOCS was established to create a series of articles dedicated to increasing the skin of color dermatology knowledge base of the Cutis readership and beyond; however, increased readership and more citations are needed to amplify the reach of the articles published by these skin of color experts. Cutis’s collaboration with SOCS is one mechanism to increase the skin of color literature, but skin of color and DEI articles outside of this collaboration should continue to be published in each issue of Cutis.

The collaboration between SOCS and Cutis was and continues to be a forward-thinking step toward improving skin of color dermatology education, but there is still work to be done across the medical literature with regard to increasing intentional publication of skin of color articles. Nondermatologist clinicians in the Cutis readership benefit from knowledge of skin of color, as all specialties and primary care will see increased patient diversity in their examination rooms.

To further ensure that primary care is not left behind, Cutis has partnered with The Journal of Family Practice to produce a new column called Dx Across the Skin of Color Spectrum (https://www.mdedge.com/dermatology/dx-across-skin-color-spectrum), which is co-published in both journals.^9,10 These one-page fact sheets highlight images of dermatologic conditions in skin of color as well as images of the same condition in lighter skin, a concept suggested by Cutis Associate Editor, Dr. Candrice R. Heath. The goal of this new column is to increase the accurate diagnosis of dermatologic conditions in skin of color and to highlight health disparities related to a particular condition in an easy-to-understand format. Uniquely, Dr. Heath co-authors this content with family physician Dr. Richard P. Usatine.

Final Thoughts

The entire community of medical journals should continue to develop creative ways to educate their readership. Medical professionals stay up-to-date on best practices through journal articles, textbooks, conferences, and even podcasts. Therefore, it is best to incorporate skin of color knowledge throughout all educational programming, particularly through enduring materials such as journal articles. Wilson et al⁷ suggested that a minimum of 16.8% of a dermatology journal’s articles in each issue should focus on skin of color in addition to special focus issues, as this will work toward more equitable dermatologic care.

Knowledge is only part of the equation; compassionate care with cultural humility is the other part. Publishing scientific facts about biology and structure, diagnosis, and treatment selection in skin of color, as well as committing to lifelong learning about the differences in our patients despite the absence of shared life or cultural experiences, may be the key to truly impacting health equity.¹¹ We believe that together we will get there one journal article and one citation at a time.

The US population is becoming more diverse. By 2044, it is predicted that there will be a majority minority population in the United States.¹ Therefore, it is imperative to continue to develop educational mechanisms for all dermatologists to increase and maintain competency in skin of color dermatology, which will contribute to the achievement of health equity for patients with all skin tones and hair types.

Not only is clinical skin of color education necessary, but diversity, equity, and inclusion (DEI) education for dermatologists also is critical. Clinical examination,² diagnosis, and treatment of skin and hair disorders across the skin of color spectrum with cultural humility is essential to achieve health equity. If trainees, dermatologists, other specialists, and primary care clinicians are not frequently exposed to patients with darker skin tones and coily hair, the nuances in diagnosing and treating these patients must be learned in alternate ways.

To ready the nation’s physicians and clinicians to care for the growing diverse population, exposure to more images of dermatologic diseases in those with darker skin tones in journal articles, textbooks, conference lectures, and online dermatology image libraries is necessary to help close the skin of color training and practice gap.^3,4 The following initiatives demonstrate how Cutis has sought to address these educational gaps and remains committed to improving DEI education in dermatology.

Collaboration With the Skin of Color Society

The Skin of Color Society (SOCS), which was founded in 2004 by Dr. Susan C. Taylor, is a dermatologic organization with more than 800 members representing 32 countries. Its mission includes promoting awareness and excellence within skin of color dermatology through research, education, and mentorship. The SOCS has utilized strategic partnerships with national and international dermatologists, as well as professional medical organizations and community, industry, and corporate groups, to ultimately ensure that patients with skin of color receive the expert care they deserve.⁵ In 2017, Cutis published the inaugural article in its collaboration with the SOCS,⁶ and more articles, which undergo regular peer review, continue to be published quarterly (https://www.mdedge.com/dermatology/skin-color).

Increase Number of Journal Articles on Skin of Color Topics

Increasing the number of journal articles on skin of color–related topics needs to be intentional, as it is a tool that has been identified as a necessary part of enhancing awareness and subsequently improving patient care. Wilson et al⁷ used stringent criteria to review all articles published from January 2018 to October 2020 in 52 dermatology journals for inclusion of topics on skin of color, hair in patients with skin of color, diversity and inclusion, and socioeconomic and health care disparities in the skin of color population. The journals they reviewed included publications based on continents with majority skin of color populations, such as Asia, as well as those with minority skin of color populations, such as Europe. During the study period, the percentage of articles covering skin of color ranged from 2.04% to 61.8%, with an average of 16.8%.⁷

The total number of Cutis articles published during the study period was 709, with 132 (18.62%) meeting the investigators’ criteria for articles on skin of color; these included case reports in which at least 1 patient with skin of color was featured.⁷ Overall, Cutis ranked 16th of the 52 journals for inclusion of skin of color content. Cutis was one of only a few journals based in North America, a non–skin-of-color–predominant continent, to make the top 16 in this study.⁷

Some of the 132 skin of color articles published in Cutis were the result of the journal’s collaboration with the SOCS. Through this collaboration, articles were published on a variety of skin of color topics, including DEI (6), alopecia and hair care (5), dermoscopy/optical coherence tomography imaging (1), atopic dermatitis (1), cosmetics (1), hidradenitis suppurativa (1), pigmentation (1), rosacea (1), and skin cancer (2). These articles also resulted in a number of podcast discussions (https://www.mdedge.com/podcasts/dermatology-weekly), including one on dealing with DEI, one on pigmentation, and one on dermoscopy/optical coherence tomography imaging. The latter featured the SOCS Scientific Symposium poster winners in 2020.

The number of articles published specifically through Cutis’s collaboration with the SOCS accounted for only a small part of the journal’s 132 skin of color articles identified in the study by Wilson et al.⁷ We speculate that Cutis’s display of intentional commitment to supporting the inclusion of skin of color articles in the journal may in turn encourage its broader readership to submit more skin of color–focused articles for peer review.

Wilson et al⁷ specifically remarked that “Cutis’s [Skin of Color] section in each issue is a promising idea.” They also highlighted Clinics in Dermatology for committing an entire issue to skin of color; however, despite this initiative, Clinics in Dermatology still ranked 35th of 52 journals with regard to the overall percentage of skin of color articles published.⁷ This suggests that a journal publishing one special issue on skin of color annually is a helpful addition to the literature, but increasing the number of articles related to skin of color in each journal issue, similar to Cutis, will ultimately result in a higher overall number of skin of color articles in the dermatology literature.

Both Amuzie et al⁴ and Wilson et al⁷ concluded that the higher a journal’s impact factor, the lower the number of skin of color articles published.However, skin of color articles published in high-impact journals received a higher number of citations than those in other lower-impact journals.⁴ High-impact journals may use Cutis as a model for increasing the number of skin of color articles they publish, which will have a notable impact on increasing skin of color knowledge and educating dermatologists.

Coverage of Diversity, Equity, and Inclusion

In another study, Bray et al⁸ conducted a PubMed search of articles indexed for MEDLINE from January 2008 to July 2019 to quantify the number of articles specifically focused on DEI in a variety of medical specialties. The field of dermatology had the highest number of articles published on DEI (25) compared to the other specialties, including family medicine (23), orthopedic surgery (12), internal medicine (9), general surgery (7), radiology (6), ophthalmology (2), and anesthesiology (2).⁸ However, Wilson et al⁷ found that, out of all the categories of skin of color articles published in dermatology journals during their study period, those focused on DEI made up less than 1% of the total number of articles. Dermatology is off to a great start compared to other specialties, but there is still more work to do in dermatology for DEI. Cutis’s collaboration with the SOCS has resulted in 6 DEI articles published since 2017.

Think Beyond Dermatology Education

The collaboration between Cutis and the SOCS was established to create a series of articles dedicated to increasing the skin of color dermatology knowledge base of the Cutis readership and beyond; however, increased readership and more citations are needed to amplify the reach of the articles published by these skin of color experts. Cutis’s collaboration with SOCS is one mechanism to increase the skin of color literature, but skin of color and DEI articles outside of this collaboration should continue to be published in each issue of Cutis.

The collaboration between SOCS and Cutis was and continues to be a forward-thinking step toward improving skin of color dermatology education, but there is still work to be done across the medical literature with regard to increasing intentional publication of skin of color articles. Nondermatologist clinicians in the Cutis readership benefit from knowledge of skin of color, as all specialties and primary care will see increased patient diversity in their examination rooms.

To further ensure that primary care is not left behind, Cutis has partnered with The Journal of Family Practice to produce a new column called Dx Across the Skin of Color Spectrum (https://www.mdedge.com/dermatology/dx-across-skin-color-spectrum), which is co-published in both journals.^9,10 These one-page fact sheets highlight images of dermatologic conditions in skin of color as well as images of the same condition in lighter skin, a concept suggested by Cutis Associate Editor, Dr. Candrice R. Heath. The goal of this new column is to increase the accurate diagnosis of dermatologic conditions in skin of color and to highlight health disparities related to a particular condition in an easy-to-understand format. Uniquely, Dr. Heath co-authors this content with family physician Dr. Richard P. Usatine.

Final Thoughts

The entire community of medical journals should continue to develop creative ways to educate their readership. Medical professionals stay up-to-date on best practices through journal articles, textbooks, conferences, and even podcasts. Therefore, it is best to incorporate skin of color knowledge throughout all educational programming, particularly through enduring materials such as journal articles. Wilson et al⁷ suggested that a minimum of 16.8% of a dermatology journal’s articles in each issue should focus on skin of color in addition to special focus issues, as this will work toward more equitable dermatologic care.

Knowledge is only part of the equation; compassionate care with cultural humility is the other part. Publishing scientific facts about biology and structure, diagnosis, and treatment selection in skin of color, as well as committing to lifelong learning about the differences in our patients despite the absence of shared life or cultural experiences, may be the key to truly impacting health equity.¹¹ We believe that together we will get there one journal article and one citation at a time.

This fall, the Supreme Court of the United States (SCOTUS) will announce when they will hear oral arguments for Dobbs v Jackson Women’s Health Organization. The court will examine a Mississippi law, known as the “Gestational Age Act,” originally passed in 2018, that sought to “limit abortions to fifteen weeks’ gestation except in a medical emergency or in cases of severe fetal abnormality.”¹ This sets the stage for SCOTUS to make a major ruling on abortion, one which could affirm or upend landmark decisions and nearly 50 years of abortion legislative precedent. Additionally, SCOTUS’ recent decision to not intervene on Texas’ Senate Bill 8 (SB8), which essentially bans all abortions after 6 weeks’ gestational age, may foreshadow how this case will be decided. The current abortion restrictions in Texas and the implications of SB8 will be discussed in a forthcoming column.

SCOTUS and abortion rights

The decision to hear this case comes on the heels of another recent decision regarding a Louisiana law in June Medical Services v Russo. This case examined Louisiana Act 620, which would have required physicians to have hospital admitting privileges within 30 miles of where they provide abortion services.² The law was deemed constitutionally invalid, with the majority noting the law would have drastically burdened a woman’s right to access abortion services. The Court ruled similarly in 2016 in Whole Women’s Health (WWH) v Hellerstedt, in which WWH challenged Texas House Bill 2, a nearly identical law requiring admitting privileges for abortion care providers. In both of these cases, SCOTUS pointed to precedent set by Southeastern Pennsylvania v Casey, which established that it is unconstitutional for a state to create an “undue burden” on a woman’s right to abortion prior to fetal viability.³ The precedent to this, Roe v Wade, and 5 decades of abortion legislation set may be upended by a SCOTUS decision this next term.

Dobbs v Jackson

On March 19, 2018, Mississippi enacted the “Gestational Age Act” into law. The newly enacted law would limit abortions to 15 weeks’ gestation except in a medical emergency or in cases of severe fetal anomalies. Jackson Women’s Health Organization, the only licensed abortion provider in the state, challenged the constitutionality of the law with legal support from Center for Reproductive Rights (CRR). The US District Court for the Southern District of Mississippi granted summary judgement in favor of the clinic and placed an injunction on the law’s enforcement. The state appealed to the Fifth Circuit Court of Appeals, which upheld the district court decision in a 3-0 decision in November 2019. Mississippi appealed to the Supreme Court, with their petition focusing on multiple questions from the appeals process. After repeatedly rescheduling the case, and multiple reviews in conference, SCOTUS agreed to hear the case. Most recently, the state has narrowed its argument, changing course, and attacking Roe v Wade directly. In a brief submitted in July 2021, the state argues the court should hold that all pre-viability prohibitions on elective abortions are constitutional.

Interestingly, during this time the Mississippi legislature also passed a law, House Bill 2116, also known as the “fetal heartbeat bill,” banning abortion with gestational ages after detection of a fetal heartbeat. This was also challenged, deemed unconstitutional, and affirmed on appeal by the Fifth US Circuit Court.

While recent challenges have focused on the “undue burden” state laws placed on those trying to access abortion care, this case will bring the issue of “viability” and gestational age limits to the forefront.^4,5 In addition to Roe v Wade, the Court will have the opportunity to reexamine other relevant precedent, such as Southeastern Pennsylvania v Casey, in considering the most recent arguments of the state. In this most recent brief, the state argues that the Court should, “reject viability as a barrier to prohibiting elective abortions” and that a “viability rule has no constitutional basis.” The state goes on to argue the “Constitution does not protect a right to abortion or limit States’ authority to restrict it.”⁶ The language and tone in this brief are more direct and aggressive than the states’ petition submitted last June.

However, the composition of the Court is different than in the past. This case will be argued with Justice Amy Coney Barrett seated in place of Justice Ruth Bader Ginsburg, who was a strong advocate for women’s rights.⁷ She joins Justices Neil Gorsuch and Brett Kavanaugh, also appointed by President Donald Trump and widely viewed as conservative judges, tipping the scales to a more conservative Supreme Court. This case will also be argued in a polarized political environment.^8,9 Given the conservative Supreme Court in the setting of an increasingly politically charged environment, reproductive right advocates are understandably worried that members of the anti-abortion movement view this as an opportunity to weaken or remove federal constitutional protections for abortion.

Continue to: Potential outcome of Dobbs v Jackson...

Should SCOTUS choose to rule in favor of Mississippi, it could severely weaken, or even overturn Roe v Wade. This would leave a legal path for states with pre-Roe abortion bans and currently unenforced post-Roe bans to take effect. These “trigger” laws are bans or severe restrictions on abortion providers and patients intended to take effect if Roe were to be overturned. Alternatively, the Court may overturn Southeastern Pennsylvania v Casey, but maintain Roe v Wade, essentially leaving the regulation of pre-viability abortion care to individual states. Currently 21 states have laws that would restrict the legal status of abortion.¹⁰ In addition, state legislatures are aggressively introducing abortion restrictions. As of June 2021, there have been 561 abortion restrictions, including 165 abortion bans, introduced across 47 states, putting 2021 on course to be the most devastating anti-abortion state legislative session in decades.¹¹

The damage caused by such restriction on abortion care would be significant. It would block or push access out of reach for many. The negative effects of such legislative action would most heavily burden those already marginalized by systemic, structural inequalities including those of low socioeconomic status, people of color, young people, those in rural communities, and members of the LGBTQ community. The medical community has long recognized the harm caused by restricting access to abortion care. Restriction of access to safe abortion care paradoxically has been shown not to decrease the incidence of abortion, but rather increases the number of unsafe abortions.¹² The American College of Obstetricians and Gynecologists (ACOG) acknowledge “individuals require access to safe, legal abortion” and that this represents “a necessary component for comprehensive health care.”^13,14 They joined the American Medical Association and other professional groups in a 2019 amicus brief to SCOTUS opposing restrictions on abortion access.¹⁵ In addition, government laws restricting access to abortion care undermine the fundamental relationship between a person and their physician, limiting a physician’s obligation to honor patient autonomy and provide appropriate medical care.

By taking up the question whether all pre-viability bans on elective abortions violate the Constitution, SCOTUS is indicating a possible willingness to revisit the central holding of abortion jurisprudence. Their decision regarding this case will likely be the most significant ruling regarding the legal status of abortion care in decades, and will significantly affect the delivery of abortion care in the future.

Action items

• Reach out to your representatives to support the Women’s Health Protection Act, an initiative introduced to Congress to protect access to abortion care. If you reside in a state where your federal representatives support the Women’s Health Protection Act, reach out to friends and colleagues in states without supportive elected officials and ask them to call their representatives and ask them to support the bill.
• Get involved with local grassroots groups fighting to protect abortion access.
• Continue to speak out against laws and policies designed to limit access to safe abortion care.
• Connect with your local ACOG chapter for more ways to become involved.
• As always, make sure you are registered to vote, and exercise your right whenever you can.

This fall, the Supreme Court of the United States (SCOTUS) will announce when they will hear oral arguments for Dobbs v Jackson Women’s Health Organization. The court will examine a Mississippi law, known as the “Gestational Age Act,” originally passed in 2018, that sought to “limit abortions to fifteen weeks’ gestation except in a medical emergency or in cases of severe fetal abnormality.”¹ This sets the stage for SCOTUS to make a major ruling on abortion, one which could affirm or upend landmark decisions and nearly 50 years of abortion legislative precedent. Additionally, SCOTUS’ recent decision to not intervene on Texas’ Senate Bill 8 (SB8), which essentially bans all abortions after 6 weeks’ gestational age, may foreshadow how this case will be decided. The current abortion restrictions in Texas and the implications of SB8 will be discussed in a forthcoming column.

SCOTUS and abortion rights

The decision to hear this case comes on the heels of another recent decision regarding a Louisiana law in June Medical Services v Russo. This case examined Louisiana Act 620, which would have required physicians to have hospital admitting privileges within 30 miles of where they provide abortion services.² The law was deemed constitutionally invalid, with the majority noting the law would have drastically burdened a woman’s right to access abortion services. The Court ruled similarly in 2016 in Whole Women’s Health (WWH) v Hellerstedt, in which WWH challenged Texas House Bill 2, a nearly identical law requiring admitting privileges for abortion care providers. In both of these cases, SCOTUS pointed to precedent set by Southeastern Pennsylvania v Casey, which established that it is unconstitutional for a state to create an “undue burden” on a woman’s right to abortion prior to fetal viability.³ The precedent to this, Roe v Wade, and 5 decades of abortion legislation set may be upended by a SCOTUS decision this next term.

Dobbs v Jackson

On March 19, 2018, Mississippi enacted the “Gestational Age Act” into law. The newly enacted law would limit abortions to 15 weeks’ gestation except in a medical emergency or in cases of severe fetal anomalies. Jackson Women’s Health Organization, the only licensed abortion provider in the state, challenged the constitutionality of the law with legal support from Center for Reproductive Rights (CRR). The US District Court for the Southern District of Mississippi granted summary judgement in favor of the clinic and placed an injunction on the law’s enforcement. The state appealed to the Fifth Circuit Court of Appeals, which upheld the district court decision in a 3-0 decision in November 2019. Mississippi appealed to the Supreme Court, with their petition focusing on multiple questions from the appeals process. After repeatedly rescheduling the case, and multiple reviews in conference, SCOTUS agreed to hear the case. Most recently, the state has narrowed its argument, changing course, and attacking Roe v Wade directly. In a brief submitted in July 2021, the state argues the court should hold that all pre-viability prohibitions on elective abortions are constitutional.

Interestingly, during this time the Mississippi legislature also passed a law, House Bill 2116, also known as the “fetal heartbeat bill,” banning abortion with gestational ages after detection of a fetal heartbeat. This was also challenged, deemed unconstitutional, and affirmed on appeal by the Fifth US Circuit Court.

While recent challenges have focused on the “undue burden” state laws placed on those trying to access abortion care, this case will bring the issue of “viability” and gestational age limits to the forefront.^4,5 In addition to Roe v Wade, the Court will have the opportunity to reexamine other relevant precedent, such as Southeastern Pennsylvania v Casey, in considering the most recent arguments of the state. In this most recent brief, the state argues that the Court should, “reject viability as a barrier to prohibiting elective abortions” and that a “viability rule has no constitutional basis.” The state goes on to argue the “Constitution does not protect a right to abortion or limit States’ authority to restrict it.”⁶ The language and tone in this brief are more direct and aggressive than the states’ petition submitted last June.

However, the composition of the Court is different than in the past. This case will be argued with Justice Amy Coney Barrett seated in place of Justice Ruth Bader Ginsburg, who was a strong advocate for women’s rights.⁷ She joins Justices Neil Gorsuch and Brett Kavanaugh, also appointed by President Donald Trump and widely viewed as conservative judges, tipping the scales to a more conservative Supreme Court. This case will also be argued in a polarized political environment.^8,9 Given the conservative Supreme Court in the setting of an increasingly politically charged environment, reproductive right advocates are understandably worried that members of the anti-abortion movement view this as an opportunity to weaken or remove federal constitutional protections for abortion.

Continue to: Potential outcome of Dobbs v Jackson...

Should SCOTUS choose to rule in favor of Mississippi, it could severely weaken, or even overturn Roe v Wade. This would leave a legal path for states with pre-Roe abortion bans and currently unenforced post-Roe bans to take effect. These “trigger” laws are bans or severe restrictions on abortion providers and patients intended to take effect if Roe were to be overturned. Alternatively, the Court may overturn Southeastern Pennsylvania v Casey, but maintain Roe v Wade, essentially leaving the regulation of pre-viability abortion care to individual states. Currently 21 states have laws that would restrict the legal status of abortion.¹⁰ In addition, state legislatures are aggressively introducing abortion restrictions. As of June 2021, there have been 561 abortion restrictions, including 165 abortion bans, introduced across 47 states, putting 2021 on course to be the most devastating anti-abortion state legislative session in decades.¹¹

The damage caused by such restriction on abortion care would be significant. It would block or push access out of reach for many. The negative effects of such legislative action would most heavily burden those already marginalized by systemic, structural inequalities including those of low socioeconomic status, people of color, young people, those in rural communities, and members of the LGBTQ community. The medical community has long recognized the harm caused by restricting access to abortion care. Restriction of access to safe abortion care paradoxically has been shown not to decrease the incidence of abortion, but rather increases the number of unsafe abortions.¹² The American College of Obstetricians and Gynecologists (ACOG) acknowledge “individuals require access to safe, legal abortion” and that this represents “a necessary component for comprehensive health care.”^13,14 They joined the American Medical Association and other professional groups in a 2019 amicus brief to SCOTUS opposing restrictions on abortion access.¹⁵ In addition, government laws restricting access to abortion care undermine the fundamental relationship between a person and their physician, limiting a physician’s obligation to honor patient autonomy and provide appropriate medical care.

By taking up the question whether all pre-viability bans on elective abortions violate the Constitution, SCOTUS is indicating a possible willingness to revisit the central holding of abortion jurisprudence. Their decision regarding this case will likely be the most significant ruling regarding the legal status of abortion care in decades, and will significantly affect the delivery of abortion care in the future.

Action items

• Reach out to your representatives to support the Women’s Health Protection Act, an initiative introduced to Congress to protect access to abortion care. If you reside in a state where your federal representatives support the Women’s Health Protection Act, reach out to friends and colleagues in states without supportive elected officials and ask them to call their representatives and ask them to support the bill.
• Get involved with local grassroots groups fighting to protect abortion access.
• Continue to speak out against laws and policies designed to limit access to safe abortion care.
• Connect with your local ACOG chapter for more ways to become involved.
• As always, make sure you are registered to vote, and exercise your right whenever you can.

This fall, the Supreme Court of the United States (SCOTUS) will announce when they will hear oral arguments for Dobbs v Jackson Women’s Health Organization. The court will examine a Mississippi law, known as the “Gestational Age Act,” originally passed in 2018, that sought to “limit abortions to fifteen weeks’ gestation except in a medical emergency or in cases of severe fetal abnormality.”¹ This sets the stage for SCOTUS to make a major ruling on abortion, one which could affirm or upend landmark decisions and nearly 50 years of abortion legislative precedent. Additionally, SCOTUS’ recent decision to not intervene on Texas’ Senate Bill 8 (SB8), which essentially bans all abortions after 6 weeks’ gestational age, may foreshadow how this case will be decided. The current abortion restrictions in Texas and the implications of SB8 will be discussed in a forthcoming column.

SCOTUS and abortion rights

The decision to hear this case comes on the heels of another recent decision regarding a Louisiana law in June Medical Services v Russo. This case examined Louisiana Act 620, which would have required physicians to have hospital admitting privileges within 30 miles of where they provide abortion services.² The law was deemed constitutionally invalid, with the majority noting the law would have drastically burdened a woman’s right to access abortion services. The Court ruled similarly in 2016 in Whole Women’s Health (WWH) v Hellerstedt, in which WWH challenged Texas House Bill 2, a nearly identical law requiring admitting privileges for abortion care providers. In both of these cases, SCOTUS pointed to precedent set by Southeastern Pennsylvania v Casey, which established that it is unconstitutional for a state to create an “undue burden” on a woman’s right to abortion prior to fetal viability.³ The precedent to this, Roe v Wade, and 5 decades of abortion legislation set may be upended by a SCOTUS decision this next term.

Dobbs v Jackson

On March 19, 2018, Mississippi enacted the “Gestational Age Act” into law. The newly enacted law would limit abortions to 15 weeks’ gestation except in a medical emergency or in cases of severe fetal anomalies. Jackson Women’s Health Organization, the only licensed abortion provider in the state, challenged the constitutionality of the law with legal support from Center for Reproductive Rights (CRR). The US District Court for the Southern District of Mississippi granted summary judgement in favor of the clinic and placed an injunction on the law’s enforcement. The state appealed to the Fifth Circuit Court of Appeals, which upheld the district court decision in a 3-0 decision in November 2019. Mississippi appealed to the Supreme Court, with their petition focusing on multiple questions from the appeals process. After repeatedly rescheduling the case, and multiple reviews in conference, SCOTUS agreed to hear the case. Most recently, the state has narrowed its argument, changing course, and attacking Roe v Wade directly. In a brief submitted in July 2021, the state argues the court should hold that all pre-viability prohibitions on elective abortions are constitutional.

Interestingly, during this time the Mississippi legislature also passed a law, House Bill 2116, also known as the “fetal heartbeat bill,” banning abortion with gestational ages after detection of a fetal heartbeat. This was also challenged, deemed unconstitutional, and affirmed on appeal by the Fifth US Circuit Court.

While recent challenges have focused on the “undue burden” state laws placed on those trying to access abortion care, this case will bring the issue of “viability” and gestational age limits to the forefront.^4,5 In addition to Roe v Wade, the Court will have the opportunity to reexamine other relevant precedent, such as Southeastern Pennsylvania v Casey, in considering the most recent arguments of the state. In this most recent brief, the state argues that the Court should, “reject viability as a barrier to prohibiting elective abortions” and that a “viability rule has no constitutional basis.” The state goes on to argue the “Constitution does not protect a right to abortion or limit States’ authority to restrict it.”⁶ The language and tone in this brief are more direct and aggressive than the states’ petition submitted last June.

However, the composition of the Court is different than in the past. This case will be argued with Justice Amy Coney Barrett seated in place of Justice Ruth Bader Ginsburg, who was a strong advocate for women’s rights.⁷ She joins Justices Neil Gorsuch and Brett Kavanaugh, also appointed by President Donald Trump and widely viewed as conservative judges, tipping the scales to a more conservative Supreme Court. This case will also be argued in a polarized political environment.^8,9 Given the conservative Supreme Court in the setting of an increasingly politically charged environment, reproductive right advocates are understandably worried that members of the anti-abortion movement view this as an opportunity to weaken or remove federal constitutional protections for abortion.

Continue to: Potential outcome of Dobbs v Jackson...

Should SCOTUS choose to rule in favor of Mississippi, it could severely weaken, or even overturn Roe v Wade. This would leave a legal path for states with pre-Roe abortion bans and currently unenforced post-Roe bans to take effect. These “trigger” laws are bans or severe restrictions on abortion providers and patients intended to take effect if Roe were to be overturned. Alternatively, the Court may overturn Southeastern Pennsylvania v Casey, but maintain Roe v Wade, essentially leaving the regulation of pre-viability abortion care to individual states. Currently 21 states have laws that would restrict the legal status of abortion.¹⁰ In addition, state legislatures are aggressively introducing abortion restrictions. As of June 2021, there have been 561 abortion restrictions, including 165 abortion bans, introduced across 47 states, putting 2021 on course to be the most devastating anti-abortion state legislative session in decades.¹¹

The damage caused by such restriction on abortion care would be significant. It would block or push access out of reach for many. The negative effects of such legislative action would most heavily burden those already marginalized by systemic, structural inequalities including those of low socioeconomic status, people of color, young people, those in rural communities, and members of the LGBTQ community. The medical community has long recognized the harm caused by restricting access to abortion care. Restriction of access to safe abortion care paradoxically has been shown not to decrease the incidence of abortion, but rather increases the number of unsafe abortions.¹² The American College of Obstetricians and Gynecologists (ACOG) acknowledge “individuals require access to safe, legal abortion” and that this represents “a necessary component for comprehensive health care.”^13,14 They joined the American Medical Association and other professional groups in a 2019 amicus brief to SCOTUS opposing restrictions on abortion access.¹⁵ In addition, government laws restricting access to abortion care undermine the fundamental relationship between a person and their physician, limiting a physician’s obligation to honor patient autonomy and provide appropriate medical care.

By taking up the question whether all pre-viability bans on elective abortions violate the Constitution, SCOTUS is indicating a possible willingness to revisit the central holding of abortion jurisprudence. Their decision regarding this case will likely be the most significant ruling regarding the legal status of abortion care in decades, and will significantly affect the delivery of abortion care in the future.

Action items

• Reach out to your representatives to support the Women’s Health Protection Act, an initiative introduced to Congress to protect access to abortion care. If you reside in a state where your federal representatives support the Women’s Health Protection Act, reach out to friends and colleagues in states without supportive elected officials and ask them to call their representatives and ask them to support the bill.
• Get involved with local grassroots groups fighting to protect abortion access.
• Continue to speak out against laws and policies designed to limit access to safe abortion care.
• Connect with your local ACOG chapter for more ways to become involved.
• As always, make sure you are registered to vote, and exercise your right whenever you can.

Atopic dermatitis (AD) is an incredibly common chronic skin disease, affecting up to 25% of children and 7% of adults in the United States.^1,2 Despite the prevalence of this disease and its impact on patient quality of life, research and scholarly work in AD has been limited until recent years. A PubMed search of articles indexed for MEDLINE using the term atopic dermatitis showed that there were fewer than 500 articles published in 2000 and 965 in 2010; with our more recent acceleration in research, there were 2168 articles published in 2020 and more than 1300 published in just the first half of 2021 (through June). This new research includes insights into the pathogenesis of AD and study of the disease impact and comorbidities as well as an extensive amount of drug development and clinical trial work for new topical and systemic therapies.

New Agents to Treat AD

The 2016 approval of crisaborole,³ a phosphodiesterase 4 inhibitor, followed by the approval of dupilumab, an IL-4 and IL-13 pathway inhibitor and the first biologic agent approved for AD,⁴ ushered in a new age of therapy. We currently are awaiting the incorporation of a new set of topical nonsteroidal agents, oral Janus kinase (JAK) inhibitors, and new biologic agents for AD, several of which have completed phase 3 trials and extended safety evaluations. How these new drugs will impact our standard treatment across the spectrum of care for AD is not yet known.

The emergence of new systemic therapies is timely, as the most used systemic medications previously were oral corticosteroids, despite their use being advised against in standard practice guidelines. Other agents such as methotrexate, cyclosporine, azathioprine, and mycophenolate are discussed in the literature and AD treatment guidelines as being potentially useful, though absence of US Food and Drug Administration (FDA) approval and the need for frequent laboratory monitoring, as well as drug-specific side effects and an increased risk of infection, limit their use in the United States, especially in pediatric and adolescent populations.⁵

The approval of dupilumab as a systemic therapy—initially for adults and subsequently for teenagers (12–17 years of age) and then children (6–11 years of age)—has markedly influenced the standard of care for moderate to severe AD. This agent has been shown to have a considerable impact on disease severity and quality of life, with a good safety profile and the added benefit of not requiring continuous (or any) laboratory monitoring.^6-8 Ongoing studies of dupilumab in children (ClinicalTrials.gov identifiers NCT02612454, NCT03346434), including those younger than 1 year,⁹ raise the question of how commonly this medication might be incorporated into care across the entire age spectrum of patients with AD. What standards will there be for assessment of severity, disease impact, and persistence to warrant use in younger ages? Will early treatment with novel systemic agents change the overall course of the disease and minimize the development of comorbidities? The answers to these questions remain to be seen.

JAK Inhibitors for AD
Additional novel therapeutics currently are undergoing studies for treatment of AD, most notably the oral JAK inhibitors upadacitinib,¹⁰ baricitinib,¹¹ and abrocitinib.¹² Each of these agents has completed phase 3 trials for AD. Two of these agents—upadacitinib and baricitinib—have prior FDA approval for use in other disease states. Of note, baricitinib is already approved for treatment of moderate to severe AD in adults in more than 40 countries¹³; however, the use of these agents in other diseases brings about concerns of malignancy, severe infection, and thrombosis. In the clinical trials for AD, many of these events have not been seen, but the number of patients treated is limited, and longer-term safety assessment is important.^10,11

How will the oral JAK inhibitors be incorporated into care compared to biologic agents such as dupilumab? Tolerance and more serious potential adverse events are concerns, with nausea, headaches, and acneform eruptions being associated with some of the medications, in addition to potential issues with herpes simplex and zoster infections. However, oral JAK inhibitors have the benefit of not requiring injections, something that many patients may prefer, and data show that these drugs generally are associated with a rapid reduction in pruritus and, depending on the drug, very quick and profound effects on objective signs of AD.^10-12 Two head-to-head studies have been completed comparing dupilumab to oral JAK inhibitors in adults: the JADE COMPARE trial examining dupilumab vs abrocitinib¹² and the Heads UP trial comparing dupilumab vs upadacitinib.¹⁴ Compared to dupilumab, higher-dose abrocitinib showed more rapid responses, superiority in itch response, and similarity or superiority in other outcomes depending on the time point of the evaluation. Adverse event profiles differed; for example, abrocitinib was associated with more nausea, acneform eruptions, and herpes zoster, while dupilumab had higher rates of conjunctivitis.¹² Upadacitinib, which was only studied at higher dosing (30 mg daily), showed superiority to dupilumab in itch response and in improvement in AD severity in multiple outcome measures; however, there were increases in serious infections, eczema herpeticum, herpes zoster, and laboratory-related adverse events.¹⁴ Dupilumab has the advantage of studies of extended use along with real-world experience, generally with excellent safety and tolerance other than injection-site reactions and conjunctivitis.⁸ Biologics targeting IL-13—tralokinumab and lebrikizumab—also are to be added to our armamentarium.^15,16 The addition of these agents and JAK inhibitors as new systemic treatment options points to the quickly evolving future of AD treatment for patients with extensive disease.

New topical therapies in development provide even more treatment options. New nonsteroidal topicals include topical JAK inhibitors such as ruxolitinib¹⁷; tapinarof,¹⁸ an aryl hydrocarbon receptor modulator; and phosphodiesterase 4 inhibitors. These agents may be useful either as monotherapy, as studied, potentially without the regional limitations associated with stronger topical corticosteroids, but also should be useful in clinical practice as part of therapeutic regimens with other topical steroid and nonsteroidal agents.

The Microbiome and AD

In addition, research looking at topical microbes as specific interventions that may mediate the microbiome and inflammation of AD are intriguing. A recent phase 1 trial from the University of California San Diego¹⁹ indicated that topical bacteriotherapy directed at decreasing Staphylococcus aureus may provide an impact in AD. Observations by Kong et al²⁰ showed that gram-negative microbiome differences are seen in AD patients compared to unaffected individuals, which has fueled studies showing that Roseomonas mucosa, a gram-negative skin commensal, when applied as a topical live biotherapeutic agent has improved disease severity in children and adults with AD.²¹ Although further studies are underway, these initial data suggest a role for microbiome-modifying therapies as AD treatment.

Chronic Hand Eczema

Chronic hand eczema (CHE), which has considerable overlap with AD in many patients, especially children and adolescents,^22-24 is another area of interesting research. This high-prevalence condition is associated with allergic and irritant contact dermatitis^24-26—conditions that are both considered alternative diagnoses for and exacerbators of AD²⁷—and is a disease process currently being targeted for new therapies. Delgocitinib (NCT04872101, NCT04871711), the novel JAK inhibitor ARQ-252 (NCT04378569), among other topical agents, as well as systemic therapeutics such as gusacitinib (NCT03728504), are in active trials for CHE. Given CHE’s impact on quality of life²⁸ and its overlap with AD, investigation into this disorder can help drive future AD research as well as lead to better knowledge and treatment of CHE.

Final Thoughts

Despite the promising results of these myriad new therapies in AD, there are many factors that influence how and when we use these drugs, including their approval status, FDA labeling, and the ability of patients to access and afford treatment. Additionally, continued study is needed to evaluate the long-term safety and extended efficacy of newer drugs, such as the oral JAK inhibitors. Despite these hurdles, the current landscape of research and development is rapidly evolving. Compared to the many years when only one main group of therapies was a reasonable option for patients, the future of AD treatment looks bright.

Atopic dermatitis (AD) is an incredibly common chronic skin disease, affecting up to 25% of children and 7% of adults in the United States.^1,2 Despite the prevalence of this disease and its impact on patient quality of life, research and scholarly work in AD has been limited until recent years. A PubMed search of articles indexed for MEDLINE using the term atopic dermatitis showed that there were fewer than 500 articles published in 2000 and 965 in 2010; with our more recent acceleration in research, there were 2168 articles published in 2020 and more than 1300 published in just the first half of 2021 (through June). This new research includes insights into the pathogenesis of AD and study of the disease impact and comorbidities as well as an extensive amount of drug development and clinical trial work for new topical and systemic therapies.

New Agents to Treat AD

The 2016 approval of crisaborole,³ a phosphodiesterase 4 inhibitor, followed by the approval of dupilumab, an IL-4 and IL-13 pathway inhibitor and the first biologic agent approved for AD,⁴ ushered in a new age of therapy. We currently are awaiting the incorporation of a new set of topical nonsteroidal agents, oral Janus kinase (JAK) inhibitors, and new biologic agents for AD, several of which have completed phase 3 trials and extended safety evaluations. How these new drugs will impact our standard treatment across the spectrum of care for AD is not yet known.

The emergence of new systemic therapies is timely, as the most used systemic medications previously were oral corticosteroids, despite their use being advised against in standard practice guidelines. Other agents such as methotrexate, cyclosporine, azathioprine, and mycophenolate are discussed in the literature and AD treatment guidelines as being potentially useful, though absence of US Food and Drug Administration (FDA) approval and the need for frequent laboratory monitoring, as well as drug-specific side effects and an increased risk of infection, limit their use in the United States, especially in pediatric and adolescent populations.⁵

The approval of dupilumab as a systemic therapy—initially for adults and subsequently for teenagers (12–17 years of age) and then children (6–11 years of age)—has markedly influenced the standard of care for moderate to severe AD. This agent has been shown to have a considerable impact on disease severity and quality of life, with a good safety profile and the added benefit of not requiring continuous (or any) laboratory monitoring.^6-8 Ongoing studies of dupilumab in children (ClinicalTrials.gov identifiers NCT02612454, NCT03346434), including those younger than 1 year,⁹ raise the question of how commonly this medication might be incorporated into care across the entire age spectrum of patients with AD. What standards will there be for assessment of severity, disease impact, and persistence to warrant use in younger ages? Will early treatment with novel systemic agents change the overall course of the disease and minimize the development of comorbidities? The answers to these questions remain to be seen.

JAK Inhibitors for AD
Additional novel therapeutics currently are undergoing studies for treatment of AD, most notably the oral JAK inhibitors upadacitinib,¹⁰ baricitinib,¹¹ and abrocitinib.¹² Each of these agents has completed phase 3 trials for AD. Two of these agents—upadacitinib and baricitinib—have prior FDA approval for use in other disease states. Of note, baricitinib is already approved for treatment of moderate to severe AD in adults in more than 40 countries¹³; however, the use of these agents in other diseases brings about concerns of malignancy, severe infection, and thrombosis. In the clinical trials for AD, many of these events have not been seen, but the number of patients treated is limited, and longer-term safety assessment is important.^10,11

How will the oral JAK inhibitors be incorporated into care compared to biologic agents such as dupilumab? Tolerance and more serious potential adverse events are concerns, with nausea, headaches, and acneform eruptions being associated with some of the medications, in addition to potential issues with herpes simplex and zoster infections. However, oral JAK inhibitors have the benefit of not requiring injections, something that many patients may prefer, and data show that these drugs generally are associated with a rapid reduction in pruritus and, depending on the drug, very quick and profound effects on objective signs of AD.^10-12 Two head-to-head studies have been completed comparing dupilumab to oral JAK inhibitors in adults: the JADE COMPARE trial examining dupilumab vs abrocitinib¹² and the Heads UP trial comparing dupilumab vs upadacitinib.¹⁴ Compared to dupilumab, higher-dose abrocitinib showed more rapid responses, superiority in itch response, and similarity or superiority in other outcomes depending on the time point of the evaluation. Adverse event profiles differed; for example, abrocitinib was associated with more nausea, acneform eruptions, and herpes zoster, while dupilumab had higher rates of conjunctivitis.¹² Upadacitinib, which was only studied at higher dosing (30 mg daily), showed superiority to dupilumab in itch response and in improvement in AD severity in multiple outcome measures; however, there were increases in serious infections, eczema herpeticum, herpes zoster, and laboratory-related adverse events.¹⁴ Dupilumab has the advantage of studies of extended use along with real-world experience, generally with excellent safety and tolerance other than injection-site reactions and conjunctivitis.⁸ Biologics targeting IL-13—tralokinumab and lebrikizumab—also are to be added to our armamentarium.^15,16 The addition of these agents and JAK inhibitors as new systemic treatment options points to the quickly evolving future of AD treatment for patients with extensive disease.

New topical therapies in development provide even more treatment options. New nonsteroidal topicals include topical JAK inhibitors such as ruxolitinib¹⁷; tapinarof,¹⁸ an aryl hydrocarbon receptor modulator; and phosphodiesterase 4 inhibitors. These agents may be useful either as monotherapy, as studied, potentially without the regional limitations associated with stronger topical corticosteroids, but also should be useful in clinical practice as part of therapeutic regimens with other topical steroid and nonsteroidal agents.

The Microbiome and AD

In addition, research looking at topical microbes as specific interventions that may mediate the microbiome and inflammation of AD are intriguing. A recent phase 1 trial from the University of California San Diego¹⁹ indicated that topical bacteriotherapy directed at decreasing Staphylococcus aureus may provide an impact in AD. Observations by Kong et al²⁰ showed that gram-negative microbiome differences are seen in AD patients compared to unaffected individuals, which has fueled studies showing that Roseomonas mucosa, a gram-negative skin commensal, when applied as a topical live biotherapeutic agent has improved disease severity in children and adults with AD.²¹ Although further studies are underway, these initial data suggest a role for microbiome-modifying therapies as AD treatment.

Chronic Hand Eczema

Chronic hand eczema (CHE), which has considerable overlap with AD in many patients, especially children and adolescents,^22-24 is another area of interesting research. This high-prevalence condition is associated with allergic and irritant contact dermatitis^24-26—conditions that are both considered alternative diagnoses for and exacerbators of AD²⁷—and is a disease process currently being targeted for new therapies. Delgocitinib (NCT04872101, NCT04871711), the novel JAK inhibitor ARQ-252 (NCT04378569), among other topical agents, as well as systemic therapeutics such as gusacitinib (NCT03728504), are in active trials for CHE. Given CHE’s impact on quality of life²⁸ and its overlap with AD, investigation into this disorder can help drive future AD research as well as lead to better knowledge and treatment of CHE.

Final Thoughts

Despite the promising results of these myriad new therapies in AD, there are many factors that influence how and when we use these drugs, including their approval status, FDA labeling, and the ability of patients to access and afford treatment. Additionally, continued study is needed to evaluate the long-term safety and extended efficacy of newer drugs, such as the oral JAK inhibitors. Despite these hurdles, the current landscape of research and development is rapidly evolving. Compared to the many years when only one main group of therapies was a reasonable option for patients, the future of AD treatment looks bright.

Atopic dermatitis (AD) is an incredibly common chronic skin disease, affecting up to 25% of children and 7% of adults in the United States.^1,2 Despite the prevalence of this disease and its impact on patient quality of life, research and scholarly work in AD has been limited until recent years. A PubMed search of articles indexed for MEDLINE using the term atopic dermatitis showed that there were fewer than 500 articles published in 2000 and 965 in 2010; with our more recent acceleration in research, there were 2168 articles published in 2020 and more than 1300 published in just the first half of 2021 (through June). This new research includes insights into the pathogenesis of AD and study of the disease impact and comorbidities as well as an extensive amount of drug development and clinical trial work for new topical and systemic therapies.

New Agents to Treat AD

The 2016 approval of crisaborole,³ a phosphodiesterase 4 inhibitor, followed by the approval of dupilumab, an IL-4 and IL-13 pathway inhibitor and the first biologic agent approved for AD,⁴ ushered in a new age of therapy. We currently are awaiting the incorporation of a new set of topical nonsteroidal agents, oral Janus kinase (JAK) inhibitors, and new biologic agents for AD, several of which have completed phase 3 trials and extended safety evaluations. How these new drugs will impact our standard treatment across the spectrum of care for AD is not yet known.

The emergence of new systemic therapies is timely, as the most used systemic medications previously were oral corticosteroids, despite their use being advised against in standard practice guidelines. Other agents such as methotrexate, cyclosporine, azathioprine, and mycophenolate are discussed in the literature and AD treatment guidelines as being potentially useful, though absence of US Food and Drug Administration (FDA) approval and the need for frequent laboratory monitoring, as well as drug-specific side effects and an increased risk of infection, limit their use in the United States, especially in pediatric and adolescent populations.⁵

The approval of dupilumab as a systemic therapy—initially for adults and subsequently for teenagers (12–17 years of age) and then children (6–11 years of age)—has markedly influenced the standard of care for moderate to severe AD. This agent has been shown to have a considerable impact on disease severity and quality of life, with a good safety profile and the added benefit of not requiring continuous (or any) laboratory monitoring.^6-8 Ongoing studies of dupilumab in children (ClinicalTrials.gov identifiers NCT02612454, NCT03346434), including those younger than 1 year,⁹ raise the question of how commonly this medication might be incorporated into care across the entire age spectrum of patients with AD. What standards will there be for assessment of severity, disease impact, and persistence to warrant use in younger ages? Will early treatment with novel systemic agents change the overall course of the disease and minimize the development of comorbidities? The answers to these questions remain to be seen.

JAK Inhibitors for AD
Additional novel therapeutics currently are undergoing studies for treatment of AD, most notably the oral JAK inhibitors upadacitinib,¹⁰ baricitinib,¹¹ and abrocitinib.¹² Each of these agents has completed phase 3 trials for AD. Two of these agents—upadacitinib and baricitinib—have prior FDA approval for use in other disease states. Of note, baricitinib is already approved for treatment of moderate to severe AD in adults in more than 40 countries¹³; however, the use of these agents in other diseases brings about concerns of malignancy, severe infection, and thrombosis. In the clinical trials for AD, many of these events have not been seen, but the number of patients treated is limited, and longer-term safety assessment is important.^10,11

How will the oral JAK inhibitors be incorporated into care compared to biologic agents such as dupilumab? Tolerance and more serious potential adverse events are concerns, with nausea, headaches, and acneform eruptions being associated with some of the medications, in addition to potential issues with herpes simplex and zoster infections. However, oral JAK inhibitors have the benefit of not requiring injections, something that many patients may prefer, and data show that these drugs generally are associated with a rapid reduction in pruritus and, depending on the drug, very quick and profound effects on objective signs of AD.^10-12 Two head-to-head studies have been completed comparing dupilumab to oral JAK inhibitors in adults: the JADE COMPARE trial examining dupilumab vs abrocitinib¹² and the Heads UP trial comparing dupilumab vs upadacitinib.¹⁴ Compared to dupilumab, higher-dose abrocitinib showed more rapid responses, superiority in itch response, and similarity or superiority in other outcomes depending on the time point of the evaluation. Adverse event profiles differed; for example, abrocitinib was associated with more nausea, acneform eruptions, and herpes zoster, while dupilumab had higher rates of conjunctivitis.¹² Upadacitinib, which was only studied at higher dosing (30 mg daily), showed superiority to dupilumab in itch response and in improvement in AD severity in multiple outcome measures; however, there were increases in serious infections, eczema herpeticum, herpes zoster, and laboratory-related adverse events.¹⁴ Dupilumab has the advantage of studies of extended use along with real-world experience, generally with excellent safety and tolerance other than injection-site reactions and conjunctivitis.⁸ Biologics targeting IL-13—tralokinumab and lebrikizumab—also are to be added to our armamentarium.^15,16 The addition of these agents and JAK inhibitors as new systemic treatment options points to the quickly evolving future of AD treatment for patients with extensive disease.

New topical therapies in development provide even more treatment options. New nonsteroidal topicals include topical JAK inhibitors such as ruxolitinib¹⁷; tapinarof,¹⁸ an aryl hydrocarbon receptor modulator; and phosphodiesterase 4 inhibitors. These agents may be useful either as monotherapy, as studied, potentially without the regional limitations associated with stronger topical corticosteroids, but also should be useful in clinical practice as part of therapeutic regimens with other topical steroid and nonsteroidal agents.

The Microbiome and AD

In addition, research looking at topical microbes as specific interventions that may mediate the microbiome and inflammation of AD are intriguing. A recent phase 1 trial from the University of California San Diego¹⁹ indicated that topical bacteriotherapy directed at decreasing Staphylococcus aureus may provide an impact in AD. Observations by Kong et al²⁰ showed that gram-negative microbiome differences are seen in AD patients compared to unaffected individuals, which has fueled studies showing that Roseomonas mucosa, a gram-negative skin commensal, when applied as a topical live biotherapeutic agent has improved disease severity in children and adults with AD.²¹ Although further studies are underway, these initial data suggest a role for microbiome-modifying therapies as AD treatment.

Chronic Hand Eczema

Chronic hand eczema (CHE), which has considerable overlap with AD in many patients, especially children and adolescents,^22-24 is another area of interesting research. This high-prevalence condition is associated with allergic and irritant contact dermatitis^24-26—conditions that are both considered alternative diagnoses for and exacerbators of AD²⁷—and is a disease process currently being targeted for new therapies. Delgocitinib (NCT04872101, NCT04871711), the novel JAK inhibitor ARQ-252 (NCT04378569), among other topical agents, as well as systemic therapeutics such as gusacitinib (NCT03728504), are in active trials for CHE. Given CHE’s impact on quality of life²⁸ and its overlap with AD, investigation into this disorder can help drive future AD research as well as lead to better knowledge and treatment of CHE.

Final Thoughts

Despite the promising results of these myriad new therapies in AD, there are many factors that influence how and when we use these drugs, including their approval status, FDA labeling, and the ability of patients to access and afford treatment. Additionally, continued study is needed to evaluate the long-term safety and extended efficacy of newer drugs, such as the oral JAK inhibitors. Despite these hurdles, the current landscape of research and development is rapidly evolving. Compared to the many years when only one main group of therapies was a reasonable option for patients, the future of AD treatment looks bright.

As an esophagologist that does not perform fundoplication, LINX, or TIF, I find it difficult to debate the merits of one procedure over another based on my experience. In fact, I have always stated that it is difficult to assess a procedure or test that one has not used. That being said, maybe the fact that I have not performed these procedures makes me more objective and I can only use my experience with patients and the data to make the case that we need options beyond Nissen fundoplication.

The recent VA Randomized trial in refractory GERD published by Spechler and colleagues once again highlighted the fact that there are some patients that require a mechanical solution to reflux disease.¹ In this study, the authors carefully defined a patient population with refractory GERD and showed that Nissen fundoplication was superior to medical management in patients who did not respond to proton pump inhibitors. However, of the 27 patients who underwent fundoplication, one patient had major complications which required a repeat operation and prolonged hospital stay. These findings highlight the main problem with Nissen fundoplication. Dr. Watson elegantly argued in his assertion during our debate that Nissen and fundoplication are not the same. In this position, he was noting the side effects associated with Nissen fundoplication,² and he focused his argument on the comparison between a partial wrap versus LINX and TIF to level the playing field. On that note, I agree with Dr. Watson that a well-done partial fundoplication is a great option for patients with a mechanical problem.

Nonetheless, I think we have the capacity to do better than Nissen fundoplication, and thus, a safer standardized reversible surgical option and a less invasive endoscopic approach have great appeal. Redo operations have an escalating risk of severe debilitating consequences and we should do everything possible to reduce that risk.³ The LINX and the TIF procedure have data to support their effectiveness, and the initial studies suggest a more favorable side effect profile.^4,5 The ability to perform these procedures in patients with hiatal hernia and the fact that these approaches do not exclude the possibility of fundoplication in the future make them an attractive alternative.

In the end, more rigorous comparative studies should be performed to truly determine which approach is better. Although we have good surgical and medical options, we all recognize that they are not perfect and we should not settle on the current state of GERD management.

John E. Pandolfino, MD, MSCI, is the Hans Popper Professor of Medicine and Division Chief, Gastroenterology and Hepatology at Northwestern University, Chicago. He disclosed relationships with Ethicon/Johnson & Johnson, Endogastric Solutions, and Medtronic. These remarks were made during one of the AGA Postgraduate Course sessions held at DDW 2021.

References

1. Spechler SJ et al. N Engl J Med. 2019 Oct 17;381[16]:1513-23.

2. Yadlapati R et al. Am J Gastroenterol. 2018 Aug;113[8]:1137-47.

3. Singhal S et al. J Gastrointest Surg. 2018 Feb;22[2]:177-86.

4. Ganz RA et al. Clin Gastroenterol Hepatol. 2016 May;14(5):671-7.

5. Testoni PA et al. Endosc Int Open. 2019 May;7(5):E647-E654.

As an esophagologist that does not perform fundoplication, LINX, or TIF, I find it difficult to debate the merits of one procedure over another based on my experience. In fact, I have always stated that it is difficult to assess a procedure or test that one has not used. That being said, maybe the fact that I have not performed these procedures makes me more objective and I can only use my experience with patients and the data to make the case that we need options beyond Nissen fundoplication.

The recent VA Randomized trial in refractory GERD published by Spechler and colleagues once again highlighted the fact that there are some patients that require a mechanical solution to reflux disease.¹ In this study, the authors carefully defined a patient population with refractory GERD and showed that Nissen fundoplication was superior to medical management in patients who did not respond to proton pump inhibitors. However, of the 27 patients who underwent fundoplication, one patient had major complications which required a repeat operation and prolonged hospital stay. These findings highlight the main problem with Nissen fundoplication. Dr. Watson elegantly argued in his assertion during our debate that Nissen and fundoplication are not the same. In this position, he was noting the side effects associated with Nissen fundoplication,² and he focused his argument on the comparison between a partial wrap versus LINX and TIF to level the playing field. On that note, I agree with Dr. Watson that a well-done partial fundoplication is a great option for patients with a mechanical problem.

Nonetheless, I think we have the capacity to do better than Nissen fundoplication, and thus, a safer standardized reversible surgical option and a less invasive endoscopic approach have great appeal. Redo operations have an escalating risk of severe debilitating consequences and we should do everything possible to reduce that risk.³ The LINX and the TIF procedure have data to support their effectiveness, and the initial studies suggest a more favorable side effect profile.^4,5 The ability to perform these procedures in patients with hiatal hernia and the fact that these approaches do not exclude the possibility of fundoplication in the future make them an attractive alternative.

In the end, more rigorous comparative studies should be performed to truly determine which approach is better. Although we have good surgical and medical options, we all recognize that they are not perfect and we should not settle on the current state of GERD management.

John E. Pandolfino, MD, MSCI, is the Hans Popper Professor of Medicine and Division Chief, Gastroenterology and Hepatology at Northwestern University, Chicago. He disclosed relationships with Ethicon/Johnson & Johnson, Endogastric Solutions, and Medtronic. These remarks were made during one of the AGA Postgraduate Course sessions held at DDW 2021.

References

1. Spechler SJ et al. N Engl J Med. 2019 Oct 17;381[16]:1513-23.

2. Yadlapati R et al. Am J Gastroenterol. 2018 Aug;113[8]:1137-47.

3. Singhal S et al. J Gastrointest Surg. 2018 Feb;22[2]:177-86.

4. Ganz RA et al. Clin Gastroenterol Hepatol. 2016 May;14(5):671-7.

5. Testoni PA et al. Endosc Int Open. 2019 May;7(5):E647-E654.

As an esophagologist that does not perform fundoplication, LINX, or TIF, I find it difficult to debate the merits of one procedure over another based on my experience. In fact, I have always stated that it is difficult to assess a procedure or test that one has not used. That being said, maybe the fact that I have not performed these procedures makes me more objective and I can only use my experience with patients and the data to make the case that we need options beyond Nissen fundoplication.

The recent VA Randomized trial in refractory GERD published by Spechler and colleagues once again highlighted the fact that there are some patients that require a mechanical solution to reflux disease.¹ In this study, the authors carefully defined a patient population with refractory GERD and showed that Nissen fundoplication was superior to medical management in patients who did not respond to proton pump inhibitors. However, of the 27 patients who underwent fundoplication, one patient had major complications which required a repeat operation and prolonged hospital stay. These findings highlight the main problem with Nissen fundoplication. Dr. Watson elegantly argued in his assertion during our debate that Nissen and fundoplication are not the same. In this position, he was noting the side effects associated with Nissen fundoplication,² and he focused his argument on the comparison between a partial wrap versus LINX and TIF to level the playing field. On that note, I agree with Dr. Watson that a well-done partial fundoplication is a great option for patients with a mechanical problem.

Nonetheless, I think we have the capacity to do better than Nissen fundoplication, and thus, a safer standardized reversible surgical option and a less invasive endoscopic approach have great appeal. Redo operations have an escalating risk of severe debilitating consequences and we should do everything possible to reduce that risk.³ The LINX and the TIF procedure have data to support their effectiveness, and the initial studies suggest a more favorable side effect profile.^4,5 The ability to perform these procedures in patients with hiatal hernia and the fact that these approaches do not exclude the possibility of fundoplication in the future make them an attractive alternative.

In the end, more rigorous comparative studies should be performed to truly determine which approach is better. Although we have good surgical and medical options, we all recognize that they are not perfect and we should not settle on the current state of GERD management.

John E. Pandolfino, MD, MSCI, is the Hans Popper Professor of Medicine and Division Chief, Gastroenterology and Hepatology at Northwestern University, Chicago. He disclosed relationships with Ethicon/Johnson & Johnson, Endogastric Solutions, and Medtronic. These remarks were made during one of the AGA Postgraduate Course sessions held at DDW 2021.

References

1. Spechler SJ et al. N Engl J Med. 2019 Oct 17;381[16]:1513-23.

2. Yadlapati R et al. Am J Gastroenterol. 2018 Aug;113[8]:1137-47.

3. Singhal S et al. J Gastrointest Surg. 2018 Feb;22[2]:177-86.

4. Ganz RA et al. Clin Gastroenterol Hepatol. 2016 May;14(5):671-7.

5. Testoni PA et al. Endosc Int Open. 2019 May;7(5):E647-E654.

For those of us treating patients with liver disease throughout the pandemic, we have anticipated evidence-based guidance regarding the contribution of specific liver disease phenotypes and immune suppression/transplantation on COVID-19 susceptibility and outcome. Now, data are emerging to help answer some of the major questions surrounding COVID-19 and the liver.

Does the virus itself cause liver disease?

The answer to this question is still a bit unclear. Multiple early reports^1-11 stated that hospitalized patients with SARS-CoV-2 infection frequently had elevated values on liver biochemistry tests. For example, the reported incidence of elevated serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels ranged from 14% to 83%, yet the magnitude of enzyme elevation was generally reported to be mild and normalized as COVID-19 symptoms improved.

Unsurprisingly, patients with severe liver injury (defined as AST and ALT levels more than five times the upper limit of normal) were more likely to have a complicated clinical course, including having elevated inflammatory markers and requiring intensive care unit admission, renal replacement therapy, and/or intubation. Currier and colleagues reported that patients with COVID-19 who had elevated AST and ALT levels had significantly higher odds of these same adverse outcomes and death.

This reflects the multifactorial pathogenesis of enzyme elevation, including a direct injurious effect of the virus on hepatocytes, cytokine or immune-mediated liver damage, drug hepatoxicity, or hypoxia and systemic inflammation.

Pellegrini and colleagues reported that 7% of patients infected with SARS-CoV-2 developed acute liver failure during their hospitalization, with a resulting mortality rate of 74%. Wagner and colleagues suggested that the pattern of peak elevated enzyme elevation was prognostic of severe clinical outcomes in hospitalized patients with COVID-19. Patients with a predominantly mixed pattern (AST/ALT and alkaline phosphatase elevations) had worse outcomes than those with a hepatocellular phenotype (isolated AST and/or ALT elevation).

Severe liver injury associated with SARS-CoV-2 infection is uncommon in children. However, elevated AST and ALT levels may be seen in association with multisystem inflammatory syndrome.^12-15
 

Are patients with preexisting chronic liver disease more susceptible to adverse outcomes?

Early observations suggested that patients with chronic liver disease, such as cirrhosis, who acquire SARS-CoV-2 have high rates of hospitalization and mortality. However, it is unclear whether all such patients are affected or whether certain subgroups are at higher risk.

In results that they hoped would allow for better risk stratification and personalization of care, Kim and colleagues reported that patients with alcohol-related liver disease, decompensated cirrhosis, and hepatocellular carcinoma have the highest risk for all-cause mortality from COVID-19. Separate presentations at Digestive Disease Week 2021 confirmed that patients with preexisting liver disease had a threefold higher rate of mortality, thromboembolism, acute respiratory distress syndrome, and a severe COVID-19 disease course, and that patients with both COVID-19 and cirrhosis had significantly higher rates of mortality (18% vs. 13%), ICU admission (46% vs. 34%), and longer lengths of stay than those without cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease, and its impact on the course of SARS-CoV-2 infection (and vice versa) is controversial. However, metabolic risk factors, such as obesity, diabetes mellitus, and hypertension, are known to be associated with severe illness from COVID-19. It was also reported that hepatic steatosis was associated with worse outcomes in patients with liver injury and SARS-CoV-2 infection, and that a higher proportion of patients with NAFLD required mechanical ventilation during their hospital course (47% vs. 17%) and had increased mortality (41% vs. 17%).
 

Do immunosuppressed patients face unique risks from infection?

Data from a limited case series, patient registries, and multicenter international studies have indicated that the clinical outcome of SARS-CoV-2 infection in adults with autoimmune hepatitis (AIH) was comparable to that noted in nonimmunosuppressed persons. However, it has also been suggested that a more complicated relationship exists between this virus and autoimmunity because immunosuppression may actually protect against the inappropriate immune response, or cytokine storm, engendered during severe SARS-CoV-2 infection.

The complexity of this relationship is further illustrated by a report from Bril and colleagues that described a case of AIH that developed after a patient had received a COVID-19 vaccine. The authors were careful to state that a causal relationship between receipt of the vaccine and the onset of AIH cannot be proven.
 

What’s the impact on liver transplant recipients?

Findings are limited regarding clinical outcomes and disease severity of SARS-CoV-2 infection in liver transplant recipients, but initial reports raised concern for high rates of adverse outcomes.^16-25

Tien and colleagues reported an increased risk for COVID-related death among liver transplant recipients. Separate international multicenter studies published in 2020 and 2021 found that liver transplant patients with COVID-19 had a significantly higher risk for hospitalization but no higher risk for mortality, thrombosis, or ICU requirement, compared with patients with COVID-19 who had not undergone liver transplantation. Increased age and the presence of comorbidities were determinants of the severity of SARS-CoV-2 infection and of mortality among liver transplant recipients.

Clearly, more data are needed to address the influence of liver transplantation in patients with COVID-19; however, some risk/protective factors have been cited. For example, Belli and colleagues reported that the use of tacrolimus was associated with a better outcome. Conversely, baseline immunosuppression containing mycophenolate mofetil was an independent predictor of severe COVID-19 in liver transplant recipients.
 

Do COVID-19 vaccines work differently in patients with liver disease?

Unfortunately, we haven’t been able to address many of our patients’ questions related to vaccine efficacy, safety, and durability. Data are limited because immunocompromised patients were excluded from the phase 3 trials of the COVID-19 vaccines.

We also need greater clarity on the robustness of the response to these vaccines in liver transplant recipients. Rabinowich and colleagues evaluated humoral antibody responses after vaccination with the mRNA-based vaccine BNT162b2 (BioNTech/Pfizer) and confirmed lower immunogenicity in liver transplant recipients. Antibodies were detectable in only 48% of patients, compared with 100% of healthy controls; in addition, antibody titers were significantly lower. Unfortunately, there are no data on the correlation of protection from SARS-CoV-2 with antibody titers.

Additional data will be required to assess vaccine effectiveness in protecting against severe COVID-19 as well as to determine the magnitude of humoral vaccine responses in recipients treated with high-dose steroids and mycophenolate mofetil. In addition, we eagerly await studies that determine whether booster doses are required.
 

What’s the bottom line?

In the face of the COVID-19 pandemic, our understanding of the impact on our patients remains a work in progress.

As we await more clarity, there are a few practical points of clinical relevance we take away from the literature, the recently released joint Statement on COVID-19 Vaccination in Solid Organ Transplant Recipients, and the American Association for the Study of Liver Diseases (AASLD) consensus statement. These suggest clinicians take the following steps:

• When assessing patients with SARS-CoV-2 infection and elevated AST and ALT levels, the first objective is to rule out etiologies unrelated to COVID-19, specifically other viruses and drug-induced injury, as well as nonhepatic causes (e.g., myositis, cardiac injury, ischemia).
• Reduction in immunosuppression in SARS-CoV-2–infected patients with AIH should be considered carefully and generally undertaken only in those with severe illness.
• Pretransplant SARS-CoV-2 vaccination is recommended for all liver transplant candidates and liver transplant recipients as well as their household members and caregivers, to reduce exposure for these patients, along with continued adherence to protective measures (masking and social distancing).
• Continuation of a stable posttransplant immunosuppression regimen at the time of vaccination is recommended to avoid the risk for organ rejection until more comprehensive data are available.

For updated responses to the evolving guidelines, visit the AASLD’s resource center.
 

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, pediatric liver care center; medical director emeritus, liver transplantation; and professor, University of Cincinnati College of Medicine, department of pediatrics, Cincinnati Children’s Hospital Medical Center. He has served as director of the division of gastroenterology, hepatology and nutrition at Cincinnati Children’s for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for this news organization. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. He has disclosed no relevant financial relationships.

References

1. Bloom PB et al. Hepatology. 2021 Mar;73:890-900.

2. Guan WJ et al. N Engl J Med. 2020 Apr;382:1708-20.

3. Chen N et al. Lancet. 2020 Feb;395:507-13.

4. Fan Z et al. Clin Gastroenterol Hepatol. 2020 Jun;18:1561-6.

5. Huang C et al. Lancet. 2020 Feb;395:497-506.

6. Xu L et al. Liver Int. 2020 May;40:998-1004.

7. Zhang C et al. Lancet Gastroenterol Hepatol. 2020 May;5:428-30.

8. Richardson S et al. JAMA. 2020 May;323:2052-9.

9. Phipps MM et al. Hepatology. 2020 Sep;72:807-17.

10. Ferm S et al. Clin Gastroenterol Hepatol. 2020 Sep;18:2378-9.

11. Hundt MA et al. Hepatology. 2020 Oct;72:1169-76.

12. Zhou YH et al. Pediatr Obes. 2020 Dec;15:e12723.

13. Kehar M et al. J Pediatr Gastroenterol Nutr. 2021 Jun;72:807-814.

14. Lu X et al. N Engl J Med. 2020 Apr;382:1663-5.

15. Cantor A et al. Hepatology. 2020 Nov;72:1522-7.

16. Kim D et al. Clin Gastroenterol Hepatol. 2021 Jul;19:1469-79.

17. Colmenero J et al. J Hepatol. 2021 Jan;74:148-155.

18. Lee BT et al. Gastroenterology. 2020 Sep;159:1176-8.e2.

19. Becchetti C et al. Gut. 2020 Oct;69:1832-40.

20. Belli LS et al. Lancet Gastroenterol Hepatol. 2020 Aug;5:724-5.

21. Bhoori S et al. Lancet Gastroenterol Hepatol. 2020 Jun;5:532-3.

22. Rabiee A et al; COLD Consortium. Hepatology. 2020 Dec;72:1900-11.

23. Belli LS et al. Gastroenterology. 2021 Mar;160:1151-63.e3.

24. Webb GJ et al. Lancet Gastroenterol Hepatol. 2020 Nov;5:1008-16.

25. Marjot T et al. J Hepatol. 2021 Mar;74:567-77.

A version of this article first appeared on Medscape.com.

For those of us treating patients with liver disease throughout the pandemic, we have anticipated evidence-based guidance regarding the contribution of specific liver disease phenotypes and immune suppression/transplantation on COVID-19 susceptibility and outcome. Now, data are emerging to help answer some of the major questions surrounding COVID-19 and the liver.

Does the virus itself cause liver disease?

The answer to this question is still a bit unclear. Multiple early reports^1-11 stated that hospitalized patients with SARS-CoV-2 infection frequently had elevated values on liver biochemistry tests. For example, the reported incidence of elevated serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels ranged from 14% to 83%, yet the magnitude of enzyme elevation was generally reported to be mild and normalized as COVID-19 symptoms improved.

Unsurprisingly, patients with severe liver injury (defined as AST and ALT levels more than five times the upper limit of normal) were more likely to have a complicated clinical course, including having elevated inflammatory markers and requiring intensive care unit admission, renal replacement therapy, and/or intubation. Currier and colleagues reported that patients with COVID-19 who had elevated AST and ALT levels had significantly higher odds of these same adverse outcomes and death.

This reflects the multifactorial pathogenesis of enzyme elevation, including a direct injurious effect of the virus on hepatocytes, cytokine or immune-mediated liver damage, drug hepatoxicity, or hypoxia and systemic inflammation.

Pellegrini and colleagues reported that 7% of patients infected with SARS-CoV-2 developed acute liver failure during their hospitalization, with a resulting mortality rate of 74%. Wagner and colleagues suggested that the pattern of peak elevated enzyme elevation was prognostic of severe clinical outcomes in hospitalized patients with COVID-19. Patients with a predominantly mixed pattern (AST/ALT and alkaline phosphatase elevations) had worse outcomes than those with a hepatocellular phenotype (isolated AST and/or ALT elevation).

Severe liver injury associated with SARS-CoV-2 infection is uncommon in children. However, elevated AST and ALT levels may be seen in association with multisystem inflammatory syndrome.^12-15
 

Are patients with preexisting chronic liver disease more susceptible to adverse outcomes?

Early observations suggested that patients with chronic liver disease, such as cirrhosis, who acquire SARS-CoV-2 have high rates of hospitalization and mortality. However, it is unclear whether all such patients are affected or whether certain subgroups are at higher risk.

In results that they hoped would allow for better risk stratification and personalization of care, Kim and colleagues reported that patients with alcohol-related liver disease, decompensated cirrhosis, and hepatocellular carcinoma have the highest risk for all-cause mortality from COVID-19. Separate presentations at Digestive Disease Week 2021 confirmed that patients with preexisting liver disease had a threefold higher rate of mortality, thromboembolism, acute respiratory distress syndrome, and a severe COVID-19 disease course, and that patients with both COVID-19 and cirrhosis had significantly higher rates of mortality (18% vs. 13%), ICU admission (46% vs. 34%), and longer lengths of stay than those without cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease, and its impact on the course of SARS-CoV-2 infection (and vice versa) is controversial. However, metabolic risk factors, such as obesity, diabetes mellitus, and hypertension, are known to be associated with severe illness from COVID-19. It was also reported that hepatic steatosis was associated with worse outcomes in patients with liver injury and SARS-CoV-2 infection, and that a higher proportion of patients with NAFLD required mechanical ventilation during their hospital course (47% vs. 17%) and had increased mortality (41% vs. 17%).
 

Do immunosuppressed patients face unique risks from infection?

Data from a limited case series, patient registries, and multicenter international studies have indicated that the clinical outcome of SARS-CoV-2 infection in adults with autoimmune hepatitis (AIH) was comparable to that noted in nonimmunosuppressed persons. However, it has also been suggested that a more complicated relationship exists between this virus and autoimmunity because immunosuppression may actually protect against the inappropriate immune response, or cytokine storm, engendered during severe SARS-CoV-2 infection.

The complexity of this relationship is further illustrated by a report from Bril and colleagues that described a case of AIH that developed after a patient had received a COVID-19 vaccine. The authors were careful to state that a causal relationship between receipt of the vaccine and the onset of AIH cannot be proven.
 

What’s the impact on liver transplant recipients?

Findings are limited regarding clinical outcomes and disease severity of SARS-CoV-2 infection in liver transplant recipients, but initial reports raised concern for high rates of adverse outcomes.^16-25

Tien and colleagues reported an increased risk for COVID-related death among liver transplant recipients. Separate international multicenter studies published in 2020 and 2021 found that liver transplant patients with COVID-19 had a significantly higher risk for hospitalization but no higher risk for mortality, thrombosis, or ICU requirement, compared with patients with COVID-19 who had not undergone liver transplantation. Increased age and the presence of comorbidities were determinants of the severity of SARS-CoV-2 infection and of mortality among liver transplant recipients.

Clearly, more data are needed to address the influence of liver transplantation in patients with COVID-19; however, some risk/protective factors have been cited. For example, Belli and colleagues reported that the use of tacrolimus was associated with a better outcome. Conversely, baseline immunosuppression containing mycophenolate mofetil was an independent predictor of severe COVID-19 in liver transplant recipients.
 

Do COVID-19 vaccines work differently in patients with liver disease?

Unfortunately, we haven’t been able to address many of our patients’ questions related to vaccine efficacy, safety, and durability. Data are limited because immunocompromised patients were excluded from the phase 3 trials of the COVID-19 vaccines.

We also need greater clarity on the robustness of the response to these vaccines in liver transplant recipients. Rabinowich and colleagues evaluated humoral antibody responses after vaccination with the mRNA-based vaccine BNT162b2 (BioNTech/Pfizer) and confirmed lower immunogenicity in liver transplant recipients. Antibodies were detectable in only 48% of patients, compared with 100% of healthy controls; in addition, antibody titers were significantly lower. Unfortunately, there are no data on the correlation of protection from SARS-CoV-2 with antibody titers.

Additional data will be required to assess vaccine effectiveness in protecting against severe COVID-19 as well as to determine the magnitude of humoral vaccine responses in recipients treated with high-dose steroids and mycophenolate mofetil. In addition, we eagerly await studies that determine whether booster doses are required.
 

What’s the bottom line?

In the face of the COVID-19 pandemic, our understanding of the impact on our patients remains a work in progress.

As we await more clarity, there are a few practical points of clinical relevance we take away from the literature, the recently released joint Statement on COVID-19 Vaccination in Solid Organ Transplant Recipients, and the American Association for the Study of Liver Diseases (AASLD) consensus statement. These suggest clinicians take the following steps:

• When assessing patients with SARS-CoV-2 infection and elevated AST and ALT levels, the first objective is to rule out etiologies unrelated to COVID-19, specifically other viruses and drug-induced injury, as well as nonhepatic causes (e.g., myositis, cardiac injury, ischemia).
• Reduction in immunosuppression in SARS-CoV-2–infected patients with AIH should be considered carefully and generally undertaken only in those with severe illness.
• Pretransplant SARS-CoV-2 vaccination is recommended for all liver transplant candidates and liver transplant recipients as well as their household members and caregivers, to reduce exposure for these patients, along with continued adherence to protective measures (masking and social distancing).
• Continuation of a stable posttransplant immunosuppression regimen at the time of vaccination is recommended to avoid the risk for organ rejection until more comprehensive data are available.

For updated responses to the evolving guidelines, visit the AASLD’s resource center.
 

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, pediatric liver care center; medical director emeritus, liver transplantation; and professor, University of Cincinnati College of Medicine, department of pediatrics, Cincinnati Children’s Hospital Medical Center. He has served as director of the division of gastroenterology, hepatology and nutrition at Cincinnati Children’s for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for this news organization. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. He has disclosed no relevant financial relationships.

References

1. Bloom PB et al. Hepatology. 2021 Mar;73:890-900.

2. Guan WJ et al. N Engl J Med. 2020 Apr;382:1708-20.

3. Chen N et al. Lancet. 2020 Feb;395:507-13.

4. Fan Z et al. Clin Gastroenterol Hepatol. 2020 Jun;18:1561-6.

5. Huang C et al. Lancet. 2020 Feb;395:497-506.

6. Xu L et al. Liver Int. 2020 May;40:998-1004.

7. Zhang C et al. Lancet Gastroenterol Hepatol. 2020 May;5:428-30.

8. Richardson S et al. JAMA. 2020 May;323:2052-9.

9. Phipps MM et al. Hepatology. 2020 Sep;72:807-17.

10. Ferm S et al. Clin Gastroenterol Hepatol. 2020 Sep;18:2378-9.

11. Hundt MA et al. Hepatology. 2020 Oct;72:1169-76.

12. Zhou YH et al. Pediatr Obes. 2020 Dec;15:e12723.

13. Kehar M et al. J Pediatr Gastroenterol Nutr. 2021 Jun;72:807-814.

14. Lu X et al. N Engl J Med. 2020 Apr;382:1663-5.

15. Cantor A et al. Hepatology. 2020 Nov;72:1522-7.

16. Kim D et al. Clin Gastroenterol Hepatol. 2021 Jul;19:1469-79.

17. Colmenero J et al. J Hepatol. 2021 Jan;74:148-155.

18. Lee BT et al. Gastroenterology. 2020 Sep;159:1176-8.e2.

19. Becchetti C et al. Gut. 2020 Oct;69:1832-40.

20. Belli LS et al. Lancet Gastroenterol Hepatol. 2020 Aug;5:724-5.

21. Bhoori S et al. Lancet Gastroenterol Hepatol. 2020 Jun;5:532-3.

22. Rabiee A et al; COLD Consortium. Hepatology. 2020 Dec;72:1900-11.

23. Belli LS et al. Gastroenterology. 2021 Mar;160:1151-63.e3.

24. Webb GJ et al. Lancet Gastroenterol Hepatol. 2020 Nov;5:1008-16.

25. Marjot T et al. J Hepatol. 2021 Mar;74:567-77.

A version of this article first appeared on Medscape.com.

For those of us treating patients with liver disease throughout the pandemic, we have anticipated evidence-based guidance regarding the contribution of specific liver disease phenotypes and immune suppression/transplantation on COVID-19 susceptibility and outcome. Now, data are emerging to help answer some of the major questions surrounding COVID-19 and the liver.

Does the virus itself cause liver disease?

The answer to this question is still a bit unclear. Multiple early reports^1-11 stated that hospitalized patients with SARS-CoV-2 infection frequently had elevated values on liver biochemistry tests. For example, the reported incidence of elevated serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels ranged from 14% to 83%, yet the magnitude of enzyme elevation was generally reported to be mild and normalized as COVID-19 symptoms improved.

Unsurprisingly, patients with severe liver injury (defined as AST and ALT levels more than five times the upper limit of normal) were more likely to have a complicated clinical course, including having elevated inflammatory markers and requiring intensive care unit admission, renal replacement therapy, and/or intubation. Currier and colleagues reported that patients with COVID-19 who had elevated AST and ALT levels had significantly higher odds of these same adverse outcomes and death.

This reflects the multifactorial pathogenesis of enzyme elevation, including a direct injurious effect of the virus on hepatocytes, cytokine or immune-mediated liver damage, drug hepatoxicity, or hypoxia and systemic inflammation.

Pellegrini and colleagues reported that 7% of patients infected with SARS-CoV-2 developed acute liver failure during their hospitalization, with a resulting mortality rate of 74%. Wagner and colleagues suggested that the pattern of peak elevated enzyme elevation was prognostic of severe clinical outcomes in hospitalized patients with COVID-19. Patients with a predominantly mixed pattern (AST/ALT and alkaline phosphatase elevations) had worse outcomes than those with a hepatocellular phenotype (isolated AST and/or ALT elevation).

Severe liver injury associated with SARS-CoV-2 infection is uncommon in children. However, elevated AST and ALT levels may be seen in association with multisystem inflammatory syndrome.^12-15
 

Are patients with preexisting chronic liver disease more susceptible to adverse outcomes?

Early observations suggested that patients with chronic liver disease, such as cirrhosis, who acquire SARS-CoV-2 have high rates of hospitalization and mortality. However, it is unclear whether all such patients are affected or whether certain subgroups are at higher risk.

In results that they hoped would allow for better risk stratification and personalization of care, Kim and colleagues reported that patients with alcohol-related liver disease, decompensated cirrhosis, and hepatocellular carcinoma have the highest risk for all-cause mortality from COVID-19. Separate presentations at Digestive Disease Week 2021 confirmed that patients with preexisting liver disease had a threefold higher rate of mortality, thromboembolism, acute respiratory distress syndrome, and a severe COVID-19 disease course, and that patients with both COVID-19 and cirrhosis had significantly higher rates of mortality (18% vs. 13%), ICU admission (46% vs. 34%), and longer lengths of stay than those without cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease, and its impact on the course of SARS-CoV-2 infection (and vice versa) is controversial. However, metabolic risk factors, such as obesity, diabetes mellitus, and hypertension, are known to be associated with severe illness from COVID-19. It was also reported that hepatic steatosis was associated with worse outcomes in patients with liver injury and SARS-CoV-2 infection, and that a higher proportion of patients with NAFLD required mechanical ventilation during their hospital course (47% vs. 17%) and had increased mortality (41% vs. 17%).
 

Do immunosuppressed patients face unique risks from infection?

Data from a limited case series, patient registries, and multicenter international studies have indicated that the clinical outcome of SARS-CoV-2 infection in adults with autoimmune hepatitis (AIH) was comparable to that noted in nonimmunosuppressed persons. However, it has also been suggested that a more complicated relationship exists between this virus and autoimmunity because immunosuppression may actually protect against the inappropriate immune response, or cytokine storm, engendered during severe SARS-CoV-2 infection.

The complexity of this relationship is further illustrated by a report from Bril and colleagues that described a case of AIH that developed after a patient had received a COVID-19 vaccine. The authors were careful to state that a causal relationship between receipt of the vaccine and the onset of AIH cannot be proven.
 

What’s the impact on liver transplant recipients?

Findings are limited regarding clinical outcomes and disease severity of SARS-CoV-2 infection in liver transplant recipients, but initial reports raised concern for high rates of adverse outcomes.^16-25

Tien and colleagues reported an increased risk for COVID-related death among liver transplant recipients. Separate international multicenter studies published in 2020 and 2021 found that liver transplant patients with COVID-19 had a significantly higher risk for hospitalization but no higher risk for mortality, thrombosis, or ICU requirement, compared with patients with COVID-19 who had not undergone liver transplantation. Increased age and the presence of comorbidities were determinants of the severity of SARS-CoV-2 infection and of mortality among liver transplant recipients.

Clearly, more data are needed to address the influence of liver transplantation in patients with COVID-19; however, some risk/protective factors have been cited. For example, Belli and colleagues reported that the use of tacrolimus was associated with a better outcome. Conversely, baseline immunosuppression containing mycophenolate mofetil was an independent predictor of severe COVID-19 in liver transplant recipients.
 

Do COVID-19 vaccines work differently in patients with liver disease?

Unfortunately, we haven’t been able to address many of our patients’ questions related to vaccine efficacy, safety, and durability. Data are limited because immunocompromised patients were excluded from the phase 3 trials of the COVID-19 vaccines.

We also need greater clarity on the robustness of the response to these vaccines in liver transplant recipients. Rabinowich and colleagues evaluated humoral antibody responses after vaccination with the mRNA-based vaccine BNT162b2 (BioNTech/Pfizer) and confirmed lower immunogenicity in liver transplant recipients. Antibodies were detectable in only 48% of patients, compared with 100% of healthy controls; in addition, antibody titers were significantly lower. Unfortunately, there are no data on the correlation of protection from SARS-CoV-2 with antibody titers.

Additional data will be required to assess vaccine effectiveness in protecting against severe COVID-19 as well as to determine the magnitude of humoral vaccine responses in recipients treated with high-dose steroids and mycophenolate mofetil. In addition, we eagerly await studies that determine whether booster doses are required.
 

What’s the bottom line?

In the face of the COVID-19 pandemic, our understanding of the impact on our patients remains a work in progress.

As we await more clarity, there are a few practical points of clinical relevance we take away from the literature, the recently released joint Statement on COVID-19 Vaccination in Solid Organ Transplant Recipients, and the American Association for the Study of Liver Diseases (AASLD) consensus statement. These suggest clinicians take the following steps:

• When assessing patients with SARS-CoV-2 infection and elevated AST and ALT levels, the first objective is to rule out etiologies unrelated to COVID-19, specifically other viruses and drug-induced injury, as well as nonhepatic causes (e.g., myositis, cardiac injury, ischemia).
• Reduction in immunosuppression in SARS-CoV-2–infected patients with AIH should be considered carefully and generally undertaken only in those with severe illness.
• Pretransplant SARS-CoV-2 vaccination is recommended for all liver transplant candidates and liver transplant recipients as well as their household members and caregivers, to reduce exposure for these patients, along with continued adherence to protective measures (masking and social distancing).
• Continuation of a stable posttransplant immunosuppression regimen at the time of vaccination is recommended to avoid the risk for organ rejection until more comprehensive data are available.

For updated responses to the evolving guidelines, visit the AASLD’s resource center.
 

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, pediatric liver care center; medical director emeritus, liver transplantation; and professor, University of Cincinnati College of Medicine, department of pediatrics, Cincinnati Children’s Hospital Medical Center. He has served as director of the division of gastroenterology, hepatology and nutrition at Cincinnati Children’s for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for this news organization. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. He has disclosed no relevant financial relationships.

References

1. Bloom PB et al. Hepatology. 2021 Mar;73:890-900.

2. Guan WJ et al. N Engl J Med. 2020 Apr;382:1708-20.

3. Chen N et al. Lancet. 2020 Feb;395:507-13.

4. Fan Z et al. Clin Gastroenterol Hepatol. 2020 Jun;18:1561-6.

5. Huang C et al. Lancet. 2020 Feb;395:497-506.

6. Xu L et al. Liver Int. 2020 May;40:998-1004.

7. Zhang C et al. Lancet Gastroenterol Hepatol. 2020 May;5:428-30.

8. Richardson S et al. JAMA. 2020 May;323:2052-9.

9. Phipps MM et al. Hepatology. 2020 Sep;72:807-17.

10. Ferm S et al. Clin Gastroenterol Hepatol. 2020 Sep;18:2378-9.

11. Hundt MA et al. Hepatology. 2020 Oct;72:1169-76.

12. Zhou YH et al. Pediatr Obes. 2020 Dec;15:e12723.

13. Kehar M et al. J Pediatr Gastroenterol Nutr. 2021 Jun;72:807-814.

14. Lu X et al. N Engl J Med. 2020 Apr;382:1663-5.

15. Cantor A et al. Hepatology. 2020 Nov;72:1522-7.

16. Kim D et al. Clin Gastroenterol Hepatol. 2021 Jul;19:1469-79.

17. Colmenero J et al. J Hepatol. 2021 Jan;74:148-155.

18. Lee BT et al. Gastroenterology. 2020 Sep;159:1176-8.e2.

19. Becchetti C et al. Gut. 2020 Oct;69:1832-40.

20. Belli LS et al. Lancet Gastroenterol Hepatol. 2020 Aug;5:724-5.

21. Bhoori S et al. Lancet Gastroenterol Hepatol. 2020 Jun;5:532-3.

22. Rabiee A et al; COLD Consortium. Hepatology. 2020 Dec;72:1900-11.

23. Belli LS et al. Gastroenterology. 2021 Mar;160:1151-63.e3.

24. Webb GJ et al. Lancet Gastroenterol Hepatol. 2020 Nov;5:1008-16.

25. Marjot T et al. J Hepatol. 2021 Mar;74:567-77.

A version of this article first appeared on Medscape.com.

With the number of pediatric infections with SARS-CoV-2 rising it is not surprising that children with persistent symptoms are beginning to accumulate. Who are these pediatric “long haulers” and do they differ from their adult counterparts? The answer is far from clear because the terms “long COVID” and “long hauler” are not well defined. But, I suspect we will find that they will be similar in most respects.

In a recent Guest Essay in the New York Times, two medical school professors attempt to inject some common sense into the long hauler phenomenon. (“The Truth About Long Covid is Complicated. Better Treatment Isn’t,” Adam Gaffney and Zackary Berger, The New York Times, Aug. 18, 2021).

The authors divide the patients with long COVID into three categories. The first includes those who are complaining of persistent cough and fatigue for up to 3 months, a not unexpected course for patients recovering from a significant respiratory illness like pneumonia.

The second group comprises patients who developed acute respiratory distress syndrome during the course of their SARS-CoV-2 infection. These unfortunate individuals likely incurred lung damage that may have triggered renal damage and delirium and may never regain full function.

The third group of patients reports a wide variety of less specific symptoms including, but not limited to, severe fatigue, brain fog, shortness of breath, gastrointestinal symptoms, chronic pain, and palpitations.

The authors of the essay refer to several studies in which there was little if any correlation between these patients’ complaints and their antibody levels. In fact, one study of adolescents found that in a group with similar symptoms many of the individuals had no serologic evidence of SARS-CoV-2 infection.

Unfortunately, the lay public, the media, and some physicians make no distinction between these three groups and lump them all under the same long COVID umbrella. The resulting confusion seeds unwarranted anxiety among the first and third groups and may prevent some individuals from receiving the appropriate attention they deserve.

I suspect that like me, many of you see some similarities between this third group of long COVID patients and adolescents whose persistent symptoms don’t quite fit with their primary illness. Patients labeled as having post-concussion syndrome or “chronic Lyme disease” come immediately to mind. In both conditions, many of the patients had little if any evidence of severe insult from the initial event but continue to complain about a variety of symptoms including severe fatigue and brain fog.

We have done a very poor job of properly managing these patients. And there are a lot of them. A large part of the problem is labeling. In the old days one might have said these patients were having “psychosomatic” symptoms. But, while it may be an accurate description, like the term “retardation” it has been permanently tarnished. Fortunately, most of us are smart enough to avoid telling these patients that it is all in their heads.

However, convincing an individual that many of his symptoms may be the result of the psychological insult from the original disease compounded by other stresses and lifestyle factors can be a difficult sell. The task is made particularly difficult when there continue to be physicians who will miss or ignore the obvious and embark on therapeutic endeavors that are not only ineffective but can serve as a distraction from the real work of listening to and engaging these patients whose suffering may be just as real as that of those long haulers with structural damage.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

With the number of pediatric infections with SARS-CoV-2 rising it is not surprising that children with persistent symptoms are beginning to accumulate. Who are these pediatric “long haulers” and do they differ from their adult counterparts? The answer is far from clear because the terms “long COVID” and “long hauler” are not well defined. But, I suspect we will find that they will be similar in most respects.

In a recent Guest Essay in the New York Times, two medical school professors attempt to inject some common sense into the long hauler phenomenon. (“The Truth About Long Covid is Complicated. Better Treatment Isn’t,” Adam Gaffney and Zackary Berger, The New York Times, Aug. 18, 2021).

The authors divide the patients with long COVID into three categories. The first includes those who are complaining of persistent cough and fatigue for up to 3 months, a not unexpected course for patients recovering from a significant respiratory illness like pneumonia.

The second group comprises patients who developed acute respiratory distress syndrome during the course of their SARS-CoV-2 infection. These unfortunate individuals likely incurred lung damage that may have triggered renal damage and delirium and may never regain full function.

The third group of patients reports a wide variety of less specific symptoms including, but not limited to, severe fatigue, brain fog, shortness of breath, gastrointestinal symptoms, chronic pain, and palpitations.

The authors of the essay refer to several studies in which there was little if any correlation between these patients’ complaints and their antibody levels. In fact, one study of adolescents found that in a group with similar symptoms many of the individuals had no serologic evidence of SARS-CoV-2 infection.

Unfortunately, the lay public, the media, and some physicians make no distinction between these three groups and lump them all under the same long COVID umbrella. The resulting confusion seeds unwarranted anxiety among the first and third groups and may prevent some individuals from receiving the appropriate attention they deserve.

I suspect that like me, many of you see some similarities between this third group of long COVID patients and adolescents whose persistent symptoms don’t quite fit with their primary illness. Patients labeled as having post-concussion syndrome or “chronic Lyme disease” come immediately to mind. In both conditions, many of the patients had little if any evidence of severe insult from the initial event but continue to complain about a variety of symptoms including severe fatigue and brain fog.

We have done a very poor job of properly managing these patients. And there are a lot of them. A large part of the problem is labeling. In the old days one might have said these patients were having “psychosomatic” symptoms. But, while it may be an accurate description, like the term “retardation” it has been permanently tarnished. Fortunately, most of us are smart enough to avoid telling these patients that it is all in their heads.

However, convincing an individual that many of his symptoms may be the result of the psychological insult from the original disease compounded by other stresses and lifestyle factors can be a difficult sell. The task is made particularly difficult when there continue to be physicians who will miss or ignore the obvious and embark on therapeutic endeavors that are not only ineffective but can serve as a distraction from the real work of listening to and engaging these patients whose suffering may be just as real as that of those long haulers with structural damage.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

With the number of pediatric infections with SARS-CoV-2 rising it is not surprising that children with persistent symptoms are beginning to accumulate. Who are these pediatric “long haulers” and do they differ from their adult counterparts? The answer is far from clear because the terms “long COVID” and “long hauler” are not well defined. But, I suspect we will find that they will be similar in most respects.

In a recent Guest Essay in the New York Times, two medical school professors attempt to inject some common sense into the long hauler phenomenon. (“The Truth About Long Covid is Complicated. Better Treatment Isn’t,” Adam Gaffney and Zackary Berger, The New York Times, Aug. 18, 2021).

The authors divide the patients with long COVID into three categories. The first includes those who are complaining of persistent cough and fatigue for up to 3 months, a not unexpected course for patients recovering from a significant respiratory illness like pneumonia.

The second group comprises patients who developed acute respiratory distress syndrome during the course of their SARS-CoV-2 infection. These unfortunate individuals likely incurred lung damage that may have triggered renal damage and delirium and may never regain full function.

The third group of patients reports a wide variety of less specific symptoms including, but not limited to, severe fatigue, brain fog, shortness of breath, gastrointestinal symptoms, chronic pain, and palpitations.

The authors of the essay refer to several studies in which there was little if any correlation between these patients’ complaints and their antibody levels. In fact, one study of adolescents found that in a group with similar symptoms many of the individuals had no serologic evidence of SARS-CoV-2 infection.

Unfortunately, the lay public, the media, and some physicians make no distinction between these three groups and lump them all under the same long COVID umbrella. The resulting confusion seeds unwarranted anxiety among the first and third groups and may prevent some individuals from receiving the appropriate attention they deserve.

I suspect that like me, many of you see some similarities between this third group of long COVID patients and adolescents whose persistent symptoms don’t quite fit with their primary illness. Patients labeled as having post-concussion syndrome or “chronic Lyme disease” come immediately to mind. In both conditions, many of the patients had little if any evidence of severe insult from the initial event but continue to complain about a variety of symptoms including severe fatigue and brain fog.

We have done a very poor job of properly managing these patients. And there are a lot of them. A large part of the problem is labeling. In the old days one might have said these patients were having “psychosomatic” symptoms. But, while it may be an accurate description, like the term “retardation” it has been permanently tarnished. Fortunately, most of us are smart enough to avoid telling these patients that it is all in their heads.

However, convincing an individual that many of his symptoms may be the result of the psychological insult from the original disease compounded by other stresses and lifestyle factors can be a difficult sell. The task is made particularly difficult when there continue to be physicians who will miss or ignore the obvious and embark on therapeutic endeavors that are not only ineffective but can serve as a distraction from the real work of listening to and engaging these patients whose suffering may be just as real as that of those long haulers with structural damage.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

Not sure if you’ve heard the news, but eating a single hot dog will apparently cost you 36 minutes of healthy life. My first thought when hearing this was of course the same as everyone else’s: Poor Joey Chestnut, multiyear winner of Nathan’s annual hot dog–eating contest.

He won this year’s contest with 76 hot dogs, which puts his total number of competition-consumed hot dogs at 1,089 – which cost him, it would seem, 27.2 days of healthy life. Unless, of course, every hot dog he inhaled came with a bun hosting two portions of sesame seeds, which in turn would buy him 50 extra minutes of life (25 minutes per portion, you see) and would consequently have extended his life by 10.6 days.

Clearly, the obvious solution here is to ensure that all hot dog buns have two portions of sesame seeds on them moving forward; that way, hot dogs can transition from being poisonous killers to antiaging medicine.

The other solution, albeit less exciting, perhaps, is for researchers to stop studying single foods’ impacts on health, and/or for journals to stop publishing them, and/or for the media to stop promoting them – because they are all as ridiculously useless as the example above highlighting findings from a newly published study in Nature Food, entitled “Small targeted dietary changes can yield substantial gains for human health and the environment.”

While no doubt we would all love for diet and health to be so well understood that we could choose specific single foods (knowing that they would prolong our lives) while avoiding single foods that would shorten it, there’s this unfortunate truth that the degree of confounding among food alone is staggering. People eat thousands of different foods in thousands of different dietary combinations. Moreover, most (all?) research conducted on dietary impacts of single foods on health don’t actually track consumption of those specific foods over time, let alone their interactions with all other foods consumed, but rather at moments in time.

In the case of the “hot dogs will kill you unless there are sesame seeds on your bun” article, for example, the researchers utilized one solitary dietary recall session upon which to base their ridiculously specific, ridiculous conclusions.

People’s diets also change over time for various reasons, and of course people themselves are very different. You might imagine that people whose diets are rich in chicken wings, sugared soda, and hot dogs will have markedly different lifestyles and demographics than those whose diets are rich in walnuts, sashimi, and avocados.

So why do we keep seeing studies like this being published? Is it because they’re basically clickbait catnip for journals and newspapers, and in our publish-or-perish attention-seeking world, that means they not only get a pass but they get a press release? Is it because peer review is broken and everyone knows it? Is it because as a society, we’re frogs who have been steeping for decades in the ever-heated pot of nutritional nonsense, and consequently don’t think to question it?

I don’t know the answer to any of those questions, but one thing I do know: Studies on single foods’ impact on life length are pointless, impossible, and idiotic, and people who share them noncritically should be forever shunned – or at the very least, forever ignored.

Yoni Freedhoff, MD, is an associate professor of family medicine at the University of Ottawa and medical director of the Bariatric Medical Institute, a nonsurgical weight-management center.

A version of this article first appeared on Medscape.com.

Not sure if you’ve heard the news, but eating a single hot dog will apparently cost you 36 minutes of healthy life. My first thought when hearing this was of course the same as everyone else’s: Poor Joey Chestnut, multiyear winner of Nathan’s annual hot dog–eating contest.

He won this year’s contest with 76 hot dogs, which puts his total number of competition-consumed hot dogs at 1,089 – which cost him, it would seem, 27.2 days of healthy life. Unless, of course, every hot dog he inhaled came with a bun hosting two portions of sesame seeds, which in turn would buy him 50 extra minutes of life (25 minutes per portion, you see) and would consequently have extended his life by 10.6 days.

Clearly, the obvious solution here is to ensure that all hot dog buns have two portions of sesame seeds on them moving forward; that way, hot dogs can transition from being poisonous killers to antiaging medicine.

The other solution, albeit less exciting, perhaps, is for researchers to stop studying single foods’ impacts on health, and/or for journals to stop publishing them, and/or for the media to stop promoting them – because they are all as ridiculously useless as the example above highlighting findings from a newly published study in Nature Food, entitled “Small targeted dietary changes can yield substantial gains for human health and the environment.”

While no doubt we would all love for diet and health to be so well understood that we could choose specific single foods (knowing that they would prolong our lives) while avoiding single foods that would shorten it, there’s this unfortunate truth that the degree of confounding among food alone is staggering. People eat thousands of different foods in thousands of different dietary combinations. Moreover, most (all?) research conducted on dietary impacts of single foods on health don’t actually track consumption of those specific foods over time, let alone their interactions with all other foods consumed, but rather at moments in time.

In the case of the “hot dogs will kill you unless there are sesame seeds on your bun” article, for example, the researchers utilized one solitary dietary recall session upon which to base their ridiculously specific, ridiculous conclusions.

People’s diets also change over time for various reasons, and of course people themselves are very different. You might imagine that people whose diets are rich in chicken wings, sugared soda, and hot dogs will have markedly different lifestyles and demographics than those whose diets are rich in walnuts, sashimi, and avocados.

So why do we keep seeing studies like this being published? Is it because they’re basically clickbait catnip for journals and newspapers, and in our publish-or-perish attention-seeking world, that means they not only get a pass but they get a press release? Is it because peer review is broken and everyone knows it? Is it because as a society, we’re frogs who have been steeping for decades in the ever-heated pot of nutritional nonsense, and consequently don’t think to question it?

I don’t know the answer to any of those questions, but one thing I do know: Studies on single foods’ impact on life length are pointless, impossible, and idiotic, and people who share them noncritically should be forever shunned – or at the very least, forever ignored.

Yoni Freedhoff, MD, is an associate professor of family medicine at the University of Ottawa and medical director of the Bariatric Medical Institute, a nonsurgical weight-management center.

A version of this article first appeared on Medscape.com.

Not sure if you’ve heard the news, but eating a single hot dog will apparently cost you 36 minutes of healthy life. My first thought when hearing this was of course the same as everyone else’s: Poor Joey Chestnut, multiyear winner of Nathan’s annual hot dog–eating contest.

He won this year’s contest with 76 hot dogs, which puts his total number of competition-consumed hot dogs at 1,089 – which cost him, it would seem, 27.2 days of healthy life. Unless, of course, every hot dog he inhaled came with a bun hosting two portions of sesame seeds, which in turn would buy him 50 extra minutes of life (25 minutes per portion, you see) and would consequently have extended his life by 10.6 days.

Clearly, the obvious solution here is to ensure that all hot dog buns have two portions of sesame seeds on them moving forward; that way, hot dogs can transition from being poisonous killers to antiaging medicine.

The other solution, albeit less exciting, perhaps, is for researchers to stop studying single foods’ impacts on health, and/or for journals to stop publishing them, and/or for the media to stop promoting them – because they are all as ridiculously useless as the example above highlighting findings from a newly published study in Nature Food, entitled “Small targeted dietary changes can yield substantial gains for human health and the environment.”

While no doubt we would all love for diet and health to be so well understood that we could choose specific single foods (knowing that they would prolong our lives) while avoiding single foods that would shorten it, there’s this unfortunate truth that the degree of confounding among food alone is staggering. People eat thousands of different foods in thousands of different dietary combinations. Moreover, most (all?) research conducted on dietary impacts of single foods on health don’t actually track consumption of those specific foods over time, let alone their interactions with all other foods consumed, but rather at moments in time.

In the case of the “hot dogs will kill you unless there are sesame seeds on your bun” article, for example, the researchers utilized one solitary dietary recall session upon which to base their ridiculously specific, ridiculous conclusions.

People’s diets also change over time for various reasons, and of course people themselves are very different. You might imagine that people whose diets are rich in chicken wings, sugared soda, and hot dogs will have markedly different lifestyles and demographics than those whose diets are rich in walnuts, sashimi, and avocados.

So why do we keep seeing studies like this being published? Is it because they’re basically clickbait catnip for journals and newspapers, and in our publish-or-perish attention-seeking world, that means they not only get a pass but they get a press release? Is it because peer review is broken and everyone knows it? Is it because as a society, we’re frogs who have been steeping for decades in the ever-heated pot of nutritional nonsense, and consequently don’t think to question it?

I don’t know the answer to any of those questions, but one thing I do know: Studies on single foods’ impact on life length are pointless, impossible, and idiotic, and people who share them noncritically should be forever shunned – or at the very least, forever ignored.

Yoni Freedhoff, MD, is an associate professor of family medicine at the University of Ottawa and medical director of the Bariatric Medical Institute, a nonsurgical weight-management center.

A version of this article first appeared on Medscape.com.

The diagnosis of bipolar II disorder is one of the most common challenges in psychiatric practice. Bipolar II disorder is frequently misdiagnosed as major depressive disorder (MDD) because symptoms of transient hypomanic episodes are either insufficiently probed or are rather vague. However, there are many valuable biographical clues that can expedite the diagnosis of bipolar II disorder.

The late Hagop S. Akiskal, MD, who passed away in January 2021, was an internationally recognized expert in mood disorders, and a dear friend for decades. He was a keen observer of human behavior who delved into the “life stories” of patients seeking help for depression. By thinking “outside the DSM box,” Dr. Akiskal was the first to recognize and codify a variety of behavioral and biographical clues for the bipolar spectrum (of which he was a pioneer) in patients presenting with a chief complaint of depression. He proposed a colorful set of behavioral stigmata in most patients with bipolar II disorder by carefully canvassing the life experiences of the patients he treated in the mood disorder clinic he established in the 1970s, which is believed to have been the first mood specialty clinic in the country.

Based on a review of >1,000 patients in his clinic who presented with depressive symptoms and were ultimately diagnosed as bipolar II disorder, Dr. Akiskal highlighted what he labeled as “behavioral activation, flamboyance and extravagance” among those patients. He referred to the cluster of those behaviors as “the soft spectrum” of bipolar disorder, which manifests in a set of distinctive behaviors in addition to depressive symptoms. He found that research tools such as the DSM-based Structured Clinical Interview often fail and frequently lead to a misdiagnosis of bipolar II disorder as MDD. This often condemns the patient to multiple failed trials of antidepressant monotherapy, and a delay in improvement, thus increasing the risk of job loss, disrupted relationships, and even suicide.

Over 3 decades, Dr. Akiskal developed the Mood Clinic Data Questionnaire (MCDQ) to systematize unstructured observations of patients presenting with a chief complaint of depression. His tool expedites the diagnosis of bipolar II disorder by understanding the patient as an individual, revealing personal and behavioral features consistent with what he labeled as episodic “hyperthymia” within the context of recurrent depression. This “social and behavioral phenotype,” as Dr. Akiskal called it, is rarely observed among patients with MDD.

By examining many patients with bipolar II disorder, Dr. Akiskal identified several “triads” of behavioral traits in the patients’ biographical history and in some of their close blood relatives as well. He also noticed that temperamentally, patients with bipolar II disorder thrive on “activity” and lovingly referred to themselves as “activity junkies.” Some of them may qualify as workaholics.

Biographical features that suggest bipolar II disorder

Here is a summary of the unique biographical features of patients with bipolar II disorder that Dr. Akiskal described:

Multilingual. Speaking ≥3 languages is unusual among individuals born in the United States, but often encountered among those with bipolar II disorder.

Continue to: Eminence

Eminence. Patients with bipolar II disorder, as well as their family members, tend to have leadership roles and prominence in journalism, media, and entertainment, fields that require interpersonal charm and eloquence. Those are common features of the “hyperthymic” temperament.

Creativity. Artists, poets, painters, and musicians who experience depression are more likely to have bipolar II disorder than MDD.

Biographical instability and/or excess. This is exemplified by going to 3 colleges and not necessarily obtaining a degree, or by frequently changing one’s line of work or city of residence. A classic example is a professor of medicine who also practices law and regularly sings in the opera, or a physician who is board-certified in 3 distinct specialties.

Activity junkies. Examples include a person with boundless energy, such as a novelist who writes 3 books a year or a professional who regularly works 12 hours a day without getting exhausted but seeks treatment for depressive episodes.

Multiple substances of abuse, such as nicotine, alcohol, stimulants, and opiates.

Continue to: Multiple psychiatric comorbidities

Multiple psychiatric comorbidities, such as having 3 types of anxiety (panic attacks, social phobia, and obsessive-compulsive disorder) or bulimia, seasonal depression, and anxiety.

Multiple pleasure-seeking or “outrageous” behaviors, such as compulsive gambling, sexual addiction, car racing, or skydiving. Another example is having a history of shoplifting, paraphilia, or arrest for participating in a riot, all of which are suggestive of antisocial traits in a patient seeking help for depression.

Sexual excesses, such as dating or having sex with ≥3 individuals concurrently, sometimes on the same day, or demanding sexual intercourse from a partner several times a day. Dr. Akiskal suggested that “sexual prowess” may represent an evolutionary advantage for the perpetuation of bipolar II disorder.

Marital history, such as a history of ≥3 marriages, or maintaining ≥2 families in different cities without being married.

Flamboyance and/or ornamentation. Examples might include wearing loud, colorful clothing (especially red), wearing ≥3 rings, or having piercings in ≥3 different body parts (tongue, nipples, navel, genitalia). Having elaborate tattoos across the body is no longer unique to “hyperthymic” persons with bipolar II disorder because tattoos have become far more common in the general population than they were in the 1970s. However, some take their tattoos to extremes.

Continue to: The above behaviors...

The above behaviors are condensed in a list that Dr. Akiskal called “the rule of 3” in patients with depression (Table¹). Not all patients with bipolar II disorder will meet all the criteria of the rule of 3, but the first item in the mental status exam (appearance) alone may reflect the “soft bipolar spectrum,” such as garish clothing, red sneakers, multiple rings, bizarre hair coloring, and multiple piercings. This might prompt the clinician to ask further questions about hypomanic episodes as well as other personal behaviors related to the rule of 3.

Dr. Akiskal’s contributions to psychiatry are legendary in their originality, creativity, and clinical relevance. The rule of 3 is but one of his clinical concepts that may help identify many individuals with bipolar II disorder who are misdiagnosed as having MDD and prescribed a treatment that does not help or may exacerbate their illness course and worsen their outcome.

Based on the referrals of patients who are “treatment-resistant” to our Resident Mood Clinic, there are numerous persons in the country with bipolar II disorder (possibly millions) who are mislabeled with MDD and receiving the wrong treatments, to which they failed to respond. Their lifestyles and behaviors can provide valuable clinical insights into their true psychopathology, and that will lead to developing the right treatment plan.

The diagnosis of bipolar II disorder is one of the most common challenges in psychiatric practice. Bipolar II disorder is frequently misdiagnosed as major depressive disorder (MDD) because symptoms of transient hypomanic episodes are either insufficiently probed or are rather vague. However, there are many valuable biographical clues that can expedite the diagnosis of bipolar II disorder.

The late Hagop S. Akiskal, MD, who passed away in January 2021, was an internationally recognized expert in mood disorders, and a dear friend for decades. He was a keen observer of human behavior who delved into the “life stories” of patients seeking help for depression. By thinking “outside the DSM box,” Dr. Akiskal was the first to recognize and codify a variety of behavioral and biographical clues for the bipolar spectrum (of which he was a pioneer) in patients presenting with a chief complaint of depression. He proposed a colorful set of behavioral stigmata in most patients with bipolar II disorder by carefully canvassing the life experiences of the patients he treated in the mood disorder clinic he established in the 1970s, which is believed to have been the first mood specialty clinic in the country.

Based on a review of >1,000 patients in his clinic who presented with depressive symptoms and were ultimately diagnosed as bipolar II disorder, Dr. Akiskal highlighted what he labeled as “behavioral activation, flamboyance and extravagance” among those patients. He referred to the cluster of those behaviors as “the soft spectrum” of bipolar disorder, which manifests in a set of distinctive behaviors in addition to depressive symptoms. He found that research tools such as the DSM-based Structured Clinical Interview often fail and frequently lead to a misdiagnosis of bipolar II disorder as MDD. This often condemns the patient to multiple failed trials of antidepressant monotherapy, and a delay in improvement, thus increasing the risk of job loss, disrupted relationships, and even suicide.

Over 3 decades, Dr. Akiskal developed the Mood Clinic Data Questionnaire (MCDQ) to systematize unstructured observations of patients presenting with a chief complaint of depression. His tool expedites the diagnosis of bipolar II disorder by understanding the patient as an individual, revealing personal and behavioral features consistent with what he labeled as episodic “hyperthymia” within the context of recurrent depression. This “social and behavioral phenotype,” as Dr. Akiskal called it, is rarely observed among patients with MDD.

By examining many patients with bipolar II disorder, Dr. Akiskal identified several “triads” of behavioral traits in the patients’ biographical history and in some of their close blood relatives as well. He also noticed that temperamentally, patients with bipolar II disorder thrive on “activity” and lovingly referred to themselves as “activity junkies.” Some of them may qualify as workaholics.

Biographical features that suggest bipolar II disorder

Here is a summary of the unique biographical features of patients with bipolar II disorder that Dr. Akiskal described:

Multilingual. Speaking ≥3 languages is unusual among individuals born in the United States, but often encountered among those with bipolar II disorder.

Continue to: Eminence

Eminence. Patients with bipolar II disorder, as well as their family members, tend to have leadership roles and prominence in journalism, media, and entertainment, fields that require interpersonal charm and eloquence. Those are common features of the “hyperthymic” temperament.

Creativity. Artists, poets, painters, and musicians who experience depression are more likely to have bipolar II disorder than MDD.

Biographical instability and/or excess. This is exemplified by going to 3 colleges and not necessarily obtaining a degree, or by frequently changing one’s line of work or city of residence. A classic example is a professor of medicine who also practices law and regularly sings in the opera, or a physician who is board-certified in 3 distinct specialties.

Activity junkies. Examples include a person with boundless energy, such as a novelist who writes 3 books a year or a professional who regularly works 12 hours a day without getting exhausted but seeks treatment for depressive episodes.

Multiple substances of abuse, such as nicotine, alcohol, stimulants, and opiates.

Continue to: Multiple psychiatric comorbidities

Multiple psychiatric comorbidities, such as having 3 types of anxiety (panic attacks, social phobia, and obsessive-compulsive disorder) or bulimia, seasonal depression, and anxiety.

Multiple pleasure-seeking or “outrageous” behaviors, such as compulsive gambling, sexual addiction, car racing, or skydiving. Another example is having a history of shoplifting, paraphilia, or arrest for participating in a riot, all of which are suggestive of antisocial traits in a patient seeking help for depression.

Sexual excesses, such as dating or having sex with ≥3 individuals concurrently, sometimes on the same day, or demanding sexual intercourse from a partner several times a day. Dr. Akiskal suggested that “sexual prowess” may represent an evolutionary advantage for the perpetuation of bipolar II disorder.

Marital history, such as a history of ≥3 marriages, or maintaining ≥2 families in different cities without being married.

Flamboyance and/or ornamentation. Examples might include wearing loud, colorful clothing (especially red), wearing ≥3 rings, or having piercings in ≥3 different body parts (tongue, nipples, navel, genitalia). Having elaborate tattoos across the body is no longer unique to “hyperthymic” persons with bipolar II disorder because tattoos have become far more common in the general population than they were in the 1970s. However, some take their tattoos to extremes.

Continue to: The above behaviors...

The above behaviors are condensed in a list that Dr. Akiskal called “the rule of 3” in patients with depression (Table¹). Not all patients with bipolar II disorder will meet all the criteria of the rule of 3, but the first item in the mental status exam (appearance) alone may reflect the “soft bipolar spectrum,” such as garish clothing, red sneakers, multiple rings, bizarre hair coloring, and multiple piercings. This might prompt the clinician to ask further questions about hypomanic episodes as well as other personal behaviors related to the rule of 3.

Dr. Akiskal’s contributions to psychiatry are legendary in their originality, creativity, and clinical relevance. The rule of 3 is but one of his clinical concepts that may help identify many individuals with bipolar II disorder who are misdiagnosed as having MDD and prescribed a treatment that does not help or may exacerbate their illness course and worsen their outcome.

Based on the referrals of patients who are “treatment-resistant” to our Resident Mood Clinic, there are numerous persons in the country with bipolar II disorder (possibly millions) who are mislabeled with MDD and receiving the wrong treatments, to which they failed to respond. Their lifestyles and behaviors can provide valuable clinical insights into their true psychopathology, and that will lead to developing the right treatment plan.

The diagnosis of bipolar II disorder is one of the most common challenges in psychiatric practice. Bipolar II disorder is frequently misdiagnosed as major depressive disorder (MDD) because symptoms of transient hypomanic episodes are either insufficiently probed or are rather vague. However, there are many valuable biographical clues that can expedite the diagnosis of bipolar II disorder.

The late Hagop S. Akiskal, MD, who passed away in January 2021, was an internationally recognized expert in mood disorders, and a dear friend for decades. He was a keen observer of human behavior who delved into the “life stories” of patients seeking help for depression. By thinking “outside the DSM box,” Dr. Akiskal was the first to recognize and codify a variety of behavioral and biographical clues for the bipolar spectrum (of which he was a pioneer) in patients presenting with a chief complaint of depression. He proposed a colorful set of behavioral stigmata in most patients with bipolar II disorder by carefully canvassing the life experiences of the patients he treated in the mood disorder clinic he established in the 1970s, which is believed to have been the first mood specialty clinic in the country.

Based on a review of >1,000 patients in his clinic who presented with depressive symptoms and were ultimately diagnosed as bipolar II disorder, Dr. Akiskal highlighted what he labeled as “behavioral activation, flamboyance and extravagance” among those patients. He referred to the cluster of those behaviors as “the soft spectrum” of bipolar disorder, which manifests in a set of distinctive behaviors in addition to depressive symptoms. He found that research tools such as the DSM-based Structured Clinical Interview often fail and frequently lead to a misdiagnosis of bipolar II disorder as MDD. This often condemns the patient to multiple failed trials of antidepressant monotherapy, and a delay in improvement, thus increasing the risk of job loss, disrupted relationships, and even suicide.

Over 3 decades, Dr. Akiskal developed the Mood Clinic Data Questionnaire (MCDQ) to systematize unstructured observations of patients presenting with a chief complaint of depression. His tool expedites the diagnosis of bipolar II disorder by understanding the patient as an individual, revealing personal and behavioral features consistent with what he labeled as episodic “hyperthymia” within the context of recurrent depression. This “social and behavioral phenotype,” as Dr. Akiskal called it, is rarely observed among patients with MDD.

By examining many patients with bipolar II disorder, Dr. Akiskal identified several “triads” of behavioral traits in the patients’ biographical history and in some of their close blood relatives as well. He also noticed that temperamentally, patients with bipolar II disorder thrive on “activity” and lovingly referred to themselves as “activity junkies.” Some of them may qualify as workaholics.

Biographical features that suggest bipolar II disorder

Here is a summary of the unique biographical features of patients with bipolar II disorder that Dr. Akiskal described:

Multilingual. Speaking ≥3 languages is unusual among individuals born in the United States, but often encountered among those with bipolar II disorder.

Continue to: Eminence

Eminence. Patients with bipolar II disorder, as well as their family members, tend to have leadership roles and prominence in journalism, media, and entertainment, fields that require interpersonal charm and eloquence. Those are common features of the “hyperthymic” temperament.

Creativity. Artists, poets, painters, and musicians who experience depression are more likely to have bipolar II disorder than MDD.

Biographical instability and/or excess. This is exemplified by going to 3 colleges and not necessarily obtaining a degree, or by frequently changing one’s line of work or city of residence. A classic example is a professor of medicine who also practices law and regularly sings in the opera, or a physician who is board-certified in 3 distinct specialties.

Activity junkies. Examples include a person with boundless energy, such as a novelist who writes 3 books a year or a professional who regularly works 12 hours a day without getting exhausted but seeks treatment for depressive episodes.

Multiple substances of abuse, such as nicotine, alcohol, stimulants, and opiates.

Continue to: Multiple psychiatric comorbidities

Multiple psychiatric comorbidities, such as having 3 types of anxiety (panic attacks, social phobia, and obsessive-compulsive disorder) or bulimia, seasonal depression, and anxiety.

Multiple pleasure-seeking or “outrageous” behaviors, such as compulsive gambling, sexual addiction, car racing, or skydiving. Another example is having a history of shoplifting, paraphilia, or arrest for participating in a riot, all of which are suggestive of antisocial traits in a patient seeking help for depression.

Sexual excesses, such as dating or having sex with ≥3 individuals concurrently, sometimes on the same day, or demanding sexual intercourse from a partner several times a day. Dr. Akiskal suggested that “sexual prowess” may represent an evolutionary advantage for the perpetuation of bipolar II disorder.

Marital history, such as a history of ≥3 marriages, or maintaining ≥2 families in different cities without being married.

Flamboyance and/or ornamentation. Examples might include wearing loud, colorful clothing (especially red), wearing ≥3 rings, or having piercings in ≥3 different body parts (tongue, nipples, navel, genitalia). Having elaborate tattoos across the body is no longer unique to “hyperthymic” persons with bipolar II disorder because tattoos have become far more common in the general population than they were in the 1970s. However, some take their tattoos to extremes.

Continue to: The above behaviors...

The above behaviors are condensed in a list that Dr. Akiskal called “the rule of 3” in patients with depression (Table¹). Not all patients with bipolar II disorder will meet all the criteria of the rule of 3, but the first item in the mental status exam (appearance) alone may reflect the “soft bipolar spectrum,” such as garish clothing, red sneakers, multiple rings, bizarre hair coloring, and multiple piercings. This might prompt the clinician to ask further questions about hypomanic episodes as well as other personal behaviors related to the rule of 3.

Dr. Akiskal’s contributions to psychiatry are legendary in their originality, creativity, and clinical relevance. The rule of 3 is but one of his clinical concepts that may help identify many individuals with bipolar II disorder who are misdiagnosed as having MDD and prescribed a treatment that does not help or may exacerbate their illness course and worsen their outcome.

Based on the referrals of patients who are “treatment-resistant” to our Resident Mood Clinic, there are numerous persons in the country with bipolar II disorder (possibly millions) who are mislabeled with MDD and receiving the wrong treatments, to which they failed to respond. Their lifestyles and behaviors can provide valuable clinical insights into their true psychopathology, and that will lead to developing the right treatment plan.

In the modern-day practice of medicine, turf wars are more common than one may realize. Presently, an ongoing battle over who should be prescribing and administering ketamine for novel treatment uses is being waged among psychiatrists, anesthesiologists, family physicians, and emergency physicians. Whoever emerges victorious will determine whether psychiatric care is administered in a safe and cost-effective manner, or if it will merely benefit the bottom line of the prescriber. In this article, we discuss how ketamine may have a role for treatment-resistant depression (TRD), and why psychiatrists are uniquely qualified to prescribe and administer this medication for this purpose.

New approaches to treatment-resistant depression

Antidepressant medications, long the mainstay of depression treatment, have been shown to be safe and relatively equally effective, with varying tolerability. However, 33% percent of patients do not achieve remission after 4 trials of antidepressant therapy.¹ Most antidepressant efficacy studies report remission rates of 35% to 40%,² which means many patients require subsequent switching and/or augmentation of their treatment.³ The STAR*D trial demonstrated that after 2 adequate antidepressant trials, the likelihood of remission diminishes.⁴

After a patient’s depression is found to be treatment-resistant, the onus of guiding treatment shifts away from the patient’s primary care physician to the more specialized psychiatrist. Few would question the suitability of a psychiatrist’s expertise in handling complicated and nuanced mental illness. In order to manage TRD, psychiatrists enter a terrain of emerging novel therapies with rapid onset, different mechanisms of action, and parenteral routes of administration.

One such therapy is esketamine, the S-enantiomer of ketamine. The FDA approved the intranasal (IN) formulation of esketamine in March 2019 after the medication had been designated as a breakthrough therapy for TRD in 2013 and studied in 6 Phase III clinical trials.⁵ The S-enantiomer of ketamine is known to bind to the N-methyl-D-aspartate receptor stronger than the R-enantiomer.⁶ The mechanism of action of both stereoisomers on other receptors, such as opioid and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), is the focus of intensive research and remains to be fully elucidated, but initial studies indicate rapid neuroplasticity and synaptogenesis.⁷ What is clear is that this new intervention can provide relief to patients with TRD via a pharmacologically distinct mechanism.⁸

Ketamine may be administered intranasally, intravenously, or orally. A meta-analysis aimed at assessing differences in ketamine efficacy for depression based on route of administration have shown that both IV and IN ketamine are effective, though it is not possible to draw conclusions regarding a direct comparison based on available data.⁹ Despite several landmark published studies, such as those by Zarate et al,¹⁰ IV ketamine is not FDA-approved for TRD.

Continue to: Why psychiatrists?

Psychiatrists have been prescribing IN esketamine, which is covered by most commercial insurances and administered in certified healthcare settings under a Risk Evaluation and Mitigation Strategy program.⁵ However, anesthesiologists and emergency physicians have opened a crop of boutique and concierge health clinics offering various “packages” of IV ketamine infusions for a slew of mental ailments, including depression, anxiety, bipolar disorder, and posttraumatic stress disorder.¹¹ Minimal investigation reveals that these services are being prescribed mainly by practitioners in fields other than psychiatry. Intravenous ketamine has long been used off-label as a treatment for depression not by psychiatrists but by practitioners of anesthesiology or emergency medicine. Although these clinicians are likely familiar with ketamine as an anesthetic, they have no foundation or expertise in the diagnosis and treatment of complex mood disorders. The FDA-approved indication for esketamine falls firmly in the realm of psychiatric treatment. Physicians who have not completed a psychiatry residency have neither the training nor experience necessary to determine whether a patient is a candidate for this treatment.

One potential adverse effect of ketamine is an emergence phenomenon, colloquially named a “K-hole,” that can induce symptoms of psychosis such as disturbing hallucinations. Patients who have a history of psychosis need to be carefully evaluated for appropriateness to receive this treatment.

Furthermore, ketamine treatments administered by physicians who are not psychiatrists are billed not through insurance but mostly via private pay. A patient may therefore be charged $350 to $1,000 per infusion, to be paid out of pocket.¹¹ Tally that up over the standard 6 to 12 initial treatment infusions, followed by maintenance infusions, and these patients with profound depression are potentially building up significant debt. Does this practice align with the ethical principles of autonomy, justice, beneficence, and nonmaleficence that all physicians swore to uphold? Will psychiatrists take a stand against the financial exploitation of a vulnerable group that is desperate to find any potential relief from their depression?

In the modern-day practice of medicine, turf wars are more common than one may realize. Presently, an ongoing battle over who should be prescribing and administering ketamine for novel treatment uses is being waged among psychiatrists, anesthesiologists, family physicians, and emergency physicians. Whoever emerges victorious will determine whether psychiatric care is administered in a safe and cost-effective manner, or if it will merely benefit the bottom line of the prescriber. In this article, we discuss how ketamine may have a role for treatment-resistant depression (TRD), and why psychiatrists are uniquely qualified to prescribe and administer this medication for this purpose.

New approaches to treatment-resistant depression

Antidepressant medications, long the mainstay of depression treatment, have been shown to be safe and relatively equally effective, with varying tolerability. However, 33% percent of patients do not achieve remission after 4 trials of antidepressant therapy.¹ Most antidepressant efficacy studies report remission rates of 35% to 40%,² which means many patients require subsequent switching and/or augmentation of their treatment.³ The STAR*D trial demonstrated that after 2 adequate antidepressant trials, the likelihood of remission diminishes.⁴

After a patient’s depression is found to be treatment-resistant, the onus of guiding treatment shifts away from the patient’s primary care physician to the more specialized psychiatrist. Few would question the suitability of a psychiatrist’s expertise in handling complicated and nuanced mental illness. In order to manage TRD, psychiatrists enter a terrain of emerging novel therapies with rapid onset, different mechanisms of action, and parenteral routes of administration.

One such therapy is esketamine, the S-enantiomer of ketamine. The FDA approved the intranasal (IN) formulation of esketamine in March 2019 after the medication had been designated as a breakthrough therapy for TRD in 2013 and studied in 6 Phase III clinical trials.⁵ The S-enantiomer of ketamine is known to bind to the N-methyl-D-aspartate receptor stronger than the R-enantiomer.⁶ The mechanism of action of both stereoisomers on other receptors, such as opioid and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), is the focus of intensive research and remains to be fully elucidated, but initial studies indicate rapid neuroplasticity and synaptogenesis.⁷ What is clear is that this new intervention can provide relief to patients with TRD via a pharmacologically distinct mechanism.⁸

Ketamine may be administered intranasally, intravenously, or orally. A meta-analysis aimed at assessing differences in ketamine efficacy for depression based on route of administration have shown that both IV and IN ketamine are effective, though it is not possible to draw conclusions regarding a direct comparison based on available data.⁹ Despite several landmark published studies, such as those by Zarate et al,¹⁰ IV ketamine is not FDA-approved for TRD.

Continue to: Why psychiatrists?

Psychiatrists have been prescribing IN esketamine, which is covered by most commercial insurances and administered in certified healthcare settings under a Risk Evaluation and Mitigation Strategy program.⁵ However, anesthesiologists and emergency physicians have opened a crop of boutique and concierge health clinics offering various “packages” of IV ketamine infusions for a slew of mental ailments, including depression, anxiety, bipolar disorder, and posttraumatic stress disorder.¹¹ Minimal investigation reveals that these services are being prescribed mainly by practitioners in fields other than psychiatry. Intravenous ketamine has long been used off-label as a treatment for depression not by psychiatrists but by practitioners of anesthesiology or emergency medicine. Although these clinicians are likely familiar with ketamine as an anesthetic, they have no foundation or expertise in the diagnosis and treatment of complex mood disorders. The FDA-approved indication for esketamine falls firmly in the realm of psychiatric treatment. Physicians who have not completed a psychiatry residency have neither the training nor experience necessary to determine whether a patient is a candidate for this treatment.

One potential adverse effect of ketamine is an emergence phenomenon, colloquially named a “K-hole,” that can induce symptoms of psychosis such as disturbing hallucinations. Patients who have a history of psychosis need to be carefully evaluated for appropriateness to receive this treatment.

Furthermore, ketamine treatments administered by physicians who are not psychiatrists are billed not through insurance but mostly via private pay. A patient may therefore be charged $350 to $1,000 per infusion, to be paid out of pocket.¹¹ Tally that up over the standard 6 to 12 initial treatment infusions, followed by maintenance infusions, and these patients with profound depression are potentially building up significant debt. Does this practice align with the ethical principles of autonomy, justice, beneficence, and nonmaleficence that all physicians swore to uphold? Will psychiatrists take a stand against the financial exploitation of a vulnerable group that is desperate to find any potential relief from their depression?

In the modern-day practice of medicine, turf wars are more common than one may realize. Presently, an ongoing battle over who should be prescribing and administering ketamine for novel treatment uses is being waged among psychiatrists, anesthesiologists, family physicians, and emergency physicians. Whoever emerges victorious will determine whether psychiatric care is administered in a safe and cost-effective manner, or if it will merely benefit the bottom line of the prescriber. In this article, we discuss how ketamine may have a role for treatment-resistant depression (TRD), and why psychiatrists are uniquely qualified to prescribe and administer this medication for this purpose.

New approaches to treatment-resistant depression

Antidepressant medications, long the mainstay of depression treatment, have been shown to be safe and relatively equally effective, with varying tolerability. However, 33% percent of patients do not achieve remission after 4 trials of antidepressant therapy.¹ Most antidepressant efficacy studies report remission rates of 35% to 40%,² which means many patients require subsequent switching and/or augmentation of their treatment.³ The STAR*D trial demonstrated that after 2 adequate antidepressant trials, the likelihood of remission diminishes.⁴

After a patient’s depression is found to be treatment-resistant, the onus of guiding treatment shifts away from the patient’s primary care physician to the more specialized psychiatrist. Few would question the suitability of a psychiatrist’s expertise in handling complicated and nuanced mental illness. In order to manage TRD, psychiatrists enter a terrain of emerging novel therapies with rapid onset, different mechanisms of action, and parenteral routes of administration.

One such therapy is esketamine, the S-enantiomer of ketamine. The FDA approved the intranasal (IN) formulation of esketamine in March 2019 after the medication had been designated as a breakthrough therapy for TRD in 2013 and studied in 6 Phase III clinical trials.⁵ The S-enantiomer of ketamine is known to bind to the N-methyl-D-aspartate receptor stronger than the R-enantiomer.⁶ The mechanism of action of both stereoisomers on other receptors, such as opioid and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), is the focus of intensive research and remains to be fully elucidated, but initial studies indicate rapid neuroplasticity and synaptogenesis.⁷ What is clear is that this new intervention can provide relief to patients with TRD via a pharmacologically distinct mechanism.⁸

Ketamine may be administered intranasally, intravenously, or orally. A meta-analysis aimed at assessing differences in ketamine efficacy for depression based on route of administration have shown that both IV and IN ketamine are effective, though it is not possible to draw conclusions regarding a direct comparison based on available data.⁹ Despite several landmark published studies, such as those by Zarate et al,¹⁰ IV ketamine is not FDA-approved for TRD.

Continue to: Why psychiatrists?

Psychiatrists have been prescribing IN esketamine, which is covered by most commercial insurances and administered in certified healthcare settings under a Risk Evaluation and Mitigation Strategy program.⁵ However, anesthesiologists and emergency physicians have opened a crop of boutique and concierge health clinics offering various “packages” of IV ketamine infusions for a slew of mental ailments, including depression, anxiety, bipolar disorder, and posttraumatic stress disorder.¹¹ Minimal investigation reveals that these services are being prescribed mainly by practitioners in fields other than psychiatry. Intravenous ketamine has long been used off-label as a treatment for depression not by psychiatrists but by practitioners of anesthesiology or emergency medicine. Although these clinicians are likely familiar with ketamine as an anesthetic, they have no foundation or expertise in the diagnosis and treatment of complex mood disorders. The FDA-approved indication for esketamine falls firmly in the realm of psychiatric treatment. Physicians who have not completed a psychiatry residency have neither the training nor experience necessary to determine whether a patient is a candidate for this treatment.

One potential adverse effect of ketamine is an emergence phenomenon, colloquially named a “K-hole,” that can induce symptoms of psychosis such as disturbing hallucinations. Patients who have a history of psychosis need to be carefully evaluated for appropriateness to receive this treatment.

Furthermore, ketamine treatments administered by physicians who are not psychiatrists are billed not through insurance but mostly via private pay. A patient may therefore be charged $350 to $1,000 per infusion, to be paid out of pocket.¹¹ Tally that up over the standard 6 to 12 initial treatment infusions, followed by maintenance infusions, and these patients with profound depression are potentially building up significant debt. Does this practice align with the ethical principles of autonomy, justice, beneficence, and nonmaleficence that all physicians swore to uphold? Will psychiatrists take a stand against the financial exploitation of a vulnerable group that is desperate to find any potential relief from their depression?