Key clinical point: Genetic liability to rheumatoid arthritis (RA) was positively associated with the risk for coronary artery disease (CAD) and intracerebral hemorrhage (IA), with the high levels of C-reactive protein (CRP) appearing to mediate the association with CAD.

Major finding: Each unit increase in log odds of RA increased the risk for CAD (combined odds ratio [cOR] 1.02; P = .003) and IA (cOR 1.05; P = .001), with the levels of genetically predicted CRP influencing the risk association between RA and CAD (adjusted cOR 1.01; P = .268).

Study details: This was a two-sample Mendelian randomization study that selected 70 single nucleotide polymorphisms strongly associated with RA from a genome-wide association meta-analysis including 14,361 patients with RA and 43,923 control individuals.

Disclosures: The study was supported by research grants from Swedish Heart-Lung Foundation, the Swedish Research Council for Health, and others. The authors declared no conflicts of interest.

Source: Yuan S et al. Genetic liability to rheumatoid arthritis in relation to coronary artery disease and stroke risk. Arthritis Rheumatol. 2022 (May 18). Doi: 10.1002/art.42239

Key clinical point: Genetic liability to rheumatoid arthritis (RA) was positively associated with the risk for coronary artery disease (CAD) and intracerebral hemorrhage (IA), with the high levels of C-reactive protein (CRP) appearing to mediate the association with CAD.

Major finding: Each unit increase in log odds of RA increased the risk for CAD (combined odds ratio [cOR] 1.02; P = .003) and IA (cOR 1.05; P = .001), with the levels of genetically predicted CRP influencing the risk association between RA and CAD (adjusted cOR 1.01; P = .268).

Study details: This was a two-sample Mendelian randomization study that selected 70 single nucleotide polymorphisms strongly associated with RA from a genome-wide association meta-analysis including 14,361 patients with RA and 43,923 control individuals.

Disclosures: The study was supported by research grants from Swedish Heart-Lung Foundation, the Swedish Research Council for Health, and others. The authors declared no conflicts of interest.

Source: Yuan S et al. Genetic liability to rheumatoid arthritis in relation to coronary artery disease and stroke risk. Arthritis Rheumatol. 2022 (May 18). Doi: 10.1002/art.42239

Key clinical point: Genetic liability to rheumatoid arthritis (RA) was positively associated with the risk for coronary artery disease (CAD) and intracerebral hemorrhage (IA), with the high levels of C-reactive protein (CRP) appearing to mediate the association with CAD.

Major finding: Each unit increase in log odds of RA increased the risk for CAD (combined odds ratio [cOR] 1.02; P = .003) and IA (cOR 1.05; P = .001), with the levels of genetically predicted CRP influencing the risk association between RA and CAD (adjusted cOR 1.01; P = .268).

Study details: This was a two-sample Mendelian randomization study that selected 70 single nucleotide polymorphisms strongly associated with RA from a genome-wide association meta-analysis including 14,361 patients with RA and 43,923 control individuals.

Disclosures: The study was supported by research grants from Swedish Heart-Lung Foundation, the Swedish Research Council for Health, and others. The authors declared no conflicts of interest.

Source: Yuan S et al. Genetic liability to rheumatoid arthritis in relation to coronary artery disease and stroke risk. Arthritis Rheumatol. 2022 (May 18). Doi: 10.1002/art.42239

Key clinical point: This real-world study found no evidence of increased risk for malignancy in patients with rheumatoid arthritis (RA) who initiated tofacitinib vs. tumor necrosis factor inhibitors (TNFi).

Major finding: The risk for cumulative malignancies in patients who initiated tofacitinib vs. TNFi was not higher in the real-world evidence (RWE) cohort (pooled weighted hazard ratio [pwHR] 1.01; 95% CI 0.83-1.22), but was numerically higher in the randomized controlled trial (RCT)-duplicate cohort of patients aged ≥50 years with at least one cardiovascular risk factor (pwHR 1.17; 95% CI 0.85-1.62).

Study details: This was a population-based observational, STAR-RA, study including 83,295 patients in the RWE cohort and 27,035 patients in the RCT-duplicate cohort who initiated tofacitinib or TNFi.

Disclosures: The study was supported by the Brigham and Women’s Hospital & Harvard Medical School (BWHHMS). SC Kim and RJ Desai reported receiving research grants to BWHHMS from various sources.

Source: Khosrow-Khavar F et al. Tofacitinib and risk of malignancy: Results from the Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA) Study. Arthritis Rheumatol. 2022 (May 29). Doi: 10.1002/art.42250

Key clinical point: This real-world study found no evidence of increased risk for malignancy in patients with rheumatoid arthritis (RA) who initiated tofacitinib vs. tumor necrosis factor inhibitors (TNFi).

Major finding: The risk for cumulative malignancies in patients who initiated tofacitinib vs. TNFi was not higher in the real-world evidence (RWE) cohort (pooled weighted hazard ratio [pwHR] 1.01; 95% CI 0.83-1.22), but was numerically higher in the randomized controlled trial (RCT)-duplicate cohort of patients aged ≥50 years with at least one cardiovascular risk factor (pwHR 1.17; 95% CI 0.85-1.62).

Study details: This was a population-based observational, STAR-RA, study including 83,295 patients in the RWE cohort and 27,035 patients in the RCT-duplicate cohort who initiated tofacitinib or TNFi.

Disclosures: The study was supported by the Brigham and Women’s Hospital & Harvard Medical School (BWHHMS). SC Kim and RJ Desai reported receiving research grants to BWHHMS from various sources.

Source: Khosrow-Khavar F et al. Tofacitinib and risk of malignancy: Results from the Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA) Study. Arthritis Rheumatol. 2022 (May 29). Doi: 10.1002/art.42250

Key clinical point: This real-world study found no evidence of increased risk for malignancy in patients with rheumatoid arthritis (RA) who initiated tofacitinib vs. tumor necrosis factor inhibitors (TNFi).

Major finding: The risk for cumulative malignancies in patients who initiated tofacitinib vs. TNFi was not higher in the real-world evidence (RWE) cohort (pooled weighted hazard ratio [pwHR] 1.01; 95% CI 0.83-1.22), but was numerically higher in the randomized controlled trial (RCT)-duplicate cohort of patients aged ≥50 years with at least one cardiovascular risk factor (pwHR 1.17; 95% CI 0.85-1.62).

Study details: This was a population-based observational, STAR-RA, study including 83,295 patients in the RWE cohort and 27,035 patients in the RCT-duplicate cohort who initiated tofacitinib or TNFi.

Disclosures: The study was supported by the Brigham and Women’s Hospital & Harvard Medical School (BWHHMS). SC Kim and RJ Desai reported receiving research grants to BWHHMS from various sources.

Source: Khosrow-Khavar F et al. Tofacitinib and risk of malignancy: Results from the Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR-RA) Study. Arthritis Rheumatol. 2022 (May 29). Doi: 10.1002/art.42250

Key clinical point: Reduced doses of rituximab can be considered in patients with rheumatoid arthritis (RA) who have had treatment failure with multiple biologic disease-modifying antirheumatic drugs (bDMARD), significant comorbidities, and an initial sustained clinical response.

Major finding: Over a 60-month follow-up, only 7.5% and 5.9% of patients relapsed on low-dose and standard-dose rituximab, respectively (P = .6), with patients on low-dose vs. standard-dose rituximab having significantly lower rates of serious adverse events (incidence rate: 0.77 vs. 1.57 per 1000 person-years; P < .0001) and drug discontinuation due to treatment failure (37.9% vs. 63.6%; P < .0001).

Study details: This was a prospective, observational study including 361 patients with established RA and prior failure using bDMARD who received low-dose (n = 81) or standard-dose (n  =280) rituximab.

Disclosures: The study was partly supported by the Pancretan Health Association. The authors declared no conflicts of interest.

Source: Bertsias A et al. Rheumatoid arthritis patients initiating rituximab with low number of previous bDMARDs failures may effectively reduce rituximab dose and experience fewer serious adverse events than patients on full dose: A 5-year cohort study. Arthritis Res Ther. 2022;24:132 (Jun 2). Doi: 10.1186/s13075-022-02826-6

Key clinical point: Reduced doses of rituximab can be considered in patients with rheumatoid arthritis (RA) who have had treatment failure with multiple biologic disease-modifying antirheumatic drugs (bDMARD), significant comorbidities, and an initial sustained clinical response.

Major finding: Over a 60-month follow-up, only 7.5% and 5.9% of patients relapsed on low-dose and standard-dose rituximab, respectively (P = .6), with patients on low-dose vs. standard-dose rituximab having significantly lower rates of serious adverse events (incidence rate: 0.77 vs. 1.57 per 1000 person-years; P < .0001) and drug discontinuation due to treatment failure (37.9% vs. 63.6%; P < .0001).

Study details: This was a prospective, observational study including 361 patients with established RA and prior failure using bDMARD who received low-dose (n = 81) or standard-dose (n  =280) rituximab.

Disclosures: The study was partly supported by the Pancretan Health Association. The authors declared no conflicts of interest.

Source: Bertsias A et al. Rheumatoid arthritis patients initiating rituximab with low number of previous bDMARDs failures may effectively reduce rituximab dose and experience fewer serious adverse events than patients on full dose: A 5-year cohort study. Arthritis Res Ther. 2022;24:132 (Jun 2). Doi: 10.1186/s13075-022-02826-6

Key clinical point: Reduced doses of rituximab can be considered in patients with rheumatoid arthritis (RA) who have had treatment failure with multiple biologic disease-modifying antirheumatic drugs (bDMARD), significant comorbidities, and an initial sustained clinical response.

Major finding: Over a 60-month follow-up, only 7.5% and 5.9% of patients relapsed on low-dose and standard-dose rituximab, respectively (P = .6), with patients on low-dose vs. standard-dose rituximab having significantly lower rates of serious adverse events (incidence rate: 0.77 vs. 1.57 per 1000 person-years; P < .0001) and drug discontinuation due to treatment failure (37.9% vs. 63.6%; P < .0001).

Study details: This was a prospective, observational study including 361 patients with established RA and prior failure using bDMARD who received low-dose (n = 81) or standard-dose (n  =280) rituximab.

Disclosures: The study was partly supported by the Pancretan Health Association. The authors declared no conflicts of interest.

Source: Bertsias A et al. Rheumatoid arthritis patients initiating rituximab with low number of previous bDMARDs failures may effectively reduce rituximab dose and experience fewer serious adverse events than patients on full dose: A 5-year cohort study. Arthritis Res Ther. 2022;24:132 (Jun 2). Doi: 10.1186/s13075-022-02826-6

Key clinical point: Obefazimod (ABX464) at a dose of 50 mg showed promising efficacy and was safe and well-tolerated in patients with moderate-to-severely active rheumatoid arthritis (RA).

Major finding: A dose of 50 mg ABX464 vs. placebo was associated with numerically more severe adverse events (14.3% vs. 5%) but with no malignancies, opportunistic infections, or deaths, and a significant reduction in the Disease Activity Score 28-C reactive protein (−1.41 vs. −0.60; P = .043) and Clinical Disease Activity Index Score (−15.8 vs. −6.9; P = .020) at week 12.

Study details: This was a phase 2 trial including 60 patients with moderate-to-severely active RA and inadequate response to methotrexate or anti-tumor necrosis factor alpha therapy who were randomly assigned to ABX464 or placebo in combination with methotrexate for 12 weeks.

Disclosures: The study was supported by Abivax. C Daien reported receiving consulting fees, punctual links, or research grants from Abivax and other sources. Ten authors reported being current/former employees or investigators contracted by Abivax.

Source: Daien C et al. Safety and efficacy of the miR-124 upregulator ABX464 (obefazimod, 50 and 100 mg per day) in patients with active rheumatoid arthritis and inadequate response to methotrexate and/or anti-TNFα therapy: A placebo-controlled phase II study. Ann Rheum Dis. 2022 (May 31). Doi: 10.1136/annrheumdis-2022-222228

Key clinical point: Obefazimod (ABX464) at a dose of 50 mg showed promising efficacy and was safe and well-tolerated in patients with moderate-to-severely active rheumatoid arthritis (RA).

Major finding: A dose of 50 mg ABX464 vs. placebo was associated with numerically more severe adverse events (14.3% vs. 5%) but with no malignancies, opportunistic infections, or deaths, and a significant reduction in the Disease Activity Score 28-C reactive protein (−1.41 vs. −0.60; P = .043) and Clinical Disease Activity Index Score (−15.8 vs. −6.9; P = .020) at week 12.

Study details: This was a phase 2 trial including 60 patients with moderate-to-severely active RA and inadequate response to methotrexate or anti-tumor necrosis factor alpha therapy who were randomly assigned to ABX464 or placebo in combination with methotrexate for 12 weeks.

Disclosures: The study was supported by Abivax. C Daien reported receiving consulting fees, punctual links, or research grants from Abivax and other sources. Ten authors reported being current/former employees or investigators contracted by Abivax.

Source: Daien C et al. Safety and efficacy of the miR-124 upregulator ABX464 (obefazimod, 50 and 100 mg per day) in patients with active rheumatoid arthritis and inadequate response to methotrexate and/or anti-TNFα therapy: A placebo-controlled phase II study. Ann Rheum Dis. 2022 (May 31). Doi: 10.1136/annrheumdis-2022-222228

Key clinical point: Obefazimod (ABX464) at a dose of 50 mg showed promising efficacy and was safe and well-tolerated in patients with moderate-to-severely active rheumatoid arthritis (RA).

Major finding: A dose of 50 mg ABX464 vs. placebo was associated with numerically more severe adverse events (14.3% vs. 5%) but with no malignancies, opportunistic infections, or deaths, and a significant reduction in the Disease Activity Score 28-C reactive protein (−1.41 vs. −0.60; P = .043) and Clinical Disease Activity Index Score (−15.8 vs. −6.9; P = .020) at week 12.

Study details: This was a phase 2 trial including 60 patients with moderate-to-severely active RA and inadequate response to methotrexate or anti-tumor necrosis factor alpha therapy who were randomly assigned to ABX464 or placebo in combination with methotrexate for 12 weeks.

Disclosures: The study was supported by Abivax. C Daien reported receiving consulting fees, punctual links, or research grants from Abivax and other sources. Ten authors reported being current/former employees or investigators contracted by Abivax.

Source: Daien C et al. Safety and efficacy of the miR-124 upregulator ABX464 (obefazimod, 50 and 100 mg per day) in patients with active rheumatoid arthritis and inadequate response to methotrexate and/or anti-TNFα therapy: A placebo-controlled phase II study. Ann Rheum Dis. 2022 (May 31). Doi: 10.1136/annrheumdis-2022-222228

Key clinical point: A dose of 5 or 10 mg tofacitinib twice daily improved clinical efficacy outcomes compared with placebo in patients with moderate-to-severe rheumatoid arthritis (RA) regardless of baseline body mass index (BMI).

Major finding: The American College of Rheumatology 20/50/70 response rates at 6 months were significantly higher in patients who received 5 or 10 mg tofacitinib vs. placebo (P < .05) and were comparable across baseline BMI (<25, 25 to <30, and ≥30 kg/m²) categories.

Study details: This was a post hoc analysis of six phase 3 trials including 3880 patients with moderate-to-severe RA who were randomly assigned to receive tofacitinib (5 or 10 mg), placebo, or active controls (methotrexate or adalimumab).

Disclosures: The study was sponsored by Pfizer Inc. Several authors reported being on speaker’s bureaus or receiving grants, consulting fees, or other remuneration from various sources, including Pfizer. Five authors reported being employees or shareholders of Pfizer or companies contracting with Pfizer.

Source: Dikranian AH et al. Efficacy of tofacitinib in patients with rheumatoid arthritis stratified by baseline body mass index: An analysis of pooled data from phase 3 studies. RMD Open. 2022;8:e002103 (May 16). Doi: 10.1136/rmdopen-2021-002103

Key clinical point: A dose of 5 or 10 mg tofacitinib twice daily improved clinical efficacy outcomes compared with placebo in patients with moderate-to-severe rheumatoid arthritis (RA) regardless of baseline body mass index (BMI).

Major finding: The American College of Rheumatology 20/50/70 response rates at 6 months were significantly higher in patients who received 5 or 10 mg tofacitinib vs. placebo (P < .05) and were comparable across baseline BMI (<25, 25 to <30, and ≥30 kg/m²) categories.

Study details: This was a post hoc analysis of six phase 3 trials including 3880 patients with moderate-to-severe RA who were randomly assigned to receive tofacitinib (5 or 10 mg), placebo, or active controls (methotrexate or adalimumab).

Disclosures: The study was sponsored by Pfizer Inc. Several authors reported being on speaker’s bureaus or receiving grants, consulting fees, or other remuneration from various sources, including Pfizer. Five authors reported being employees or shareholders of Pfizer or companies contracting with Pfizer.

Source: Dikranian AH et al. Efficacy of tofacitinib in patients with rheumatoid arthritis stratified by baseline body mass index: An analysis of pooled data from phase 3 studies. RMD Open. 2022;8:e002103 (May 16). Doi: 10.1136/rmdopen-2021-002103

Key clinical point: A dose of 5 or 10 mg tofacitinib twice daily improved clinical efficacy outcomes compared with placebo in patients with moderate-to-severe rheumatoid arthritis (RA) regardless of baseline body mass index (BMI).

Major finding: The American College of Rheumatology 20/50/70 response rates at 6 months were significantly higher in patients who received 5 or 10 mg tofacitinib vs. placebo (P < .05) and were comparable across baseline BMI (<25, 25 to <30, and ≥30 kg/m²) categories.

Study details: This was a post hoc analysis of six phase 3 trials including 3880 patients with moderate-to-severe RA who were randomly assigned to receive tofacitinib (5 or 10 mg), placebo, or active controls (methotrexate or adalimumab).

Disclosures: The study was sponsored by Pfizer Inc. Several authors reported being on speaker’s bureaus or receiving grants, consulting fees, or other remuneration from various sources, including Pfizer. Five authors reported being employees or shareholders of Pfizer or companies contracting with Pfizer.

Source: Dikranian AH et al. Efficacy of tofacitinib in patients with rheumatoid arthritis stratified by baseline body mass index: An analysis of pooled data from phase 3 studies. RMD Open. 2022;8:e002103 (May 16). Doi: 10.1136/rmdopen-2021-002103

The World Health Organization declared COVID-19 a pandemic on March 11, 2020, just 4 months before the start of a new residency cycle. Referred to as “COVID interns,” PGY-1 residents transitioning out of medical school in 2020 faced an unprecedented challenge of doctoring within a confused and ill-prepared health care system, while senior residents scrambled to adjust to their rapidly changing training programs. Each subsequent week brought more sobering news of increasing hospitalizations, intensive care unit admissions, and deaths; hospitals across the country resorted to the redeployment of residents across all specialties to buffer the growing need within their internal medicine and critical care units.¹ And while the news and social media blurred into a collage of ventilator shortages, politicization of science, and “#healthcareheroes,” one study showed53.7% of medical interns (N=108) were struggling with mild to extremely severe depression, while 63.9% reported mild to severe anxiety.²

Many shortcomings of our health care system—ill preparedness, racial disparity, health illiteracy—were highlighted during the COVID-19 pandemic, and providers’ mental health was no exception.³ Classic psychosocial risk factors, such as high demands, lack of control, lack of institutional support, and absence of reward defined the workplace, leading Theorell⁴ to call it “a randomized trial for maximal worsening of the work environment.” Stress and burnout during residency are not novel concepts. A 2002 survey including 415 medical residency programs with a response from more than 4000 residents found depressive symptoms in 35% of respondents, paired with feelings of increased cynicism and decreased humanism despite major curricular reforms and duty hour limitations.⁵ Unfortunately, the statistics in the coming years hardly budged and, in the wake of the pandemic, culminated to more than 50% to 76% of physicians worldwide reporting burnout in 2020.^6-8

As a COVID intern at Brigham and Women’s Hospital (Boston, Massachusetts), I also experienced the demanding workload and witnessed the struggle of my colleagues firsthand. Brigham and Women’s Hospital, similar to many of its peer institutions, implemented frequent mental health check-ins within its curriculum. Known as the Intern Humanistic Curriculum, these check-ins essentially were an echo chamber to unload the psychological burdens of our workdays, and we eagerly shared what made us angry, sad, hopeful, and hopeless. During one such session, I learned about moral injury, a term originating in the military defined as the psychological stress resulting from actions—or the lack of actions—that violates one’s moral or ethical code.⁹ With the onslaught of patient deaths for which most of us felt unprepared, we had all endured varying degrees of moral injury. Greenberg et al⁹ described 2 potential outcomes after moral injury: (1) the development of mental health disorders such as depression and posttraumatic stress disorder, or (2) posttraumatic growth, which is the bolstering of psychological resilience. Notably, the outcome is based on the way someone is supported before, during, and after the challenging incident.⁹

With the aim of psychological growth and developing resilience, residents should prioritize mental health throughout their training. To this end, several resources are readily available, many of which I actively use or frequently revisit, which are reviewed here.

Mindfulness Meditation App

Calm (https://www.calm.com/) is one of several popular mobile applications (apps) that delivers mindfulness mediation—the practice of attending to experiences, thoughts, and emotions without bias or judgment. With more than 100 million downloads, Calm includes meditation tutorials, breathing exercises, nature scenes and sounds, and audio programs taught by mindfulness experts for $69.99 a year or $14.99 a month. Systemic reviews have demonstrated reduced sleep disturbance, decreased ruminative thoughts and emotional reactivity, and increased awareness and acceptance in those practicing mindfulness meditation. Calm users have reported these benefits, with many able to forego the time- and cost-intensive cognitive behavioral therapy that requires highly trained therapists.^10-12

Exercise to Relieve Stress

Both aerobic and anaerobic exercises are antidepressive and anxiolytic and also lower one’s overall sensitivity to stress. Whether it is governed by neurotransmitters such as the activation of the opioid systems or the release of endogenous endorphins or time spent focusing on a different task at hand, the benefits of exercise against mental stressors have been extensively studied and established.¹³ Consider obtaining a new gym membership at the start of residency or joining an intramural team. Both have the added benefit of expanding your social circle.

Socialize With Others

Social isolation and perceived loneliness are key stressors linked to neuroendocrine disturbances that underlie depression, anxiety, and even schizophrenia.^14,15 Throughout residency there will be several social events and opportunities to gather with colleagues—inside or outside of the work environment—and residents should attend as time allows. Even virtual social interactions were found to reduce stress and help in the treatment of social anxiety disorder.¹⁴

Open up to your co-residents, friends, and family about any struggles that may be invisible on the outside. Even attendings can empathize with the struggles of residency, and the mentors in place are actively trained to prioritize resident wellness. If verbal communication is not your strength, try journaling. Writing helps to untangle and better define underlying stressors and is itself meditative.^16,17 However, ensure that your journaling is focused on positive emotional responses and aims to determine the positive benefits within any stressful event; those solely expressing negative emotions were found to have higher levels of stress and anxiety afterward than they had before.¹⁷

Seek a Mental Health Specialist

As with all other human ailments, severe mental health disorders require specialists and proper medication. Unfortunately, substantial stigma accompanying mental health continues to permeate medicine, creating considerable barriers for residents in need of care.¹⁸ A 2016 survey of more than 2000 physicians found that those with mental illnesses did not seek treatment due to limited time, fear of being reported to a medical licensing board, concern over obtaining licensure, and shame or embarrassment at the diagnosis.¹⁹ Besides urging residents to seek care, more effort should be invested in addressing the stigma and ensuring confidentiality. In 2021, the internal medicine and medicine-pediatrics residency at the University of Colorado Anschutz Medical Campus (Aurora, Colorado) developed a confidential opt-out, rather than opt-in, mental health program, and appointments were made for all 80 interns in advance. In doing so, they found increased participation and self-reported wellness at a relatively low cost and simple implementation.²⁰ For trainees without such access, online or mobile therapy platforms offering electronic mental health treatment or telepsychiatry also have been employed.^21,22 The onus ultimately is still on the individual to seek the care they need. Although only an anecdotal piece of evidence, I have found the prevalence of physicians taking selective serotonin reuptake inhibitors such as escitalopram, sertraline, or fluoxetine to be strikingly common and quite beneficial.

Final Thoughts

Residency remains rife with financial, emotional, and physical stressors; even as the dust settles on the COVID-19 pandemic, the light shed on the importance of trainee mental health must remain illuminated. For the aforementioned resources to have an impact, residents need to be empowered to openly discuss mental health issues and to seek help if necessary. Finally, in 2018, the Journal of Graduate Medical Education published a 10-year prospective cohort study that found that emotional distress during residency persists in professional practice even 10 years after residency and is associated with future burnout.²³ Trainees should consider prioritizing their mental health to not only improve their quality of life in the present but also as an investment for their future.

The World Health Organization declared COVID-19 a pandemic on March 11, 2020, just 4 months before the start of a new residency cycle. Referred to as “COVID interns,” PGY-1 residents transitioning out of medical school in 2020 faced an unprecedented challenge of doctoring within a confused and ill-prepared health care system, while senior residents scrambled to adjust to their rapidly changing training programs. Each subsequent week brought more sobering news of increasing hospitalizations, intensive care unit admissions, and deaths; hospitals across the country resorted to the redeployment of residents across all specialties to buffer the growing need within their internal medicine and critical care units.¹ And while the news and social media blurred into a collage of ventilator shortages, politicization of science, and “#healthcareheroes,” one study showed53.7% of medical interns (N=108) were struggling with mild to extremely severe depression, while 63.9% reported mild to severe anxiety.²

Many shortcomings of our health care system—ill preparedness, racial disparity, health illiteracy—were highlighted during the COVID-19 pandemic, and providers’ mental health was no exception.³ Classic psychosocial risk factors, such as high demands, lack of control, lack of institutional support, and absence of reward defined the workplace, leading Theorell⁴ to call it “a randomized trial for maximal worsening of the work environment.” Stress and burnout during residency are not novel concepts. A 2002 survey including 415 medical residency programs with a response from more than 4000 residents found depressive symptoms in 35% of respondents, paired with feelings of increased cynicism and decreased humanism despite major curricular reforms and duty hour limitations.⁵ Unfortunately, the statistics in the coming years hardly budged and, in the wake of the pandemic, culminated to more than 50% to 76% of physicians worldwide reporting burnout in 2020.^6-8

As a COVID intern at Brigham and Women’s Hospital (Boston, Massachusetts), I also experienced the demanding workload and witnessed the struggle of my colleagues firsthand. Brigham and Women’s Hospital, similar to many of its peer institutions, implemented frequent mental health check-ins within its curriculum. Known as the Intern Humanistic Curriculum, these check-ins essentially were an echo chamber to unload the psychological burdens of our workdays, and we eagerly shared what made us angry, sad, hopeful, and hopeless. During one such session, I learned about moral injury, a term originating in the military defined as the psychological stress resulting from actions—or the lack of actions—that violates one’s moral or ethical code.⁹ With the onslaught of patient deaths for which most of us felt unprepared, we had all endured varying degrees of moral injury. Greenberg et al⁹ described 2 potential outcomes after moral injury: (1) the development of mental health disorders such as depression and posttraumatic stress disorder, or (2) posttraumatic growth, which is the bolstering of psychological resilience. Notably, the outcome is based on the way someone is supported before, during, and after the challenging incident.⁹

With the aim of psychological growth and developing resilience, residents should prioritize mental health throughout their training. To this end, several resources are readily available, many of which I actively use or frequently revisit, which are reviewed here.

Mindfulness Meditation App

Calm (https://www.calm.com/) is one of several popular mobile applications (apps) that delivers mindfulness mediation—the practice of attending to experiences, thoughts, and emotions without bias or judgment. With more than 100 million downloads, Calm includes meditation tutorials, breathing exercises, nature scenes and sounds, and audio programs taught by mindfulness experts for $69.99 a year or $14.99 a month. Systemic reviews have demonstrated reduced sleep disturbance, decreased ruminative thoughts and emotional reactivity, and increased awareness and acceptance in those practicing mindfulness meditation. Calm users have reported these benefits, with many able to forego the time- and cost-intensive cognitive behavioral therapy that requires highly trained therapists.^10-12

Exercise to Relieve Stress

Both aerobic and anaerobic exercises are antidepressive and anxiolytic and also lower one’s overall sensitivity to stress. Whether it is governed by neurotransmitters such as the activation of the opioid systems or the release of endogenous endorphins or time spent focusing on a different task at hand, the benefits of exercise against mental stressors have been extensively studied and established.¹³ Consider obtaining a new gym membership at the start of residency or joining an intramural team. Both have the added benefit of expanding your social circle.

Socialize With Others

Social isolation and perceived loneliness are key stressors linked to neuroendocrine disturbances that underlie depression, anxiety, and even schizophrenia.^14,15 Throughout residency there will be several social events and opportunities to gather with colleagues—inside or outside of the work environment—and residents should attend as time allows. Even virtual social interactions were found to reduce stress and help in the treatment of social anxiety disorder.¹⁴

Open up to your co-residents, friends, and family about any struggles that may be invisible on the outside. Even attendings can empathize with the struggles of residency, and the mentors in place are actively trained to prioritize resident wellness. If verbal communication is not your strength, try journaling. Writing helps to untangle and better define underlying stressors and is itself meditative.^16,17 However, ensure that your journaling is focused on positive emotional responses and aims to determine the positive benefits within any stressful event; those solely expressing negative emotions were found to have higher levels of stress and anxiety afterward than they had before.¹⁷

Seek a Mental Health Specialist

As with all other human ailments, severe mental health disorders require specialists and proper medication. Unfortunately, substantial stigma accompanying mental health continues to permeate medicine, creating considerable barriers for residents in need of care.¹⁸ A 2016 survey of more than 2000 physicians found that those with mental illnesses did not seek treatment due to limited time, fear of being reported to a medical licensing board, concern over obtaining licensure, and shame or embarrassment at the diagnosis.¹⁹ Besides urging residents to seek care, more effort should be invested in addressing the stigma and ensuring confidentiality. In 2021, the internal medicine and medicine-pediatrics residency at the University of Colorado Anschutz Medical Campus (Aurora, Colorado) developed a confidential opt-out, rather than opt-in, mental health program, and appointments were made for all 80 interns in advance. In doing so, they found increased participation and self-reported wellness at a relatively low cost and simple implementation.²⁰ For trainees without such access, online or mobile therapy platforms offering electronic mental health treatment or telepsychiatry also have been employed.^21,22 The onus ultimately is still on the individual to seek the care they need. Although only an anecdotal piece of evidence, I have found the prevalence of physicians taking selective serotonin reuptake inhibitors such as escitalopram, sertraline, or fluoxetine to be strikingly common and quite beneficial.

Final Thoughts

Residency remains rife with financial, emotional, and physical stressors; even as the dust settles on the COVID-19 pandemic, the light shed on the importance of trainee mental health must remain illuminated. For the aforementioned resources to have an impact, residents need to be empowered to openly discuss mental health issues and to seek help if necessary. Finally, in 2018, the Journal of Graduate Medical Education published a 10-year prospective cohort study that found that emotional distress during residency persists in professional practice even 10 years after residency and is associated with future burnout.²³ Trainees should consider prioritizing their mental health to not only improve their quality of life in the present but also as an investment for their future.

The World Health Organization declared COVID-19 a pandemic on March 11, 2020, just 4 months before the start of a new residency cycle. Referred to as “COVID interns,” PGY-1 residents transitioning out of medical school in 2020 faced an unprecedented challenge of doctoring within a confused and ill-prepared health care system, while senior residents scrambled to adjust to their rapidly changing training programs. Each subsequent week brought more sobering news of increasing hospitalizations, intensive care unit admissions, and deaths; hospitals across the country resorted to the redeployment of residents across all specialties to buffer the growing need within their internal medicine and critical care units.¹ And while the news and social media blurred into a collage of ventilator shortages, politicization of science, and “#healthcareheroes,” one study showed53.7% of medical interns (N=108) were struggling with mild to extremely severe depression, while 63.9% reported mild to severe anxiety.²

Many shortcomings of our health care system—ill preparedness, racial disparity, health illiteracy—were highlighted during the COVID-19 pandemic, and providers’ mental health was no exception.³ Classic psychosocial risk factors, such as high demands, lack of control, lack of institutional support, and absence of reward defined the workplace, leading Theorell⁴ to call it “a randomized trial for maximal worsening of the work environment.” Stress and burnout during residency are not novel concepts. A 2002 survey including 415 medical residency programs with a response from more than 4000 residents found depressive symptoms in 35% of respondents, paired with feelings of increased cynicism and decreased humanism despite major curricular reforms and duty hour limitations.⁵ Unfortunately, the statistics in the coming years hardly budged and, in the wake of the pandemic, culminated to more than 50% to 76% of physicians worldwide reporting burnout in 2020.^6-8

As a COVID intern at Brigham and Women’s Hospital (Boston, Massachusetts), I also experienced the demanding workload and witnessed the struggle of my colleagues firsthand. Brigham and Women’s Hospital, similar to many of its peer institutions, implemented frequent mental health check-ins within its curriculum. Known as the Intern Humanistic Curriculum, these check-ins essentially were an echo chamber to unload the psychological burdens of our workdays, and we eagerly shared what made us angry, sad, hopeful, and hopeless. During one such session, I learned about moral injury, a term originating in the military defined as the psychological stress resulting from actions—or the lack of actions—that violates one’s moral or ethical code.⁹ With the onslaught of patient deaths for which most of us felt unprepared, we had all endured varying degrees of moral injury. Greenberg et al⁹ described 2 potential outcomes after moral injury: (1) the development of mental health disorders such as depression and posttraumatic stress disorder, or (2) posttraumatic growth, which is the bolstering of psychological resilience. Notably, the outcome is based on the way someone is supported before, during, and after the challenging incident.⁹

With the aim of psychological growth and developing resilience, residents should prioritize mental health throughout their training. To this end, several resources are readily available, many of which I actively use or frequently revisit, which are reviewed here.

Mindfulness Meditation App

Calm (https://www.calm.com/) is one of several popular mobile applications (apps) that delivers mindfulness mediation—the practice of attending to experiences, thoughts, and emotions without bias or judgment. With more than 100 million downloads, Calm includes meditation tutorials, breathing exercises, nature scenes and sounds, and audio programs taught by mindfulness experts for $69.99 a year or $14.99 a month. Systemic reviews have demonstrated reduced sleep disturbance, decreased ruminative thoughts and emotional reactivity, and increased awareness and acceptance in those practicing mindfulness meditation. Calm users have reported these benefits, with many able to forego the time- and cost-intensive cognitive behavioral therapy that requires highly trained therapists.^10-12

Exercise to Relieve Stress

Both aerobic and anaerobic exercises are antidepressive and anxiolytic and also lower one’s overall sensitivity to stress. Whether it is governed by neurotransmitters such as the activation of the opioid systems or the release of endogenous endorphins or time spent focusing on a different task at hand, the benefits of exercise against mental stressors have been extensively studied and established.¹³ Consider obtaining a new gym membership at the start of residency or joining an intramural team. Both have the added benefit of expanding your social circle.

Socialize With Others

Social isolation and perceived loneliness are key stressors linked to neuroendocrine disturbances that underlie depression, anxiety, and even schizophrenia.^14,15 Throughout residency there will be several social events and opportunities to gather with colleagues—inside or outside of the work environment—and residents should attend as time allows. Even virtual social interactions were found to reduce stress and help in the treatment of social anxiety disorder.¹⁴

Open up to your co-residents, friends, and family about any struggles that may be invisible on the outside. Even attendings can empathize with the struggles of residency, and the mentors in place are actively trained to prioritize resident wellness. If verbal communication is not your strength, try journaling. Writing helps to untangle and better define underlying stressors and is itself meditative.^16,17 However, ensure that your journaling is focused on positive emotional responses and aims to determine the positive benefits within any stressful event; those solely expressing negative emotions were found to have higher levels of stress and anxiety afterward than they had before.¹⁷

Seek a Mental Health Specialist

As with all other human ailments, severe mental health disorders require specialists and proper medication. Unfortunately, substantial stigma accompanying mental health continues to permeate medicine, creating considerable barriers for residents in need of care.¹⁸ A 2016 survey of more than 2000 physicians found that those with mental illnesses did not seek treatment due to limited time, fear of being reported to a medical licensing board, concern over obtaining licensure, and shame or embarrassment at the diagnosis.¹⁹ Besides urging residents to seek care, more effort should be invested in addressing the stigma and ensuring confidentiality. In 2021, the internal medicine and medicine-pediatrics residency at the University of Colorado Anschutz Medical Campus (Aurora, Colorado) developed a confidential opt-out, rather than opt-in, mental health program, and appointments were made for all 80 interns in advance. In doing so, they found increased participation and self-reported wellness at a relatively low cost and simple implementation.²⁰ For trainees without such access, online or mobile therapy platforms offering electronic mental health treatment or telepsychiatry also have been employed.^21,22 The onus ultimately is still on the individual to seek the care they need. Although only an anecdotal piece of evidence, I have found the prevalence of physicians taking selective serotonin reuptake inhibitors such as escitalopram, sertraline, or fluoxetine to be strikingly common and quite beneficial.

Final Thoughts

Residency remains rife with financial, emotional, and physical stressors; even as the dust settles on the COVID-19 pandemic, the light shed on the importance of trainee mental health must remain illuminated. For the aforementioned resources to have an impact, residents need to be empowered to openly discuss mental health issues and to seek help if necessary. Finally, in 2018, the Journal of Graduate Medical Education published a 10-year prospective cohort study that found that emotional distress during residency persists in professional practice even 10 years after residency and is associated with future burnout.²³ Trainees should consider prioritizing their mental health to not only improve their quality of life in the present but also as an investment for their future.

The American College of Cardiology and the American Heart Association have jointly issued a comprehensive set of data standards to help clarify definitions of the cardiovascular (CV) and non-CV complications of COVID-19.

It’s the work of the ACC/AHA Task Force on Clinical Data Standards and has been endorsed by the Heart Failure Society of America and Society for Cardiac Angiography and Interventions.

There is increased importance to understanding the acute and long-term impact of COVID-19 on CV health, the writing group notes. Until now, however, there has not been “clarity or consensus” on definitions of CV conditions related to COVID-19, with different diagnostic terminologies being used for overlapping conditions, such as “myocardial injury,” “myocarditis,” “type Il myocardial infarction,” “stress cardiomyopathy,” and “inflammatory cardiomyopathy,” they point out.

Floaria Bicher/iStock/Getty Images Plus

“We, as a research community, did some things right and some things wrong surrounding the COVID pandemic,” Sandeep Das, MD, MPH, vice chair of the writing group, noted in an interview with this news organization.

“The things that we really did right is that everybody responded with enthusiasm, kind of all hands on deck with a massive crisis response, and that was fantastic,” Dr. Das said.

“However, because of the need to hurry, we didn’t structure and organize in the way that we typically would for something that was sort of a slow burn kind of problem rather than an emergency. One of the consequences of that was fragmentation of how things are collected, reported, et cetera, and that leads to confusion,” he added.

The report was published simultaneously June 23 in the Journal of the American College of Cardiology and Circulation: Cardiovascular Quality and Outcomes.
 

A necessary but not glamorous project

The new data standards for COVID-19 will help standardize definitions and set the framework to capture and better understand how COVID-19 affects CV health.

“It wasn’t exactly a glamorous-type project but, at the same time, it’s super necessary to kind of get everybody on the same page and working together,” Dr. Das said. 

Broad agreement on common vocabulary and definitions will help with efforts to pool or compare data from electronic health records, clinical registries, administrative datasets, and other databases, and determine whether these data apply to clinical practice and research endeavors, the writing group says.

They considered data elements relevant to the full range of care provided to COVID-19 patients in all care settings. Among the key items included in the document are:

• Case definitions for confirmed, probable, and suspected acute COVID-19, as well as postacute sequelae of COVID-19.
• Definitions for acute CV complications related to COVID-19, including acute myocardial injury, heart failure, shock, arrhythmia, thromboembolic complications, and .
• Data elements related to COVID-19 vaccination status, comorbidities, and preexisting CV conditions.
• Definitions for postacute CV sequelae of SARS-CoV-2 infection and long-term CV complications of COVID-19.
• Data elements for CV mortality during acute COVID-19.
• Data elements for non-CV complications to help document severity of illness and other competing diagnoses and complications that might affect CV outcomes.
• A list of symptoms and signs related to COVID-19 and CV complications.
• Data elements for diagnostic and therapeutic strategies for COVID-19 and CV conditions.
• A discussion of advanced therapies, including , extracorporeal membrane oxygenation, and end-of-life management strategies.

These data standards will be useful for researchers, registry developers, and clinicians, and they are proposed as a framework for ICD-10 code development of COVID-19–related CV conditions, the writing group says.

The standards are also of “great importance” to patients, clinicians, investigators, scientists, administrators, public health officials, policymakers, and payers, the group says.

Dr. Das said that, although there is no formal plan in place to update the document, he could see sections that might be refined.

“For example, there’s a nice long list of all the various variants, and unfortunately, I suspect that that is going to change and evolve over time,” Dr. Das told this news organization.

“We tried very hard not to include things like specifying specific treatments so we didn’t get proscriptive. We wanted to make it descriptive, so hopefully it will stand the test of time pretty well,” he added.

This research had no commercial funding. The writing group has no relevant disclosures.

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

The American College of Cardiology and the American Heart Association have jointly issued a comprehensive set of data standards to help clarify definitions of the cardiovascular (CV) and non-CV complications of COVID-19.

It’s the work of the ACC/AHA Task Force on Clinical Data Standards and has been endorsed by the Heart Failure Society of America and Society for Cardiac Angiography and Interventions.

There is increased importance to understanding the acute and long-term impact of COVID-19 on CV health, the writing group notes. Until now, however, there has not been “clarity or consensus” on definitions of CV conditions related to COVID-19, with different diagnostic terminologies being used for overlapping conditions, such as “myocardial injury,” “myocarditis,” “type Il myocardial infarction,” “stress cardiomyopathy,” and “inflammatory cardiomyopathy,” they point out.

Floaria Bicher/iStock/Getty Images Plus

“We, as a research community, did some things right and some things wrong surrounding the COVID pandemic,” Sandeep Das, MD, MPH, vice chair of the writing group, noted in an interview with this news organization.

“The things that we really did right is that everybody responded with enthusiasm, kind of all hands on deck with a massive crisis response, and that was fantastic,” Dr. Das said.

“However, because of the need to hurry, we didn’t structure and organize in the way that we typically would for something that was sort of a slow burn kind of problem rather than an emergency. One of the consequences of that was fragmentation of how things are collected, reported, et cetera, and that leads to confusion,” he added.

The report was published simultaneously June 23 in the Journal of the American College of Cardiology and Circulation: Cardiovascular Quality and Outcomes.
 

A necessary but not glamorous project

The new data standards for COVID-19 will help standardize definitions and set the framework to capture and better understand how COVID-19 affects CV health.

“It wasn’t exactly a glamorous-type project but, at the same time, it’s super necessary to kind of get everybody on the same page and working together,” Dr. Das said. 

Broad agreement on common vocabulary and definitions will help with efforts to pool or compare data from electronic health records, clinical registries, administrative datasets, and other databases, and determine whether these data apply to clinical practice and research endeavors, the writing group says.

They considered data elements relevant to the full range of care provided to COVID-19 patients in all care settings. Among the key items included in the document are:

• Case definitions for confirmed, probable, and suspected acute COVID-19, as well as postacute sequelae of COVID-19.
• Definitions for acute CV complications related to COVID-19, including acute myocardial injury, heart failure, shock, arrhythmia, thromboembolic complications, and .
• Data elements related to COVID-19 vaccination status, comorbidities, and preexisting CV conditions.
• Definitions for postacute CV sequelae of SARS-CoV-2 infection and long-term CV complications of COVID-19.
• Data elements for CV mortality during acute COVID-19.
• Data elements for non-CV complications to help document severity of illness and other competing diagnoses and complications that might affect CV outcomes.
• A list of symptoms and signs related to COVID-19 and CV complications.
• Data elements for diagnostic and therapeutic strategies for COVID-19 and CV conditions.
• A discussion of advanced therapies, including , extracorporeal membrane oxygenation, and end-of-life management strategies.

These data standards will be useful for researchers, registry developers, and clinicians, and they are proposed as a framework for ICD-10 code development of COVID-19–related CV conditions, the writing group says.

The standards are also of “great importance” to patients, clinicians, investigators, scientists, administrators, public health officials, policymakers, and payers, the group says.

Dr. Das said that, although there is no formal plan in place to update the document, he could see sections that might be refined.

“For example, there’s a nice long list of all the various variants, and unfortunately, I suspect that that is going to change and evolve over time,” Dr. Das told this news organization.

“We tried very hard not to include things like specifying specific treatments so we didn’t get proscriptive. We wanted to make it descriptive, so hopefully it will stand the test of time pretty well,” he added.

This research had no commercial funding. The writing group has no relevant disclosures.

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

The American College of Cardiology and the American Heart Association have jointly issued a comprehensive set of data standards to help clarify definitions of the cardiovascular (CV) and non-CV complications of COVID-19.

It’s the work of the ACC/AHA Task Force on Clinical Data Standards and has been endorsed by the Heart Failure Society of America and Society for Cardiac Angiography and Interventions.

There is increased importance to understanding the acute and long-term impact of COVID-19 on CV health, the writing group notes. Until now, however, there has not been “clarity or consensus” on definitions of CV conditions related to COVID-19, with different diagnostic terminologies being used for overlapping conditions, such as “myocardial injury,” “myocarditis,” “type Il myocardial infarction,” “stress cardiomyopathy,” and “inflammatory cardiomyopathy,” they point out.

Floaria Bicher/iStock/Getty Images Plus

“We, as a research community, did some things right and some things wrong surrounding the COVID pandemic,” Sandeep Das, MD, MPH, vice chair of the writing group, noted in an interview with this news organization.

“The things that we really did right is that everybody responded with enthusiasm, kind of all hands on deck with a massive crisis response, and that was fantastic,” Dr. Das said.

“However, because of the need to hurry, we didn’t structure and organize in the way that we typically would for something that was sort of a slow burn kind of problem rather than an emergency. One of the consequences of that was fragmentation of how things are collected, reported, et cetera, and that leads to confusion,” he added.

The report was published simultaneously June 23 in the Journal of the American College of Cardiology and Circulation: Cardiovascular Quality and Outcomes.
 

A necessary but not glamorous project

The new data standards for COVID-19 will help standardize definitions and set the framework to capture and better understand how COVID-19 affects CV health.

“It wasn’t exactly a glamorous-type project but, at the same time, it’s super necessary to kind of get everybody on the same page and working together,” Dr. Das said. 

Broad agreement on common vocabulary and definitions will help with efforts to pool or compare data from electronic health records, clinical registries, administrative datasets, and other databases, and determine whether these data apply to clinical practice and research endeavors, the writing group says.

They considered data elements relevant to the full range of care provided to COVID-19 patients in all care settings. Among the key items included in the document are:

• Case definitions for confirmed, probable, and suspected acute COVID-19, as well as postacute sequelae of COVID-19.
• Definitions for acute CV complications related to COVID-19, including acute myocardial injury, heart failure, shock, arrhythmia, thromboembolic complications, and .
• Data elements related to COVID-19 vaccination status, comorbidities, and preexisting CV conditions.
• Definitions for postacute CV sequelae of SARS-CoV-2 infection and long-term CV complications of COVID-19.
• Data elements for CV mortality during acute COVID-19.
• Data elements for non-CV complications to help document severity of illness and other competing diagnoses and complications that might affect CV outcomes.
• A list of symptoms and signs related to COVID-19 and CV complications.
• Data elements for diagnostic and therapeutic strategies for COVID-19 and CV conditions.
• A discussion of advanced therapies, including , extracorporeal membrane oxygenation, and end-of-life management strategies.

These data standards will be useful for researchers, registry developers, and clinicians, and they are proposed as a framework for ICD-10 code development of COVID-19–related CV conditions, the writing group says.

The standards are also of “great importance” to patients, clinicians, investigators, scientists, administrators, public health officials, policymakers, and payers, the group says.

Dr. Das said that, although there is no formal plan in place to update the document, he could see sections that might be refined.

“For example, there’s a nice long list of all the various variants, and unfortunately, I suspect that that is going to change and evolve over time,” Dr. Das told this news organization.

“We tried very hard not to include things like specifying specific treatments so we didn’t get proscriptive. We wanted to make it descriptive, so hopefully it will stand the test of time pretty well,” he added.

This research had no commercial funding. The writing group has no relevant disclosures.

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

Basal cell carcinoma (BCC) is the most common keratinocyte carcinoma and affects more than 3 million individuals per year in the United States.¹ Approximately 40% of patients diagnosed with BCC will develop another BCC within 5 years of the initial diagnosis.² Most cases are successfully treated with surgical excision and occasionally topical therapy or radiotherapy. Despite the high cure rate with conventional treatments, BCC can recur and can cause substantial destruction of the surrounding tissue if left untreated.^3-5 In some instances, BCC can even metastasize and lead to death.⁶ For patients who are poor candidates for surgical or topical treatment modalities because of locally advanced BCC (laBCC) or metastatic BCC (mBCC), systemic treatment may be indicated. Vismodegib, sonidegib, and cemiplimab are the only systemic medications approved by the US Food and Drug Administration (FDA) for the treatment of laBCC and/or mBCC. Vismodegib and sonidegib target the sonic hedgehog (SHH) signaling pathway that is abnormally activated in more than 90% of BCCs.⁷ Cemiplimab is an immune checkpoint inhibitor (ICI) that targets the programmed cell death protein 1 (PD-1) receptor.⁸ Herein, we review the clinical utility of these medications and their evolving roles in the treatment of BCC.

SHH Pathway Inhibitors

The SHH pathway is a key regulator of cell proliferation and differentiation during embryogenesis.⁷ During adulthood, SHH signaling decreases but still plays an important role in stem cell activation and in regulation of the hair follicle growth cycle.^9,10 However, de novo mutations in the genes that comprise the SHH pathway can result in aberrant constitutive activation, leading to unrestricted cell proliferation. Genetic mutations resulting in activation of Smoothened (SMO), a G-protein–coupled receptor involved in the signal transduction and propagation of the SHH pathway, have been implicated in the pathogenesis of BCC. Inactivating mutations also are commonly observed in patched homolog 1, an upstream cell-surface protein that inhibits SMO.⁷ The mechanism by which vismodegib and sonidegib, 2 of the FDA-approved oral medications for the treatment of advanced BCC, block the SHH pathway is through the selective inhibition of SMO.^7,11

Vismodegib first received FDA approval in 2012 for the treatment of laBCC and mBCC after initial results from the pivotal ERIVANCE phase 2 trial demonstrated an objective response rate (ORR) of 43% (27/63) and 30% (10/33) in patients with locally advanced and metastatic disease, respectively. In this single-arm study, all enrolled patients (63 with laBCC and 33 with mBCC) received 150 mg of oral vismodegib daily.¹² Updated results at 39 months demonstrated improved ORRs of 60% (38/63) and 48% (16/33) for the laBCC and mBCC groups, respectively. A complete response (CR) and partial response (PR) were observed in 32% (n=20) and 29% (n=18) of patients with laBCC, respectively.¹³ These results have been confirmed in subsequent studies, including the large international open-label trial known as STEVIE, with ORRs of 68.5% for 1119 cases of laBCC and 37% for 96 cases of mBCC.^14-17 The CR and PR rates were 33% and 35%, respectively, for the laBCC group. The CR and PR rates for the mBCC group were 5% and 32%, respectively.¹⁴

The FDA approval of sonidegib for laBCC—but not mBCC—occurred in 2015 after the pivotal BOLT randomized phase 2 trial demonstrated an initial ORR of 43% (18/42) for laBCC and 15% (2/13) for mBCC after administration of 200 mg of sonidegib daily.¹⁸ A final follow-up analysis at 42 months resulted in ORRs of 56% (37/66) and 8% (1/13) for the laBCC and mBCC groups, respectively.¹⁹ Additionally, improved efficacy was not observed in the 151 patients who were randomized to receive treatment with the higher 800-mg dose; however, they did experience a higher incidence of adverse events.^18,19

Currently, the true clinical differences between vismodegib and sonidegib remain uncertain, as no head-to-head trials have been conducted. Moreover, direct comparison of the data from the ERIVANCE and BOLT trials is challenging owing to fundamental differences in methodologic design, including the criteria used to assess BCC severity. The ERIVANCE trial utilized the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while BOLT used the rigorous modified RECIST. However, an expert consensus study attempted to compare the 2 trials by modifying the outcomes from BOLT with the former RECIST criteria. The expert group found that the 2 SHH inhibitors had comparable efficacy and adverse event profiles.²⁰ Nevertheless, a recent meta-analysis found that although ORRs for laBCC were similar between the 2 drugs, the CR rate for vismodegib was 31% compared with 3% for sonidegib. Additionally, for mBCC, they reported the ORR of vismodegib to be 2.7 times higher than that of sonidegib (39% vs 15%).²¹

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors have successfully been utilized in the treatment of cutaneous squamous cell carcinoma (cSCC); however, their use for treating BCC has been limited until recently.^22-25 In February 2021, cemiplimab became the first and only ICI approved for the treatment of laBCC and mBCC in patients who did not respond to or were intolerant to prior SHH inhibitor therapy.²⁶ Cemiplimab—a human monoclonal antibody against the PD-1 receptor expressed on T cells—blocks its interaction with programmed cell death ligand 1 and programmed cell death ligand 2 present on tumor cells. The blockade of the PD-1 pathway releases the inhibition of the antitumor immune response and enables appropriate cytotoxic T-cell activity to occur.⁸

The FDA approval of cemiplimab for the treatment of advanced BCC was based on an open-label, multicenter, single-arm phase 2 trial (NCT03132636) evaluating 84 patients with laBCC refractory or intolerant to SHH inhibitor therapy.²⁶ Patients received an intravenous infusion of cemiplimab 350 mg every 3 weeks for up to 93 weeks or until disease progression or unacceptable toxicity. An ORR of 31% (26/84) was observed with a CR and PR of 6% (5/84) and 25% (21/84), respectively. The median duration of follow-up was 15 months.²⁶ Given the clinically meaningful results of this trial, investigating the efficacy of other PD-1 inhibitors, such as pembrolizumab and nivolumab, for treatment of advanced BCC may prove worthwhile.

The 2 approved SHH inhibitors—vismodegib and sonidegib—appear to have similar side-effect profiles, with the most common adverse effects being muscle spasms, dysgeusia, alopecia, nausea, vomiting, diarrhea, weight loss, and fatigue.^20,21,27 These side effects occur at high frequencies (>40%) for both SHH inhibitors and often lead to discontinuation of the medication.²¹ Rates of treatment discontinuation range from 15% to 50% on average.^12-14,18 Fortunately, the majority of these adverse effects do not appear to increase in severity or frequency with prolonged use of these medications.^14,16,28

Various conservative and pharmacologic measures can be implemented to help manage side effects. For muscle spasms, which are the most commonly reported adverse effect, supplementation with magnesium, transcutaneous electrical nerve stimulation, acupuncture, massages, stretching, and thermal compresses can potentially be beneficial.²⁹ Calcium channel blockers also may be effective, as one small prospective cohort study reported a reduction in the frequency of muscle cramps with amlodipine 10 mg daily.³⁰ For alopecia, which typically is reversible and caused by SHH inhibition of the normal hair cycle, minoxidil theoretically can help, as it reduces telogen arrest and extends the anagen growth phase.^31,32 Although usually mild and self-limiting, management of dysgeusia, weight loss, and gastrointestinal upset often can be managed with dietary changes, such as smaller, more frequent meals.^33,34 Finally, alternative dosing strategies and drug holidays have been employed to mitigate these side effects and increase drug tolerability.^35,36 These are discussed in the Alternative Dosing section.

Given the essential role of the SHH pathway in embryologic development, SHH inhibitors carry a black box warning of embryofetal teratogenicity and are contraindicated in females who are pregnant or breastfeeding. For females of reproductive potential, verification of pregnancy status should be performed prior to initiating treatment with an SHH inhibitor. These patients should be counseled on the use of contraception during treatment and for at least 24 months and 20 months after cessation of vismodegib and sonidegib, respectively.^27,37,38 Male patients, even after a vasectomy, should use barrier contraception during treatment and for at least 3 months and 8 months after the final dose of vismodegib and sonidegib, respectively.^37,38

Laboratory abnormalities commonly associated with SHH inhibitors include elevated hepatic enzymes, particularly with vismodegib, and elevated creatine kinase levels, particularly with sonidegib.^28,39 Other laboratory abnormalities that can occur include hypercholesterolemia, hypercreatininemia, hyperglycemia, and increased serum lipase levels.^19,28 Although these laboratory abnormalities usually are asymptomatic and self-limiting, regular monitoring should be performed.

There also is concern that SHH inhibitors may induce the development of cSCC. A case-control study of 55 cases and 125 control patients found an increased risk for cSCC in those previously treated with vismodegib, with a hazard ratio of 8.12.⁴⁰ However, a subsequent retrospective cohort study of 1675 patients with BCC failed to find any association with cSCC among those treated with vismodegib compared to those who received standard surgical therapy.⁴¹ Clinical data for sonidegib are lacking, but the BOLT trial found that cSCC occurred in 3 patients receiving treatment with the SHH inhibitor.¹⁸ Thus, further studies are needed to more thoroughly assess this concern. Close monitoring for cSCC may be warranted in patients prescribed SHH inhibitors at this time.

Cemiplimab has demonstrated an acceptable safety profile and is generally well tolerated. In the phase 2 trial of cemiplimab for cSCC, approximately 5% of patients discontinued treatment because of adverse effects. The most commonly reported side effects of cemiplimab were diarrhea (27%), fatigue (24%), nausea (17%), constipation (15%), and rash (15%).²³ In the phase 2 trial for laBCC, grade 3 or 4 adverse events occurred in 48% of patients, with hypertension (5%) being the most common.²⁶ Although rare, immune-mediated adverse reactions also can occur, given the mechanism of action of ICIs. These side effects, ranging in severity from mild to fatal, include pneumonitis, colitis, hepatitis, nephritis, myocarditis, and hypophysitis. Therefore, close monitoring for these immune-mediated reactions is critical, but most can be managed with corticosteroids or treatment interruption if they occur.^42,43

No absolute contraindications exist for cemiplimab; however, extreme caution should be taken in immunosuppressed individuals, such as solid organ transplant recipients and those with chronic lymphocytic leukemia (CLL), as safety data are limited in these patients.^44,45 Although small retrospective studies have reported reasonable tolerability in solid organ transplant recipients treated with ICIs, an allograft rejection rate of 41% was found in a meta-analysis of 64 patients.^46-48 In CLL patients with keratinocyte carcinomas, ICIs have been safely used and have even demonstrated efficacy for CLL in some cases.^49-52

Alternative Dosing

The side effects of SHH inhibitors have led to alternative dosing strategies to prevent medication discontinuation and improve adherence. In patients with basal cell nevus syndrome, multimonth drug holidays have been shown to increase drug tolerability without compromising efficacy.^35,36 Weekly intermittent dosing regimens of vismodegib ranging from 1 week on followed by 1 to 3 weeks off demonstrated efficacy in a retrospective study of 7 patients with advanced BCC.⁵³ All 7 patients experienced improvement in their BCCs, with 3 patients experiencing CR. Importantly, treatment-related adverse effects were mild and well tolerated, with no patients terminating the medication.⁵³ Two other retrospective case series of patients with advanced BCC treated with vismodegib reported similar findings for those placed on an intermittent dosing schedule ranging from once every other day to once per week.^54,55

In the large phase 2 randomized trial known as MIKIE, 2 different intermittent dosing regimens of 150 mg vismodegib daily for patients with multiple BCCs were found to have good activity and tolerability.⁵⁶ The first group (n=116) received vismodegib for 12 weeks, then 3 rounds of 8 weeks of placebo, followed by 12 weeks of vismodegib; there was a 63% reduction in clinically evident BCCs after 73 weeks. The second group (n=113) received the medication for 24 weeks, then 3 rounds of 8 weeks of placebo, followed by 8 weeks of vismodegib; there was a 54% reduction at the end of 73 weeks.⁵⁶ Subsequent analyses found improvements in health-related quality-of-life outcomes that were similar for both groups.⁵⁷

Consequently, alternative dosing schedules appear to be a viable option for patients at risk of discontinuing treatment because of adverse effects, and current data support the recently approved recommendations of dose interruptions of up to 8 weeks to manage adverse effects in patients with laBCC or mBCC.⁵⁸ Nevertheless, further clinical studies are required to determine the optimal intermittent dosing regimen for patients treated with SHH inhibitors.

Neoadjuvant Administration

Recently, vismodegib has been studied as a neoadjuvant therapy for BCC with promising results. Several small retrospective studies and case reports have documented successful treatment of both operable and inoperable periocular laBCC, with preservation of the eye in all patients.^59-61 An open-label trial of 15 patients with advanced BCC who received neoadjuvant vismodegib for 3 to 6 months prior to surgical excision reported a mean reduction of 35% in the final surgical defect size, with no recurrence at 22 months.^62,63 The latest and largest study performed was a phase 2 open-label trial known as VISMONEO, where 44 of 55 laBCC patients (80%) receiving neoadjuvant vismodegib for a mean duration of 6 months (range, 4–10 months) achieved the primary end point of tumor surgical downstaging.⁶⁴ Of the 44 patients who had tumor downstaging, 27 (61%) experienced histologically proven CRs. Additionally, a 66% reduction in the average target lesion size was reported in this group compared to29% in the 11 patients who did not have tumor downstaging (P=.0002).⁶⁴ Thus, SHH inhibitors may hold an important neoadjuvant role in the treatment of BCC by decreasing surgical defect size and allowing for surgical management of previously inoperable cases.

Synergism With Radiation

Preliminary data suggest SHH inhibitors may help potentiate the effects of radiation therapy for the treatment of BCC. Currently, the evidence primarily is limited to case studies, with several reports describing complete remission in patients with advanced BCCs who were considered unsuitable candidates for surgery. In these cases, vismodegib was administered either prior to or concurrently with radiation treatment.^65-69 An in vitro study also documented the radiation-sensitizing effects of vismodegib in a BCC cell line.⁷⁰ Recently, a phase 2 trial (ClinicalTrials.gov identifier NCT01835626) evaluating the concurrent use of vismodegib and radiotherapy for patients with advanced BCC was completed, but data has yet to be published.

Synergism With and Benefit of Antifungal Therapy

The antifungal drug itraconazole is a potent inhibitor of the SHH pathway and may have an adjunctive role in the treatment of BCC. Similar to vismodegib and sonidegib, itraconazole acts as a direct antagonist of SMO. However, it is thought to bind to a distinct site on SMO.^71,72 An open-label, exploratory phase 2 trial of 19 patients with BCC found that oral itraconazole 200 to 400 mg daily decreased tumor proliferative index by 45% (P=.04), as measured by Ki-67; SHH activity by 65% (P=.03), as measured by GLI1 messenger RNA; and mean tumor area by 24%.⁷³ In a case series of 5 patients with mBCC refractory to conventional SHH inhibitor therapy, combined treatment with itraconazole and arsenic trioxide resulted in stable disease and a 75% reduction in SHH activity (P<.001).⁷⁴ One case report documented tumor regression leading to stable disease for 15 months in a patient with laBCC treated with itraconazole monotherapy due to being unable to afford vismodegib or sonidegib. However, within 2 months of treatment discontinuation, the lesion progressed considerably.⁷⁵ The efficacy of a topical formulation of itraconazole also has been tested in an open-label, placebo-controlled phase 2 trial, but no benefit was observed.⁷⁶

Posaconazole is a second-generation antifungal agent that may serve as a potential alternative to itraconazole.⁷⁷ Although clinical data are lacking, a basic science study found that posaconazole could inhibit the growth of SHH-dependent BCC in vivo (in mice).⁷⁸ Furthermore, posaconazole has demonstrated a better safety profile with fewer and more mild side effects than itraconazole and does not require dose adjustment for those with hepatic or renal failure.^79,80 Thus, posaconazole may be a safer alternative to itraconazole for the treatment of BCC. Further clinical studies are needed to elucidate the potential synergistic effects of these antifungal agents with the 2 currently approved SHH inhibitors for the treatment of advanced BCC.

Treatment resistance to SHH inhibitors, though uncommon, is a growing concern. Acquired mutations in the SMO binding site or downstream mediators of the SHH pathway have been shown to confer resistance to vismodegib and sonidegib.^72,81-83 In addition, it appears that there may be shared resistance among the drugs in this class. One study assessing the efficacy of sonidegib in 9 patients with laBCC resistant to vismodegib found that these patients also did not respond to sonidegib.⁸⁴ Interestingly, 1 case report documented tumor regression of an intracranial BCC in a patient treated with sonidegib and itraconazole after failure with vismodegib.⁸⁵ An in vitro study also found that itraconazole maintained SHH inhibitory activity for all drug-resistant SMO mutations that have been reported.⁷² Therefore, itraconazole monotherapy or combination therapy with a canonical SHH inhibitor may be considered for patients with recalcitrant BCC and warrants further investigation.

Taladegib is a newly developed SMO inhibitor that may serve as another promising alternative for patients who develop resistance to vismodegib or sonidegib. A phase 1 trial of taladegib for advanced BCC found an ORR of 69% (11/16) in the SHH inhibitor–naïve group and an ORR of 36% (11/32) in the group previously treated with a SHH inhibitor.⁸⁶ Additionally, the safety profile and frequency of adverse effects appear to be similar to those associated with vismodegib and sonidegib.^86,87 Unfortunately, no clinical trials evaluating taladegib for BCC are ongoing or in development at this time.

Recurrence

There appears to be a relatively high rate of recurrence for BCC patients who achieve a CR to SHH inhibitors. In a retrospective study of 116 laBCC patients who experienced a CR after vismodegib therapy, 54 patients (47%) relapsed at 36 months. Among the 54 patients that relapsed, 27 were re-treated with vismodegib, which resulted in an ORR of 85% (23/27), a CR rate of 37% (10/27), and a PR rate of 48% (13/27).⁸⁸ Another retrospective study of 35 laBCC patients who relapsed after vismodegib treatment reported a 31% (11/35) clinical recurrence rate at 6-month follow-up.⁸⁹ An observational retrospective study also assessed the efficacy of SHH inhibitor maintenance therapy for advanced BCC patients who achieved a CR.⁹⁰ In the study, 27 (64%) patients received a maintenance dose of 150 mg vismodegib once per week for 1 year, while 15 (36%) patients decided not to take a maintenance dose following CR of their BCC. All patients who took the maintenance therapy did not experience clinical recurrence at 1-year follow-up, whereas 26% of patients not on the maintenance dose relapsed.⁹⁰ Consequently, these results indicate that BCC recurrence is frequent after SHH inhibitor therapy and highlights the importance of close surveillance after CR is attained. Nevertheless, most patients still respond to treatment with SHH inhibitors after relapsing, and intermittent maintenance doses may be an effective means to reduce risk of recurrence.

Conclusion

Vismodegib and sonidegib are SHH inhibitors approved for the treatment of laBCC and mBCC. Cemiplimab is now also approved for patients who do not respond to SHH inhibitors or for whom SHH inhibitors are not tolerable. Although these systemic targeted therapies can lead to notable tumor shrinkage and even complete regression in some patients, recurrence is common, and adverse effects may limit their use. Drug resistance is an emerging issue that requires additional examination. Further clinical studies are needed to determine which patients are likely to respond to these targeted treatments.

Various intermittent and maintenance drug regimens should be evaluated for their potential to mitigate adverse effects and reduce risk of recurrence, respectively. The synergistic effects of these medications with other therapies as well as their neoadjuvant and adjuvant roles should be further investigated. For example, administration of an SHH inhibitor prior to surgical excision of a BCC may allow for a smaller surgical defect size, thereby improving cosmetic and functional outcomes. Moreover, these systemic targeted medications may allow for previously inoperable tumors to become amenable to surgical treatment.

Although SHH inhibitors and PD-1 inhibitors represent a major advancement in the field of oncodermatology, real-world efficacy and safety data in the upcoming years will be important for elucidating their true benefit for patients with BCC.

Basal cell carcinoma (BCC) is the most common keratinocyte carcinoma and affects more than 3 million individuals per year in the United States.¹ Approximately 40% of patients diagnosed with BCC will develop another BCC within 5 years of the initial diagnosis.² Most cases are successfully treated with surgical excision and occasionally topical therapy or radiotherapy. Despite the high cure rate with conventional treatments, BCC can recur and can cause substantial destruction of the surrounding tissue if left untreated.^3-5 In some instances, BCC can even metastasize and lead to death.⁶ For patients who are poor candidates for surgical or topical treatment modalities because of locally advanced BCC (laBCC) or metastatic BCC (mBCC), systemic treatment may be indicated. Vismodegib, sonidegib, and cemiplimab are the only systemic medications approved by the US Food and Drug Administration (FDA) for the treatment of laBCC and/or mBCC. Vismodegib and sonidegib target the sonic hedgehog (SHH) signaling pathway that is abnormally activated in more than 90% of BCCs.⁷ Cemiplimab is an immune checkpoint inhibitor (ICI) that targets the programmed cell death protein 1 (PD-1) receptor.⁸ Herein, we review the clinical utility of these medications and their evolving roles in the treatment of BCC.

SHH Pathway Inhibitors

The SHH pathway is a key regulator of cell proliferation and differentiation during embryogenesis.⁷ During adulthood, SHH signaling decreases but still plays an important role in stem cell activation and in regulation of the hair follicle growth cycle.^9,10 However, de novo mutations in the genes that comprise the SHH pathway can result in aberrant constitutive activation, leading to unrestricted cell proliferation. Genetic mutations resulting in activation of Smoothened (SMO), a G-protein–coupled receptor involved in the signal transduction and propagation of the SHH pathway, have been implicated in the pathogenesis of BCC. Inactivating mutations also are commonly observed in patched homolog 1, an upstream cell-surface protein that inhibits SMO.⁷ The mechanism by which vismodegib and sonidegib, 2 of the FDA-approved oral medications for the treatment of advanced BCC, block the SHH pathway is through the selective inhibition of SMO.^7,11

Vismodegib first received FDA approval in 2012 for the treatment of laBCC and mBCC after initial results from the pivotal ERIVANCE phase 2 trial demonstrated an objective response rate (ORR) of 43% (27/63) and 30% (10/33) in patients with locally advanced and metastatic disease, respectively. In this single-arm study, all enrolled patients (63 with laBCC and 33 with mBCC) received 150 mg of oral vismodegib daily.¹² Updated results at 39 months demonstrated improved ORRs of 60% (38/63) and 48% (16/33) for the laBCC and mBCC groups, respectively. A complete response (CR) and partial response (PR) were observed in 32% (n=20) and 29% (n=18) of patients with laBCC, respectively.¹³ These results have been confirmed in subsequent studies, including the large international open-label trial known as STEVIE, with ORRs of 68.5% for 1119 cases of laBCC and 37% for 96 cases of mBCC.^14-17 The CR and PR rates were 33% and 35%, respectively, for the laBCC group. The CR and PR rates for the mBCC group were 5% and 32%, respectively.¹⁴

The FDA approval of sonidegib for laBCC—but not mBCC—occurred in 2015 after the pivotal BOLT randomized phase 2 trial demonstrated an initial ORR of 43% (18/42) for laBCC and 15% (2/13) for mBCC after administration of 200 mg of sonidegib daily.¹⁸ A final follow-up analysis at 42 months resulted in ORRs of 56% (37/66) and 8% (1/13) for the laBCC and mBCC groups, respectively.¹⁹ Additionally, improved efficacy was not observed in the 151 patients who were randomized to receive treatment with the higher 800-mg dose; however, they did experience a higher incidence of adverse events.^18,19

Currently, the true clinical differences between vismodegib and sonidegib remain uncertain, as no head-to-head trials have been conducted. Moreover, direct comparison of the data from the ERIVANCE and BOLT trials is challenging owing to fundamental differences in methodologic design, including the criteria used to assess BCC severity. The ERIVANCE trial utilized the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while BOLT used the rigorous modified RECIST. However, an expert consensus study attempted to compare the 2 trials by modifying the outcomes from BOLT with the former RECIST criteria. The expert group found that the 2 SHH inhibitors had comparable efficacy and adverse event profiles.²⁰ Nevertheless, a recent meta-analysis found that although ORRs for laBCC were similar between the 2 drugs, the CR rate for vismodegib was 31% compared with 3% for sonidegib. Additionally, for mBCC, they reported the ORR of vismodegib to be 2.7 times higher than that of sonidegib (39% vs 15%).²¹

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors have successfully been utilized in the treatment of cutaneous squamous cell carcinoma (cSCC); however, their use for treating BCC has been limited until recently.^22-25 In February 2021, cemiplimab became the first and only ICI approved for the treatment of laBCC and mBCC in patients who did not respond to or were intolerant to prior SHH inhibitor therapy.²⁶ Cemiplimab—a human monoclonal antibody against the PD-1 receptor expressed on T cells—blocks its interaction with programmed cell death ligand 1 and programmed cell death ligand 2 present on tumor cells. The blockade of the PD-1 pathway releases the inhibition of the antitumor immune response and enables appropriate cytotoxic T-cell activity to occur.⁸

The FDA approval of cemiplimab for the treatment of advanced BCC was based on an open-label, multicenter, single-arm phase 2 trial (NCT03132636) evaluating 84 patients with laBCC refractory or intolerant to SHH inhibitor therapy.²⁶ Patients received an intravenous infusion of cemiplimab 350 mg every 3 weeks for up to 93 weeks or until disease progression or unacceptable toxicity. An ORR of 31% (26/84) was observed with a CR and PR of 6% (5/84) and 25% (21/84), respectively. The median duration of follow-up was 15 months.²⁶ Given the clinically meaningful results of this trial, investigating the efficacy of other PD-1 inhibitors, such as pembrolizumab and nivolumab, for treatment of advanced BCC may prove worthwhile.

The 2 approved SHH inhibitors—vismodegib and sonidegib—appear to have similar side-effect profiles, with the most common adverse effects being muscle spasms, dysgeusia, alopecia, nausea, vomiting, diarrhea, weight loss, and fatigue.^20,21,27 These side effects occur at high frequencies (>40%) for both SHH inhibitors and often lead to discontinuation of the medication.²¹ Rates of treatment discontinuation range from 15% to 50% on average.^12-14,18 Fortunately, the majority of these adverse effects do not appear to increase in severity or frequency with prolonged use of these medications.^14,16,28

Various conservative and pharmacologic measures can be implemented to help manage side effects. For muscle spasms, which are the most commonly reported adverse effect, supplementation with magnesium, transcutaneous electrical nerve stimulation, acupuncture, massages, stretching, and thermal compresses can potentially be beneficial.²⁹ Calcium channel blockers also may be effective, as one small prospective cohort study reported a reduction in the frequency of muscle cramps with amlodipine 10 mg daily.³⁰ For alopecia, which typically is reversible and caused by SHH inhibition of the normal hair cycle, minoxidil theoretically can help, as it reduces telogen arrest and extends the anagen growth phase.^31,32 Although usually mild and self-limiting, management of dysgeusia, weight loss, and gastrointestinal upset often can be managed with dietary changes, such as smaller, more frequent meals.^33,34 Finally, alternative dosing strategies and drug holidays have been employed to mitigate these side effects and increase drug tolerability.^35,36 These are discussed in the Alternative Dosing section.

Given the essential role of the SHH pathway in embryologic development, SHH inhibitors carry a black box warning of embryofetal teratogenicity and are contraindicated in females who are pregnant or breastfeeding. For females of reproductive potential, verification of pregnancy status should be performed prior to initiating treatment with an SHH inhibitor. These patients should be counseled on the use of contraception during treatment and for at least 24 months and 20 months after cessation of vismodegib and sonidegib, respectively.^27,37,38 Male patients, even after a vasectomy, should use barrier contraception during treatment and for at least 3 months and 8 months after the final dose of vismodegib and sonidegib, respectively.^37,38

Laboratory abnormalities commonly associated with SHH inhibitors include elevated hepatic enzymes, particularly with vismodegib, and elevated creatine kinase levels, particularly with sonidegib.^28,39 Other laboratory abnormalities that can occur include hypercholesterolemia, hypercreatininemia, hyperglycemia, and increased serum lipase levels.^19,28 Although these laboratory abnormalities usually are asymptomatic and self-limiting, regular monitoring should be performed.

There also is concern that SHH inhibitors may induce the development of cSCC. A case-control study of 55 cases and 125 control patients found an increased risk for cSCC in those previously treated with vismodegib, with a hazard ratio of 8.12.⁴⁰ However, a subsequent retrospective cohort study of 1675 patients with BCC failed to find any association with cSCC among those treated with vismodegib compared to those who received standard surgical therapy.⁴¹ Clinical data for sonidegib are lacking, but the BOLT trial found that cSCC occurred in 3 patients receiving treatment with the SHH inhibitor.¹⁸ Thus, further studies are needed to more thoroughly assess this concern. Close monitoring for cSCC may be warranted in patients prescribed SHH inhibitors at this time.

Cemiplimab has demonstrated an acceptable safety profile and is generally well tolerated. In the phase 2 trial of cemiplimab for cSCC, approximately 5% of patients discontinued treatment because of adverse effects. The most commonly reported side effects of cemiplimab were diarrhea (27%), fatigue (24%), nausea (17%), constipation (15%), and rash (15%).²³ In the phase 2 trial for laBCC, grade 3 or 4 adverse events occurred in 48% of patients, with hypertension (5%) being the most common.²⁶ Although rare, immune-mediated adverse reactions also can occur, given the mechanism of action of ICIs. These side effects, ranging in severity from mild to fatal, include pneumonitis, colitis, hepatitis, nephritis, myocarditis, and hypophysitis. Therefore, close monitoring for these immune-mediated reactions is critical, but most can be managed with corticosteroids or treatment interruption if they occur.^42,43

No absolute contraindications exist for cemiplimab; however, extreme caution should be taken in immunosuppressed individuals, such as solid organ transplant recipients and those with chronic lymphocytic leukemia (CLL), as safety data are limited in these patients.^44,45 Although small retrospective studies have reported reasonable tolerability in solid organ transplant recipients treated with ICIs, an allograft rejection rate of 41% was found in a meta-analysis of 64 patients.^46-48 In CLL patients with keratinocyte carcinomas, ICIs have been safely used and have even demonstrated efficacy for CLL in some cases.^49-52

Alternative Dosing

The side effects of SHH inhibitors have led to alternative dosing strategies to prevent medication discontinuation and improve adherence. In patients with basal cell nevus syndrome, multimonth drug holidays have been shown to increase drug tolerability without compromising efficacy.^35,36 Weekly intermittent dosing regimens of vismodegib ranging from 1 week on followed by 1 to 3 weeks off demonstrated efficacy in a retrospective study of 7 patients with advanced BCC.⁵³ All 7 patients experienced improvement in their BCCs, with 3 patients experiencing CR. Importantly, treatment-related adverse effects were mild and well tolerated, with no patients terminating the medication.⁵³ Two other retrospective case series of patients with advanced BCC treated with vismodegib reported similar findings for those placed on an intermittent dosing schedule ranging from once every other day to once per week.^54,55

In the large phase 2 randomized trial known as MIKIE, 2 different intermittent dosing regimens of 150 mg vismodegib daily for patients with multiple BCCs were found to have good activity and tolerability.⁵⁶ The first group (n=116) received vismodegib for 12 weeks, then 3 rounds of 8 weeks of placebo, followed by 12 weeks of vismodegib; there was a 63% reduction in clinically evident BCCs after 73 weeks. The second group (n=113) received the medication for 24 weeks, then 3 rounds of 8 weeks of placebo, followed by 8 weeks of vismodegib; there was a 54% reduction at the end of 73 weeks.⁵⁶ Subsequent analyses found improvements in health-related quality-of-life outcomes that were similar for both groups.⁵⁷

Consequently, alternative dosing schedules appear to be a viable option for patients at risk of discontinuing treatment because of adverse effects, and current data support the recently approved recommendations of dose interruptions of up to 8 weeks to manage adverse effects in patients with laBCC or mBCC.⁵⁸ Nevertheless, further clinical studies are required to determine the optimal intermittent dosing regimen for patients treated with SHH inhibitors.

Neoadjuvant Administration

Recently, vismodegib has been studied as a neoadjuvant therapy for BCC with promising results. Several small retrospective studies and case reports have documented successful treatment of both operable and inoperable periocular laBCC, with preservation of the eye in all patients.^59-61 An open-label trial of 15 patients with advanced BCC who received neoadjuvant vismodegib for 3 to 6 months prior to surgical excision reported a mean reduction of 35% in the final surgical defect size, with no recurrence at 22 months.^62,63 The latest and largest study performed was a phase 2 open-label trial known as VISMONEO, where 44 of 55 laBCC patients (80%) receiving neoadjuvant vismodegib for a mean duration of 6 months (range, 4–10 months) achieved the primary end point of tumor surgical downstaging.⁶⁴ Of the 44 patients who had tumor downstaging, 27 (61%) experienced histologically proven CRs. Additionally, a 66% reduction in the average target lesion size was reported in this group compared to29% in the 11 patients who did not have tumor downstaging (P=.0002).⁶⁴ Thus, SHH inhibitors may hold an important neoadjuvant role in the treatment of BCC by decreasing surgical defect size and allowing for surgical management of previously inoperable cases.

Synergism With Radiation

Preliminary data suggest SHH inhibitors may help potentiate the effects of radiation therapy for the treatment of BCC. Currently, the evidence primarily is limited to case studies, with several reports describing complete remission in patients with advanced BCCs who were considered unsuitable candidates for surgery. In these cases, vismodegib was administered either prior to or concurrently with radiation treatment.^65-69 An in vitro study also documented the radiation-sensitizing effects of vismodegib in a BCC cell line.⁷⁰ Recently, a phase 2 trial (ClinicalTrials.gov identifier NCT01835626) evaluating the concurrent use of vismodegib and radiotherapy for patients with advanced BCC was completed, but data has yet to be published.

Synergism With and Benefit of Antifungal Therapy

The antifungal drug itraconazole is a potent inhibitor of the SHH pathway and may have an adjunctive role in the treatment of BCC. Similar to vismodegib and sonidegib, itraconazole acts as a direct antagonist of SMO. However, it is thought to bind to a distinct site on SMO.^71,72 An open-label, exploratory phase 2 trial of 19 patients with BCC found that oral itraconazole 200 to 400 mg daily decreased tumor proliferative index by 45% (P=.04), as measured by Ki-67; SHH activity by 65% (P=.03), as measured by GLI1 messenger RNA; and mean tumor area by 24%.⁷³ In a case series of 5 patients with mBCC refractory to conventional SHH inhibitor therapy, combined treatment with itraconazole and arsenic trioxide resulted in stable disease and a 75% reduction in SHH activity (P<.001).⁷⁴ One case report documented tumor regression leading to stable disease for 15 months in a patient with laBCC treated with itraconazole monotherapy due to being unable to afford vismodegib or sonidegib. However, within 2 months of treatment discontinuation, the lesion progressed considerably.⁷⁵ The efficacy of a topical formulation of itraconazole also has been tested in an open-label, placebo-controlled phase 2 trial, but no benefit was observed.⁷⁶

Posaconazole is a second-generation antifungal agent that may serve as a potential alternative to itraconazole.⁷⁷ Although clinical data are lacking, a basic science study found that posaconazole could inhibit the growth of SHH-dependent BCC in vivo (in mice).⁷⁸ Furthermore, posaconazole has demonstrated a better safety profile with fewer and more mild side effects than itraconazole and does not require dose adjustment for those with hepatic or renal failure.^79,80 Thus, posaconazole may be a safer alternative to itraconazole for the treatment of BCC. Further clinical studies are needed to elucidate the potential synergistic effects of these antifungal agents with the 2 currently approved SHH inhibitors for the treatment of advanced BCC.

Treatment resistance to SHH inhibitors, though uncommon, is a growing concern. Acquired mutations in the SMO binding site or downstream mediators of the SHH pathway have been shown to confer resistance to vismodegib and sonidegib.^72,81-83 In addition, it appears that there may be shared resistance among the drugs in this class. One study assessing the efficacy of sonidegib in 9 patients with laBCC resistant to vismodegib found that these patients also did not respond to sonidegib.⁸⁴ Interestingly, 1 case report documented tumor regression of an intracranial BCC in a patient treated with sonidegib and itraconazole after failure with vismodegib.⁸⁵ An in vitro study also found that itraconazole maintained SHH inhibitory activity for all drug-resistant SMO mutations that have been reported.⁷² Therefore, itraconazole monotherapy or combination therapy with a canonical SHH inhibitor may be considered for patients with recalcitrant BCC and warrants further investigation.

Taladegib is a newly developed SMO inhibitor that may serve as another promising alternative for patients who develop resistance to vismodegib or sonidegib. A phase 1 trial of taladegib for advanced BCC found an ORR of 69% (11/16) in the SHH inhibitor–naïve group and an ORR of 36% (11/32) in the group previously treated with a SHH inhibitor.⁸⁶ Additionally, the safety profile and frequency of adverse effects appear to be similar to those associated with vismodegib and sonidegib.^86,87 Unfortunately, no clinical trials evaluating taladegib for BCC are ongoing or in development at this time.

Recurrence

There appears to be a relatively high rate of recurrence for BCC patients who achieve a CR to SHH inhibitors. In a retrospective study of 116 laBCC patients who experienced a CR after vismodegib therapy, 54 patients (47%) relapsed at 36 months. Among the 54 patients that relapsed, 27 were re-treated with vismodegib, which resulted in an ORR of 85% (23/27), a CR rate of 37% (10/27), and a PR rate of 48% (13/27).⁸⁸ Another retrospective study of 35 laBCC patients who relapsed after vismodegib treatment reported a 31% (11/35) clinical recurrence rate at 6-month follow-up.⁸⁹ An observational retrospective study also assessed the efficacy of SHH inhibitor maintenance therapy for advanced BCC patients who achieved a CR.⁹⁰ In the study, 27 (64%) patients received a maintenance dose of 150 mg vismodegib once per week for 1 year, while 15 (36%) patients decided not to take a maintenance dose following CR of their BCC. All patients who took the maintenance therapy did not experience clinical recurrence at 1-year follow-up, whereas 26% of patients not on the maintenance dose relapsed.⁹⁰ Consequently, these results indicate that BCC recurrence is frequent after SHH inhibitor therapy and highlights the importance of close surveillance after CR is attained. Nevertheless, most patients still respond to treatment with SHH inhibitors after relapsing, and intermittent maintenance doses may be an effective means to reduce risk of recurrence.

Conclusion

Vismodegib and sonidegib are SHH inhibitors approved for the treatment of laBCC and mBCC. Cemiplimab is now also approved for patients who do not respond to SHH inhibitors or for whom SHH inhibitors are not tolerable. Although these systemic targeted therapies can lead to notable tumor shrinkage and even complete regression in some patients, recurrence is common, and adverse effects may limit their use. Drug resistance is an emerging issue that requires additional examination. Further clinical studies are needed to determine which patients are likely to respond to these targeted treatments.

Various intermittent and maintenance drug regimens should be evaluated for their potential to mitigate adverse effects and reduce risk of recurrence, respectively. The synergistic effects of these medications with other therapies as well as their neoadjuvant and adjuvant roles should be further investigated. For example, administration of an SHH inhibitor prior to surgical excision of a BCC may allow for a smaller surgical defect size, thereby improving cosmetic and functional outcomes. Moreover, these systemic targeted medications may allow for previously inoperable tumors to become amenable to surgical treatment.

Although SHH inhibitors and PD-1 inhibitors represent a major advancement in the field of oncodermatology, real-world efficacy and safety data in the upcoming years will be important for elucidating their true benefit for patients with BCC.

Basal cell carcinoma (BCC) is the most common keratinocyte carcinoma and affects more than 3 million individuals per year in the United States.¹ Approximately 40% of patients diagnosed with BCC will develop another BCC within 5 years of the initial diagnosis.² Most cases are successfully treated with surgical excision and occasionally topical therapy or radiotherapy. Despite the high cure rate with conventional treatments, BCC can recur and can cause substantial destruction of the surrounding tissue if left untreated.^3-5 In some instances, BCC can even metastasize and lead to death.⁶ For patients who are poor candidates for surgical or topical treatment modalities because of locally advanced BCC (laBCC) or metastatic BCC (mBCC), systemic treatment may be indicated. Vismodegib, sonidegib, and cemiplimab are the only systemic medications approved by the US Food and Drug Administration (FDA) for the treatment of laBCC and/or mBCC. Vismodegib and sonidegib target the sonic hedgehog (SHH) signaling pathway that is abnormally activated in more than 90% of BCCs.⁷ Cemiplimab is an immune checkpoint inhibitor (ICI) that targets the programmed cell death protein 1 (PD-1) receptor.⁸ Herein, we review the clinical utility of these medications and their evolving roles in the treatment of BCC.

SHH Pathway Inhibitors

The SHH pathway is a key regulator of cell proliferation and differentiation during embryogenesis.⁷ During adulthood, SHH signaling decreases but still plays an important role in stem cell activation and in regulation of the hair follicle growth cycle.^9,10 However, de novo mutations in the genes that comprise the SHH pathway can result in aberrant constitutive activation, leading to unrestricted cell proliferation. Genetic mutations resulting in activation of Smoothened (SMO), a G-protein–coupled receptor involved in the signal transduction and propagation of the SHH pathway, have been implicated in the pathogenesis of BCC. Inactivating mutations also are commonly observed in patched homolog 1, an upstream cell-surface protein that inhibits SMO.⁷ The mechanism by which vismodegib and sonidegib, 2 of the FDA-approved oral medications for the treatment of advanced BCC, block the SHH pathway is through the selective inhibition of SMO.^7,11

Vismodegib first received FDA approval in 2012 for the treatment of laBCC and mBCC after initial results from the pivotal ERIVANCE phase 2 trial demonstrated an objective response rate (ORR) of 43% (27/63) and 30% (10/33) in patients with locally advanced and metastatic disease, respectively. In this single-arm study, all enrolled patients (63 with laBCC and 33 with mBCC) received 150 mg of oral vismodegib daily.¹² Updated results at 39 months demonstrated improved ORRs of 60% (38/63) and 48% (16/33) for the laBCC and mBCC groups, respectively. A complete response (CR) and partial response (PR) were observed in 32% (n=20) and 29% (n=18) of patients with laBCC, respectively.¹³ These results have been confirmed in subsequent studies, including the large international open-label trial known as STEVIE, with ORRs of 68.5% for 1119 cases of laBCC and 37% for 96 cases of mBCC.^14-17 The CR and PR rates were 33% and 35%, respectively, for the laBCC group. The CR and PR rates for the mBCC group were 5% and 32%, respectively.¹⁴

The FDA approval of sonidegib for laBCC—but not mBCC—occurred in 2015 after the pivotal BOLT randomized phase 2 trial demonstrated an initial ORR of 43% (18/42) for laBCC and 15% (2/13) for mBCC after administration of 200 mg of sonidegib daily.¹⁸ A final follow-up analysis at 42 months resulted in ORRs of 56% (37/66) and 8% (1/13) for the laBCC and mBCC groups, respectively.¹⁹ Additionally, improved efficacy was not observed in the 151 patients who were randomized to receive treatment with the higher 800-mg dose; however, they did experience a higher incidence of adverse events.^18,19

Currently, the true clinical differences between vismodegib and sonidegib remain uncertain, as no head-to-head trials have been conducted. Moreover, direct comparison of the data from the ERIVANCE and BOLT trials is challenging owing to fundamental differences in methodologic design, including the criteria used to assess BCC severity. The ERIVANCE trial utilized the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while BOLT used the rigorous modified RECIST. However, an expert consensus study attempted to compare the 2 trials by modifying the outcomes from BOLT with the former RECIST criteria. The expert group found that the 2 SHH inhibitors had comparable efficacy and adverse event profiles.²⁰ Nevertheless, a recent meta-analysis found that although ORRs for laBCC were similar between the 2 drugs, the CR rate for vismodegib was 31% compared with 3% for sonidegib. Additionally, for mBCC, they reported the ORR of vismodegib to be 2.7 times higher than that of sonidegib (39% vs 15%).²¹

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors have successfully been utilized in the treatment of cutaneous squamous cell carcinoma (cSCC); however, their use for treating BCC has been limited until recently.^22-25 In February 2021, cemiplimab became the first and only ICI approved for the treatment of laBCC and mBCC in patients who did not respond to or were intolerant to prior SHH inhibitor therapy.²⁶ Cemiplimab—a human monoclonal antibody against the PD-1 receptor expressed on T cells—blocks its interaction with programmed cell death ligand 1 and programmed cell death ligand 2 present on tumor cells. The blockade of the PD-1 pathway releases the inhibition of the antitumor immune response and enables appropriate cytotoxic T-cell activity to occur.⁸

The FDA approval of cemiplimab for the treatment of advanced BCC was based on an open-label, multicenter, single-arm phase 2 trial (NCT03132636) evaluating 84 patients with laBCC refractory or intolerant to SHH inhibitor therapy.²⁶ Patients received an intravenous infusion of cemiplimab 350 mg every 3 weeks for up to 93 weeks or until disease progression or unacceptable toxicity. An ORR of 31% (26/84) was observed with a CR and PR of 6% (5/84) and 25% (21/84), respectively. The median duration of follow-up was 15 months.²⁶ Given the clinically meaningful results of this trial, investigating the efficacy of other PD-1 inhibitors, such as pembrolizumab and nivolumab, for treatment of advanced BCC may prove worthwhile.

The 2 approved SHH inhibitors—vismodegib and sonidegib—appear to have similar side-effect profiles, with the most common adverse effects being muscle spasms, dysgeusia, alopecia, nausea, vomiting, diarrhea, weight loss, and fatigue.^20,21,27 These side effects occur at high frequencies (>40%) for both SHH inhibitors and often lead to discontinuation of the medication.²¹ Rates of treatment discontinuation range from 15% to 50% on average.^12-14,18 Fortunately, the majority of these adverse effects do not appear to increase in severity or frequency with prolonged use of these medications.^14,16,28

Various conservative and pharmacologic measures can be implemented to help manage side effects. For muscle spasms, which are the most commonly reported adverse effect, supplementation with magnesium, transcutaneous electrical nerve stimulation, acupuncture, massages, stretching, and thermal compresses can potentially be beneficial.²⁹ Calcium channel blockers also may be effective, as one small prospective cohort study reported a reduction in the frequency of muscle cramps with amlodipine 10 mg daily.³⁰ For alopecia, which typically is reversible and caused by SHH inhibition of the normal hair cycle, minoxidil theoretically can help, as it reduces telogen arrest and extends the anagen growth phase.^31,32 Although usually mild and self-limiting, management of dysgeusia, weight loss, and gastrointestinal upset often can be managed with dietary changes, such as smaller, more frequent meals.^33,34 Finally, alternative dosing strategies and drug holidays have been employed to mitigate these side effects and increase drug tolerability.^35,36 These are discussed in the Alternative Dosing section.

Given the essential role of the SHH pathway in embryologic development, SHH inhibitors carry a black box warning of embryofetal teratogenicity and are contraindicated in females who are pregnant or breastfeeding. For females of reproductive potential, verification of pregnancy status should be performed prior to initiating treatment with an SHH inhibitor. These patients should be counseled on the use of contraception during treatment and for at least 24 months and 20 months after cessation of vismodegib and sonidegib, respectively.^27,37,38 Male patients, even after a vasectomy, should use barrier contraception during treatment and for at least 3 months and 8 months after the final dose of vismodegib and sonidegib, respectively.^37,38

Laboratory abnormalities commonly associated with SHH inhibitors include elevated hepatic enzymes, particularly with vismodegib, and elevated creatine kinase levels, particularly with sonidegib.^28,39 Other laboratory abnormalities that can occur include hypercholesterolemia, hypercreatininemia, hyperglycemia, and increased serum lipase levels.^19,28 Although these laboratory abnormalities usually are asymptomatic and self-limiting, regular monitoring should be performed.

There also is concern that SHH inhibitors may induce the development of cSCC. A case-control study of 55 cases and 125 control patients found an increased risk for cSCC in those previously treated with vismodegib, with a hazard ratio of 8.12.⁴⁰ However, a subsequent retrospective cohort study of 1675 patients with BCC failed to find any association with cSCC among those treated with vismodegib compared to those who received standard surgical therapy.⁴¹ Clinical data for sonidegib are lacking, but the BOLT trial found that cSCC occurred in 3 patients receiving treatment with the SHH inhibitor.¹⁸ Thus, further studies are needed to more thoroughly assess this concern. Close monitoring for cSCC may be warranted in patients prescribed SHH inhibitors at this time.

Cemiplimab has demonstrated an acceptable safety profile and is generally well tolerated. In the phase 2 trial of cemiplimab for cSCC, approximately 5% of patients discontinued treatment because of adverse effects. The most commonly reported side effects of cemiplimab were diarrhea (27%), fatigue (24%), nausea (17%), constipation (15%), and rash (15%).²³ In the phase 2 trial for laBCC, grade 3 or 4 adverse events occurred in 48% of patients, with hypertension (5%) being the most common.²⁶ Although rare, immune-mediated adverse reactions also can occur, given the mechanism of action of ICIs. These side effects, ranging in severity from mild to fatal, include pneumonitis, colitis, hepatitis, nephritis, myocarditis, and hypophysitis. Therefore, close monitoring for these immune-mediated reactions is critical, but most can be managed with corticosteroids or treatment interruption if they occur.^42,43

No absolute contraindications exist for cemiplimab; however, extreme caution should be taken in immunosuppressed individuals, such as solid organ transplant recipients and those with chronic lymphocytic leukemia (CLL), as safety data are limited in these patients.^44,45 Although small retrospective studies have reported reasonable tolerability in solid organ transplant recipients treated with ICIs, an allograft rejection rate of 41% was found in a meta-analysis of 64 patients.^46-48 In CLL patients with keratinocyte carcinomas, ICIs have been safely used and have even demonstrated efficacy for CLL in some cases.^49-52

Alternative Dosing

The side effects of SHH inhibitors have led to alternative dosing strategies to prevent medication discontinuation and improve adherence. In patients with basal cell nevus syndrome, multimonth drug holidays have been shown to increase drug tolerability without compromising efficacy.^35,36 Weekly intermittent dosing regimens of vismodegib ranging from 1 week on followed by 1 to 3 weeks off demonstrated efficacy in a retrospective study of 7 patients with advanced BCC.⁵³ All 7 patients experienced improvement in their BCCs, with 3 patients experiencing CR. Importantly, treatment-related adverse effects were mild and well tolerated, with no patients terminating the medication.⁵³ Two other retrospective case series of patients with advanced BCC treated with vismodegib reported similar findings for those placed on an intermittent dosing schedule ranging from once every other day to once per week.^54,55

In the large phase 2 randomized trial known as MIKIE, 2 different intermittent dosing regimens of 150 mg vismodegib daily for patients with multiple BCCs were found to have good activity and tolerability.⁵⁶ The first group (n=116) received vismodegib for 12 weeks, then 3 rounds of 8 weeks of placebo, followed by 12 weeks of vismodegib; there was a 63% reduction in clinically evident BCCs after 73 weeks. The second group (n=113) received the medication for 24 weeks, then 3 rounds of 8 weeks of placebo, followed by 8 weeks of vismodegib; there was a 54% reduction at the end of 73 weeks.⁵⁶ Subsequent analyses found improvements in health-related quality-of-life outcomes that were similar for both groups.⁵⁷

Consequently, alternative dosing schedules appear to be a viable option for patients at risk of discontinuing treatment because of adverse effects, and current data support the recently approved recommendations of dose interruptions of up to 8 weeks to manage adverse effects in patients with laBCC or mBCC.⁵⁸ Nevertheless, further clinical studies are required to determine the optimal intermittent dosing regimen for patients treated with SHH inhibitors.

Neoadjuvant Administration

Recently, vismodegib has been studied as a neoadjuvant therapy for BCC with promising results. Several small retrospective studies and case reports have documented successful treatment of both operable and inoperable periocular laBCC, with preservation of the eye in all patients.^59-61 An open-label trial of 15 patients with advanced BCC who received neoadjuvant vismodegib for 3 to 6 months prior to surgical excision reported a mean reduction of 35% in the final surgical defect size, with no recurrence at 22 months.^62,63 The latest and largest study performed was a phase 2 open-label trial known as VISMONEO, where 44 of 55 laBCC patients (80%) receiving neoadjuvant vismodegib for a mean duration of 6 months (range, 4–10 months) achieved the primary end point of tumor surgical downstaging.⁶⁴ Of the 44 patients who had tumor downstaging, 27 (61%) experienced histologically proven CRs. Additionally, a 66% reduction in the average target lesion size was reported in this group compared to29% in the 11 patients who did not have tumor downstaging (P=.0002).⁶⁴ Thus, SHH inhibitors may hold an important neoadjuvant role in the treatment of BCC by decreasing surgical defect size and allowing for surgical management of previously inoperable cases.

Synergism With Radiation

Preliminary data suggest SHH inhibitors may help potentiate the effects of radiation therapy for the treatment of BCC. Currently, the evidence primarily is limited to case studies, with several reports describing complete remission in patients with advanced BCCs who were considered unsuitable candidates for surgery. In these cases, vismodegib was administered either prior to or concurrently with radiation treatment.^65-69 An in vitro study also documented the radiation-sensitizing effects of vismodegib in a BCC cell line.⁷⁰ Recently, a phase 2 trial (ClinicalTrials.gov identifier NCT01835626) evaluating the concurrent use of vismodegib and radiotherapy for patients with advanced BCC was completed, but data has yet to be published.

Synergism With and Benefit of Antifungal Therapy

The antifungal drug itraconazole is a potent inhibitor of the SHH pathway and may have an adjunctive role in the treatment of BCC. Similar to vismodegib and sonidegib, itraconazole acts as a direct antagonist of SMO. However, it is thought to bind to a distinct site on SMO.^71,72 An open-label, exploratory phase 2 trial of 19 patients with BCC found that oral itraconazole 200 to 400 mg daily decreased tumor proliferative index by 45% (P=.04), as measured by Ki-67; SHH activity by 65% (P=.03), as measured by GLI1 messenger RNA; and mean tumor area by 24%.⁷³ In a case series of 5 patients with mBCC refractory to conventional SHH inhibitor therapy, combined treatment with itraconazole and arsenic trioxide resulted in stable disease and a 75% reduction in SHH activity (P<.001).⁷⁴ One case report documented tumor regression leading to stable disease for 15 months in a patient with laBCC treated with itraconazole monotherapy due to being unable to afford vismodegib or sonidegib. However, within 2 months of treatment discontinuation, the lesion progressed considerably.⁷⁵ The efficacy of a topical formulation of itraconazole also has been tested in an open-label, placebo-controlled phase 2 trial, but no benefit was observed.⁷⁶

Posaconazole is a second-generation antifungal agent that may serve as a potential alternative to itraconazole.⁷⁷ Although clinical data are lacking, a basic science study found that posaconazole could inhibit the growth of SHH-dependent BCC in vivo (in mice).⁷⁸ Furthermore, posaconazole has demonstrated a better safety profile with fewer and more mild side effects than itraconazole and does not require dose adjustment for those with hepatic or renal failure.^79,80 Thus, posaconazole may be a safer alternative to itraconazole for the treatment of BCC. Further clinical studies are needed to elucidate the potential synergistic effects of these antifungal agents with the 2 currently approved SHH inhibitors for the treatment of advanced BCC.

Treatment resistance to SHH inhibitors, though uncommon, is a growing concern. Acquired mutations in the SMO binding site or downstream mediators of the SHH pathway have been shown to confer resistance to vismodegib and sonidegib.^72,81-83 In addition, it appears that there may be shared resistance among the drugs in this class. One study assessing the efficacy of sonidegib in 9 patients with laBCC resistant to vismodegib found that these patients also did not respond to sonidegib.⁸⁴ Interestingly, 1 case report documented tumor regression of an intracranial BCC in a patient treated with sonidegib and itraconazole after failure with vismodegib.⁸⁵ An in vitro study also found that itraconazole maintained SHH inhibitory activity for all drug-resistant SMO mutations that have been reported.⁷² Therefore, itraconazole monotherapy or combination therapy with a canonical SHH inhibitor may be considered for patients with recalcitrant BCC and warrants further investigation.

Taladegib is a newly developed SMO inhibitor that may serve as another promising alternative for patients who develop resistance to vismodegib or sonidegib. A phase 1 trial of taladegib for advanced BCC found an ORR of 69% (11/16) in the SHH inhibitor–naïve group and an ORR of 36% (11/32) in the group previously treated with a SHH inhibitor.⁸⁶ Additionally, the safety profile and frequency of adverse effects appear to be similar to those associated with vismodegib and sonidegib.^86,87 Unfortunately, no clinical trials evaluating taladegib for BCC are ongoing or in development at this time.

Recurrence

There appears to be a relatively high rate of recurrence for BCC patients who achieve a CR to SHH inhibitors. In a retrospective study of 116 laBCC patients who experienced a CR after vismodegib therapy, 54 patients (47%) relapsed at 36 months. Among the 54 patients that relapsed, 27 were re-treated with vismodegib, which resulted in an ORR of 85% (23/27), a CR rate of 37% (10/27), and a PR rate of 48% (13/27).⁸⁸ Another retrospective study of 35 laBCC patients who relapsed after vismodegib treatment reported a 31% (11/35) clinical recurrence rate at 6-month follow-up.⁸⁹ An observational retrospective study also assessed the efficacy of SHH inhibitor maintenance therapy for advanced BCC patients who achieved a CR.⁹⁰ In the study, 27 (64%) patients received a maintenance dose of 150 mg vismodegib once per week for 1 year, while 15 (36%) patients decided not to take a maintenance dose following CR of their BCC. All patients who took the maintenance therapy did not experience clinical recurrence at 1-year follow-up, whereas 26% of patients not on the maintenance dose relapsed.⁹⁰ Consequently, these results indicate that BCC recurrence is frequent after SHH inhibitor therapy and highlights the importance of close surveillance after CR is attained. Nevertheless, most patients still respond to treatment with SHH inhibitors after relapsing, and intermittent maintenance doses may be an effective means to reduce risk of recurrence.

Conclusion

Vismodegib and sonidegib are SHH inhibitors approved for the treatment of laBCC and mBCC. Cemiplimab is now also approved for patients who do not respond to SHH inhibitors or for whom SHH inhibitors are not tolerable. Although these systemic targeted therapies can lead to notable tumor shrinkage and even complete regression in some patients, recurrence is common, and adverse effects may limit their use. Drug resistance is an emerging issue that requires additional examination. Further clinical studies are needed to determine which patients are likely to respond to these targeted treatments.

Various intermittent and maintenance drug regimens should be evaluated for their potential to mitigate adverse effects and reduce risk of recurrence, respectively. The synergistic effects of these medications with other therapies as well as their neoadjuvant and adjuvant roles should be further investigated. For example, administration of an SHH inhibitor prior to surgical excision of a BCC may allow for a smaller surgical defect size, thereby improving cosmetic and functional outcomes. Moreover, these systemic targeted medications may allow for previously inoperable tumors to become amenable to surgical treatment.

Although SHH inhibitors and PD-1 inhibitors represent a major advancement in the field of oncodermatology, real-world efficacy and safety data in the upcoming years will be important for elucidating their true benefit for patients with BCC.

Key clinical point: Severe migraine without aura increased the long-term risk for atrial fibrillation (AF) by 16%-21% in both men and women. The risk for future AF was highest in women with severe migraine with aura but not significant in male counterparts.

Major finding: Men (adjusted hazard ratio [aHR] 1.21; 95% CI 1.12-1.31) and women (aHR 1.16; 95% CI 1.09-1.22) with severe migraine without aura had a modest but significantly higher risk for AF. The risk was most prominent in women with severe migraine with aura (aHR 1.48; 95% CI 1.18-1.85), but was not significant in men.

Study details: Findings are from a large-scale population-based study including 4,020,488 participants without AF, of which 4986 and 105,029 had migraine with and without aura, respectively.

Disclosures: This study was supported by a Korea Medical Device Development Fund grant funded by the Korea Government. E-K Choi and GYH Lip reported receiving research grants or speaking fees or serving as consultants or speakers for various sources.

Source: Rhee T-M et al. Type and severity of migraine determines risk of atrial fibrillation in women. Front Cardiovasc Med. 2022;9:910225 (May 31). Doi: 10.3389/fcvm.2022.910225

Key clinical point: Severe migraine without aura increased the long-term risk for atrial fibrillation (AF) by 16%-21% in both men and women. The risk for future AF was highest in women with severe migraine with aura but not significant in male counterparts.

Major finding: Men (adjusted hazard ratio [aHR] 1.21; 95% CI 1.12-1.31) and women (aHR 1.16; 95% CI 1.09-1.22) with severe migraine without aura had a modest but significantly higher risk for AF. The risk was most prominent in women with severe migraine with aura (aHR 1.48; 95% CI 1.18-1.85), but was not significant in men.

Study details: Findings are from a large-scale population-based study including 4,020,488 participants without AF, of which 4986 and 105,029 had migraine with and without aura, respectively.

Disclosures: This study was supported by a Korea Medical Device Development Fund grant funded by the Korea Government. E-K Choi and GYH Lip reported receiving research grants or speaking fees or serving as consultants or speakers for various sources.

Source: Rhee T-M et al. Type and severity of migraine determines risk of atrial fibrillation in women. Front Cardiovasc Med. 2022;9:910225 (May 31). Doi: 10.3389/fcvm.2022.910225

Key clinical point: Severe migraine without aura increased the long-term risk for atrial fibrillation (AF) by 16%-21% in both men and women. The risk for future AF was highest in women with severe migraine with aura but not significant in male counterparts.

Major finding: Men (adjusted hazard ratio [aHR] 1.21; 95% CI 1.12-1.31) and women (aHR 1.16; 95% CI 1.09-1.22) with severe migraine without aura had a modest but significantly higher risk for AF. The risk was most prominent in women with severe migraine with aura (aHR 1.48; 95% CI 1.18-1.85), but was not significant in men.

Study details: Findings are from a large-scale population-based study including 4,020,488 participants without AF, of which 4986 and 105,029 had migraine with and without aura, respectively.

Disclosures: This study was supported by a Korea Medical Device Development Fund grant funded by the Korea Government. E-K Choi and GYH Lip reported receiving research grants or speaking fees or serving as consultants or speakers for various sources.

Source: Rhee T-M et al. Type and severity of migraine determines risk of atrial fibrillation in women. Front Cardiovasc Med. 2022;9:910225 (May 31). Doi: 10.3389/fcvm.2022.910225

Key clinical point: A higher proportion of patients with migraine treated with atogepant vs. placebo showed a significant reduction in the monthly migraine days (MMD) during the 12 weeks of treatment.

Major finding: At 12 weeks, ≥50% reduction in the mean MMD was achieved by a significantly higher proportion of patients receiving 10 mg (55.6%), 30 mg (58.7%), or 60 mg (60.8%) atogepant compared with placebo (29.0%; all P < .001), with findings being similar for ≥25%, ≥75%, and 100% reduction in mean MMD. The incidence of treatment-emergent adverse events was similar among the treatment groups.

Study details: This was a secondary analysis of the ADVANCE trial including 873 patients with a ≥1-year history of migraine with or without aura who were randomly assigned to receive atogepant (10, 30, or 60 mg; n = 659) or placebo (n = 214).

Disclosures: This study was sponsored by Allergan. Some authors declared receiving speaking fees, consulting fees, personal fees, research grants, or royalties or owing stocks or stock options in various sources, including Allergan/AbbVie.

Source: Lipton RB et al. Rates of response to atogepant for migraine prophylaxis among adults:

A secondary analysis of a randomized clinical trial. JAMA Netw Open. 2022;5(6):e2215499 Jun 8). Doi:  10.1001/jamanetworkopen.2022.15499

Key clinical point: A higher proportion of patients with migraine treated with atogepant vs. placebo showed a significant reduction in the monthly migraine days (MMD) during the 12 weeks of treatment.

Major finding: At 12 weeks, ≥50% reduction in the mean MMD was achieved by a significantly higher proportion of patients receiving 10 mg (55.6%), 30 mg (58.7%), or 60 mg (60.8%) atogepant compared with placebo (29.0%; all P < .001), with findings being similar for ≥25%, ≥75%, and 100% reduction in mean MMD. The incidence of treatment-emergent adverse events was similar among the treatment groups.

Study details: This was a secondary analysis of the ADVANCE trial including 873 patients with a ≥1-year history of migraine with or without aura who were randomly assigned to receive atogepant (10, 30, or 60 mg; n = 659) or placebo (n = 214).

Disclosures: This study was sponsored by Allergan. Some authors declared receiving speaking fees, consulting fees, personal fees, research grants, or royalties or owing stocks or stock options in various sources, including Allergan/AbbVie.

Source: Lipton RB et al. Rates of response to atogepant for migraine prophylaxis among adults:

A secondary analysis of a randomized clinical trial. JAMA Netw Open. 2022;5(6):e2215499 Jun 8). Doi:  10.1001/jamanetworkopen.2022.15499

Key clinical point: A higher proportion of patients with migraine treated with atogepant vs. placebo showed a significant reduction in the monthly migraine days (MMD) during the 12 weeks of treatment.

Major finding: At 12 weeks, ≥50% reduction in the mean MMD was achieved by a significantly higher proportion of patients receiving 10 mg (55.6%), 30 mg (58.7%), or 60 mg (60.8%) atogepant compared with placebo (29.0%; all P < .001), with findings being similar for ≥25%, ≥75%, and 100% reduction in mean MMD. The incidence of treatment-emergent adverse events was similar among the treatment groups.

Study details: This was a secondary analysis of the ADVANCE trial including 873 patients with a ≥1-year history of migraine with or without aura who were randomly assigned to receive atogepant (10, 30, or 60 mg; n = 659) or placebo (n = 214).

Disclosures: This study was sponsored by Allergan. Some authors declared receiving speaking fees, consulting fees, personal fees, research grants, or royalties or owing stocks or stock options in various sources, including Allergan/AbbVie.

Source: Lipton RB et al. Rates of response to atogepant for migraine prophylaxis among adults:

A secondary analysis of a randomized clinical trial. JAMA Netw Open. 2022;5(6):e2215499 Jun 8). Doi:  10.1001/jamanetworkopen.2022.15499