The “twincretin” tirzepatide (Mounjaro) has proven successful in SURMOUNT-2, the second pivotal trial for the drug as an antiobesity agent, according to top-line results reported April 27 by tirzepatide’s manufacturer, Lilly, in a press release. The company reveals that tirzepatide achieved both of its primary endpoints in the trial, as well as all its key secondary endpoints.

The findings pave the way for tirzepatide to likely receive Food and Drug Administration approval as a treatment for obesity, perhaps before the end of 2023.

Tirzepatide received FDA approval in May 2022 for the treatment of type 2 diabetes in adults, under the brand name Mounjaro, and some people have already been using it off-label to treat obesity.

Tirzepatide is a dual glucagonlike peptide–1 (GLP-1) agonist and glucose-dependent insulinotropic polypeptide agonist. Several GLP-1 receptor agonists are already approved in the United States, including semaglutide, a once-weekly injection, which is approved as Wegovy for patients with obesity and as Ozempic for treatment of type 2 diabetes.

These agents have been incredibly popular among celebrity influencers, and with use of the #Ozempic hashtag and others on social media, this has led to unprecedented use of these products for weight loss, often among those who do not even have obesity or type 2 diabetes. Subsequently, patients with type 2 diabetes and obesity who need them have often struggled to obtain them, owing to shortages following this phenomenon.
 

SURMOUNT-2: Weight loss around 15%, less than seen in SURMOUNT-1

SURMOUNT-2 enrolled 938 adults with overweight or obesity and type 2 diabetes and had dual primary endpoints that both focused on weight loss, compared with placebo.

The first completed pivotal trial of tirzepatide for weight loss, SURMOUNT-1, enrolled people with overweight or obesity but no diabetes and had its main results reported in 2022. At the time, the weight loss achieved with tirzepatide, was described as “unprecedented,” with those given the highest dose in that trial (15 mg subcutaneously per week) losing an average of 20%-22% of body weight over 72 weeks, depending on the specific statistical analysis used.

For SURMOUNT-2’s first primary endpoint, 72 weeks of weekly subcutaneous injections with tirzepatide at dosages of 10 mg or 15 mg led to an average weight loss from baseline of 13.4% and 15.7%, respectively, compared with an average loss of 3.3% from baseline in the placebo-treated control arm.

For the second primary endpoint, 81.6% of people on the 10-mg dose and 86.4% on the 15-mg dose achieved at least 5% weight loss from baseline, compared with 30.5% of controls who had at least 5% weight loss from baseline.

In one key secondary endpoint, tirzepatide at dosages of 10 mg or 15 mg weekly produced at least a 15% cut in weight from baseline in 41.4% and 51.8% of participants, respectively, compared with a 2.6% rate of this endpoint in the placebo controls.

So the extent of weight loss seen in in SURMOUNT-2 was somewhat less than was reported in SURMOUNT-1, a finding consistent with many prior studies of incretin-based weight-loss agents, which seem to pack a more potent weight-loss punch in people without type 2 diabetes.

Lilly did not specifically report the treatment effect of tirzepatide on hemoglobin A1c in SURMOUNT-2, only saying that the effect was similar to what had been seen in the series of five SURPASS trials that led to the approval of tirzepatide for type 2 diabetes.

Lilly also reported that the safety profile of tirzepatide in SURMOUNT-2 generally matched what was seen in SURMOUNT-1 as well as in the SURPASS trials. The most common adverse events in SURMOUNT-2 involved gastrointestinal symptoms, such as nausea, diarrhea, and vomiting; these were generally mild to moderate in severity and clustered during the dose-escalation phase at the start of treatment. Treatment discontinuations caused by adverse effects were 3.8% on the 10-mg dosage, 7.4% on the 15-mg dosage, and 3.8% on placebo.

SURMOUNT-2 enrolled patients in the United States, Puerto Rico, and five other countries. All participants also received interventions designed to reduce their calorie intake and increase their physical activity.
 

More SURMOUNT-2 results at ADA in June

Lilly also announced that researchers would report more complete results from SURMOUNT-2 at the 2023 scientific sessions of the American Diabetes Association, being held in San Diego in late June, and publish the findings in a major medical journal.

Results from two additional phase 3 trials of tirzepatide in people with overweight or obesity, SURMOUNT-3 and SURMOUNT-4, are expected later in 2023.

Lilly started an application to the FDA for an indication for weight loss in October 2022 under a fast track designation by the agency, and the data collected in SURMOUNT-2 are expected to complete this application, which would then be subject to an FDA decision within about 6 months. Lilly said in its April 27 press release that it anticipates an FDA decision on this application may occur before the end of 2023.

SURMOUNT-2 and all of the other tirzepatide trials were sponsored by Lilly.

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

The “twincretin” tirzepatide (Mounjaro) has proven successful in SURMOUNT-2, the second pivotal trial for the drug as an antiobesity agent, according to top-line results reported April 27 by tirzepatide’s manufacturer, Lilly, in a press release. The company reveals that tirzepatide achieved both of its primary endpoints in the trial, as well as all its key secondary endpoints.

The findings pave the way for tirzepatide to likely receive Food and Drug Administration approval as a treatment for obesity, perhaps before the end of 2023.

Tirzepatide received FDA approval in May 2022 for the treatment of type 2 diabetes in adults, under the brand name Mounjaro, and some people have already been using it off-label to treat obesity.

Tirzepatide is a dual glucagonlike peptide–1 (GLP-1) agonist and glucose-dependent insulinotropic polypeptide agonist. Several GLP-1 receptor agonists are already approved in the United States, including semaglutide, a once-weekly injection, which is approved as Wegovy for patients with obesity and as Ozempic for treatment of type 2 diabetes.

These agents have been incredibly popular among celebrity influencers, and with use of the #Ozempic hashtag and others on social media, this has led to unprecedented use of these products for weight loss, often among those who do not even have obesity or type 2 diabetes. Subsequently, patients with type 2 diabetes and obesity who need them have often struggled to obtain them, owing to shortages following this phenomenon.
 

SURMOUNT-2: Weight loss around 15%, less than seen in SURMOUNT-1

SURMOUNT-2 enrolled 938 adults with overweight or obesity and type 2 diabetes and had dual primary endpoints that both focused on weight loss, compared with placebo.

The first completed pivotal trial of tirzepatide for weight loss, SURMOUNT-1, enrolled people with overweight or obesity but no diabetes and had its main results reported in 2022. At the time, the weight loss achieved with tirzepatide, was described as “unprecedented,” with those given the highest dose in that trial (15 mg subcutaneously per week) losing an average of 20%-22% of body weight over 72 weeks, depending on the specific statistical analysis used.

For SURMOUNT-2’s first primary endpoint, 72 weeks of weekly subcutaneous injections with tirzepatide at dosages of 10 mg or 15 mg led to an average weight loss from baseline of 13.4% and 15.7%, respectively, compared with an average loss of 3.3% from baseline in the placebo-treated control arm.

For the second primary endpoint, 81.6% of people on the 10-mg dose and 86.4% on the 15-mg dose achieved at least 5% weight loss from baseline, compared with 30.5% of controls who had at least 5% weight loss from baseline.

In one key secondary endpoint, tirzepatide at dosages of 10 mg or 15 mg weekly produced at least a 15% cut in weight from baseline in 41.4% and 51.8% of participants, respectively, compared with a 2.6% rate of this endpoint in the placebo controls.

So the extent of weight loss seen in in SURMOUNT-2 was somewhat less than was reported in SURMOUNT-1, a finding consistent with many prior studies of incretin-based weight-loss agents, which seem to pack a more potent weight-loss punch in people without type 2 diabetes.

Lilly did not specifically report the treatment effect of tirzepatide on hemoglobin A1c in SURMOUNT-2, only saying that the effect was similar to what had been seen in the series of five SURPASS trials that led to the approval of tirzepatide for type 2 diabetes.

Lilly also reported that the safety profile of tirzepatide in SURMOUNT-2 generally matched what was seen in SURMOUNT-1 as well as in the SURPASS trials. The most common adverse events in SURMOUNT-2 involved gastrointestinal symptoms, such as nausea, diarrhea, and vomiting; these were generally mild to moderate in severity and clustered during the dose-escalation phase at the start of treatment. Treatment discontinuations caused by adverse effects were 3.8% on the 10-mg dosage, 7.4% on the 15-mg dosage, and 3.8% on placebo.

SURMOUNT-2 enrolled patients in the United States, Puerto Rico, and five other countries. All participants also received interventions designed to reduce their calorie intake and increase their physical activity.
 

More SURMOUNT-2 results at ADA in June

Lilly also announced that researchers would report more complete results from SURMOUNT-2 at the 2023 scientific sessions of the American Diabetes Association, being held in San Diego in late June, and publish the findings in a major medical journal.

Results from two additional phase 3 trials of tirzepatide in people with overweight or obesity, SURMOUNT-3 and SURMOUNT-4, are expected later in 2023.

Lilly started an application to the FDA for an indication for weight loss in October 2022 under a fast track designation by the agency, and the data collected in SURMOUNT-2 are expected to complete this application, which would then be subject to an FDA decision within about 6 months. Lilly said in its April 27 press release that it anticipates an FDA decision on this application may occur before the end of 2023.

SURMOUNT-2 and all of the other tirzepatide trials were sponsored by Lilly.

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

The “twincretin” tirzepatide (Mounjaro) has proven successful in SURMOUNT-2, the second pivotal trial for the drug as an antiobesity agent, according to top-line results reported April 27 by tirzepatide’s manufacturer, Lilly, in a press release. The company reveals that tirzepatide achieved both of its primary endpoints in the trial, as well as all its key secondary endpoints.

The findings pave the way for tirzepatide to likely receive Food and Drug Administration approval as a treatment for obesity, perhaps before the end of 2023.

Tirzepatide received FDA approval in May 2022 for the treatment of type 2 diabetes in adults, under the brand name Mounjaro, and some people have already been using it off-label to treat obesity.

Tirzepatide is a dual glucagonlike peptide–1 (GLP-1) agonist and glucose-dependent insulinotropic polypeptide agonist. Several GLP-1 receptor agonists are already approved in the United States, including semaglutide, a once-weekly injection, which is approved as Wegovy for patients with obesity and as Ozempic for treatment of type 2 diabetes.

These agents have been incredibly popular among celebrity influencers, and with use of the #Ozempic hashtag and others on social media, this has led to unprecedented use of these products for weight loss, often among those who do not even have obesity or type 2 diabetes. Subsequently, patients with type 2 diabetes and obesity who need them have often struggled to obtain them, owing to shortages following this phenomenon.
 

SURMOUNT-2: Weight loss around 15%, less than seen in SURMOUNT-1

SURMOUNT-2 enrolled 938 adults with overweight or obesity and type 2 diabetes and had dual primary endpoints that both focused on weight loss, compared with placebo.

The first completed pivotal trial of tirzepatide for weight loss, SURMOUNT-1, enrolled people with overweight or obesity but no diabetes and had its main results reported in 2022. At the time, the weight loss achieved with tirzepatide, was described as “unprecedented,” with those given the highest dose in that trial (15 mg subcutaneously per week) losing an average of 20%-22% of body weight over 72 weeks, depending on the specific statistical analysis used.

For SURMOUNT-2’s first primary endpoint, 72 weeks of weekly subcutaneous injections with tirzepatide at dosages of 10 mg or 15 mg led to an average weight loss from baseline of 13.4% and 15.7%, respectively, compared with an average loss of 3.3% from baseline in the placebo-treated control arm.

For the second primary endpoint, 81.6% of people on the 10-mg dose and 86.4% on the 15-mg dose achieved at least 5% weight loss from baseline, compared with 30.5% of controls who had at least 5% weight loss from baseline.

In one key secondary endpoint, tirzepatide at dosages of 10 mg or 15 mg weekly produced at least a 15% cut in weight from baseline in 41.4% and 51.8% of participants, respectively, compared with a 2.6% rate of this endpoint in the placebo controls.

So the extent of weight loss seen in in SURMOUNT-2 was somewhat less than was reported in SURMOUNT-1, a finding consistent with many prior studies of incretin-based weight-loss agents, which seem to pack a more potent weight-loss punch in people without type 2 diabetes.

Lilly did not specifically report the treatment effect of tirzepatide on hemoglobin A1c in SURMOUNT-2, only saying that the effect was similar to what had been seen in the series of five SURPASS trials that led to the approval of tirzepatide for type 2 diabetes.

Lilly also reported that the safety profile of tirzepatide in SURMOUNT-2 generally matched what was seen in SURMOUNT-1 as well as in the SURPASS trials. The most common adverse events in SURMOUNT-2 involved gastrointestinal symptoms, such as nausea, diarrhea, and vomiting; these were generally mild to moderate in severity and clustered during the dose-escalation phase at the start of treatment. Treatment discontinuations caused by adverse effects were 3.8% on the 10-mg dosage, 7.4% on the 15-mg dosage, and 3.8% on placebo.

SURMOUNT-2 enrolled patients in the United States, Puerto Rico, and five other countries. All participants also received interventions designed to reduce their calorie intake and increase their physical activity.
 

More SURMOUNT-2 results at ADA in June

Lilly also announced that researchers would report more complete results from SURMOUNT-2 at the 2023 scientific sessions of the American Diabetes Association, being held in San Diego in late June, and publish the findings in a major medical journal.

Results from two additional phase 3 trials of tirzepatide in people with overweight or obesity, SURMOUNT-3 and SURMOUNT-4, are expected later in 2023.

Lilly started an application to the FDA for an indication for weight loss in October 2022 under a fast track designation by the agency, and the data collected in SURMOUNT-2 are expected to complete this application, which would then be subject to an FDA decision within about 6 months. Lilly said in its April 27 press release that it anticipates an FDA decision on this application may occur before the end of 2023.

SURMOUNT-2 and all of the other tirzepatide trials were sponsored by Lilly.

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

Erythema ab igne (EAI)(also known as toasted skin syndrome) was first described in the British Journal of Dermatology in the 20th century, ¹ though it was known by physicians long before. Reticular netlike skin changes were seen in association with patients who spent extended time directly next to a heat source. This association led to the name of this condition, which literally means “redness by fire.” Indeed, EAI induced by chronic heat exposure has been described across the world for centuries. For example, in the cold regions of northern China, people used to sleep on beds of hot bricks called kang to stay warm at night. The people of India’s Kashmir district carried pots of hot coals called kangri next to the skin under large woven shawls to stay warm. In the past, Irish women often spent much time by a turf- or peat-burning fire. Chronic heat exposure in these cases can lead not only to EAI but also to aggressive types of cancer, often with a latency of 30 years or more. ²

More recently, the invention of home central heating led to a stark decrease in the number of cases associated with combustion-based heat, with a transition to etiologies such as use of hot water bottles, electric blankets, and electric space heaters. Over time, technological advances led to ever-increasing potential causes for EAI, such as laptops or cell phones, car heaters and heated seats, heated blankets,^3,4 infrared lamps for food, and even medical devices such as ultrasound-based heating products and convective temperature management systems for hospitalized patients. As technology evolves, so do the potential causes of EAI, requiring clinicians to diagnose and deduce the cause through a thorough social and medical history as well as a workup on the present illness with considerations for the anatomical location.^5-7 Herein, we describe the etiology of EAI, diagnosis, and treatment options.

Clinical Characteristics

Erythema ab igne begins as mild, transient, and erythematous macules and patches in a reticular pattern that resolve minutes to hours after removal of the heat source. With weeks to months of continued or repeated application of the heat source, the affected area eventually becomes hyperpigmented where there once was erythema (Figures 1 and 2). Sometimes papules, bullae, telangiectasia, and hyperkeratosis also form. The rash usually is asymptomatic, though pain, pruritus, and dysesthesia have been reported.⁷ Dermoscopy of EAI in the hyperpigmented stage can reveal diffuse superficial dark pigmentation, telangiectasia, and mild whitish scaling.⁸ Although the pathogenesis has remained elusive over the years, lesions do seem to be mostly associated with cumulative exposure to heat rather than length of exposure.⁷

Etiology of EAI

Anatomic Location—The affected site depends on the source of heat (Table). Classic examples of this condition include a patient with EAI presenting on the anterior thighs after working in front of a hot oven or a patient with chronic back pain presenting with lower-back EAI secondary to frequent use of a hot water bottle or heating pad.⁷ With evolving technology over the last few decades, new etiologies have become more common—teenagers are presenting with anterior thigh EAI secondary to frequent laptop use^2-29; patients are holding warm cell phones in their pant pockets, leading to unilateral geometric EAI on the anterior thigh (front pocket) or buttock (back pocket)³⁰; plug-in radiators under computer desks are causing EAI on the lower legs^31-34; and automobile seat heaters have been shown to cause EAI on the posterior legs.^5,35-37 Clinicians should consider anatomic location a critical clue for etiology.

Social History—There are rarer and more highly specific causes of EAI than simple heat exposure that can be parsed from a patient’s social history. Occupational exposure has been documented, such as bakers with exposure to ovens, foundry workers with exposure to heated metals, or fast-food workers with chronic exposure to infrared food lamps.^6,7 There also are cultural practices that can cause EAI. For example, the practice of cupping with moxibustion was shown to create a specific pattern in the shape of the cultural tool used.³⁸ When footbaths with Chinese herbal remedies are performed frequently with high heat, they can lead to EAI on the feet with a linear border at the ankles. There also have been reports of kotatsu (heated tables in Japan) leading to lower-body EAI.^39,40 These cultural practices also are more common in patients with darker skin types, which can lead to hyperpigmentation that is difficult to treat, making early diagnosis important.⁷

Medical History—Case reports have shown EAI caused by patients attempting to use heat-based methods for pain relief of an underlying serious disease such as cancer, bowel pathology (abdominal EAI), spinal disc prolapse (midline back EAI),⁴¹ sickle cell anemia, and renal pathology (posterior upper flank EAI).^6,7,40-49 Patients with hypothyroidism or anorexia have been noted to have generalized EAI sparing the face secondary to repeated and extended hot baths or showers.^50-53 One patient with schizophrenia was shown to have associated thermophilia due to a delusion that led the patient to soak in hot baths for long periods of time, leading to EAI.⁵⁴ Finally, all physicians should be aware of iatrogenic causes of EAI, such as use of warming devices, ultrasound-based warming techniques, and laser therapy for lipolysis. Inquire about the patient’s surgical history or intensive care unit stays as well as alternative medicine or chiropractic visits. Obtaining a history of medical procedures can be enlightening when an etiology is not immediately clear.^7,55,56

Diagnosis

Erythema ab igne is a clinical diagnosis based on recognizable cutaneous findings and a clear history of moderate heat exposure. However, when a clinical diagnosis of EAI is not certain (eg, when unable to obtain a clear history from the patient) or when malignant transformation is suspected, a biopsy can be performed. Pathologically, hematoxylin and eosin staining of EAI classically reveals dilated small vascular channels in the superficial dermis, hence a clinically reticular rash; interface dermatitis clinically manifesting as erythema; and pigment incontinence with melanin-laden macrophages consistent with clinical hyperpigmentation. Finally, for unclear reasons, increased numbers of elastic fibers classically are seen in biopsies of EAI.⁷

 

 

Differential Diagnosis

The differential diagnosis for a reticular patch includes livedo reticularis (Figure 3), which usually manifests as a more generalized rash in patients with chronic disease or coagulopathy such as systemic lupus erythematosus, cryoglobulinemia, or Raynaud phenomenon. When differentiating EAI from livedo reticularis or cutis marmorata, consider that both alternative diagnoses are more vascular appearing and are associated with cold exposure rather than heat exposure. In cases that are less reticular, livedo racemosa can be considered in the differential diagnosis. Finally, poikiloderma of Civatte can be reticular, particularly on dermoscopy, but the distribution on the neck with submental sparing should help to distinguish it from EAI unless a heat source around the neck is identified while taking the patient’s history.⁷

In babies, a reticular generalized rash is most likely to be cutis marmorata (Figure 4), which is a physiologic response to cold exposure that resolves with rewarming of the skin. A more serious condition—cutis marmorata telangiectatica congenita (Figure 5)—usually is present at birth, most frequently involves a single extremity, and notably does not resolve with rewarming. This is an important differential for EAI in children because it can be associated with vascular and neurologic anomalies as well as limb asymmetry. Finally, port-wine stains can sometimes be reticular in appearance and can mimic the early erythematous stages of EAI. However, unlike the erythematous stage of EAI, the port-wine stains will be present at birth.⁷

Emerging in 2020, an important differential diagnosis to consider is a cutaneous manifestation of COVID-19 infection. An erythematous, reticular, chilblainlike or transient livedo reticularis–like rash has been described as a cutaneous manifestation of COVID-19. Although the pathophysiology is still being elucidated, it is suspected that this is caused by a major vaso-occlusive crisis secondary to COVID-19–induced thrombotic vasculopathy. Interestingly, the majority of patients with this COVID-related exanthem also displayed symptoms of COVID-19 (eg, fever, cough) at the time of presentation,^57-60 but there also have been cases in patients who were asymptomatic or mildly symptomatic.⁶⁰

In some cases, EAI is an indication to screen for an underlying disease. For example, uncontrolled pain is an opportunity to improve interventions such as modifying the patient’s pain-control regimen, placing a palliative care pain consultation, or checking if the patient has had age-appropriate screenings for malignancy. New focal pain in a patient with a prior diagnosis of cancer may be a sign of a new metastasis. A thermophilic patient leaves opportunity to assess for underlying medical causes such as thyroid abnormalities or social/psychological issues. Geriatric patients who are diagnosed with EAI may need to be assessed for dementia or home safety issues. Patients with a history of diabetes mellitus can unknowingly develop EAI on the lower extremities, which may signal a need to assess the patient for peripheral neuropathy. Patients with gastroparesis secondary to diabetes also may develop EAI on the abdomen secondary to heating pad use for discomfort. These examples are a reminder to consider possible secondary comorbidities in all diagnoses of EAI.⁷ 

Prognosis

Although the prognosis of EAI is excellent if caught early, failure to diagnose this condition can lead to permanent discoloration of the skin and even malignancy.⁶ A rare sequela includes squamous cell carcinoma, most commonly seen in chronic cases of the lower leg, which is likely related to chronic inflammation of the skin.^61-65 Rare cases of poorly differentiated carcinoma,⁶⁶ cutaneous marginal zone lymphoma,⁶⁷ and Merkel cell carcinoma⁶⁸ have been reported. Patients diagnosed with EAI should receive normal periodic surveillance of the skin based on their medical history, though the physician should have an increased suspicion and plan for biopsy of any nodules or ulcerations found on the skin of the affected area.⁷

Treatments

Once the diagnosis of EAI is made, treatment starts with removal of the heat source causing the rash. Because the rash usually is asymptomatic, further treatment typically is not required. The discoloration can resolve over months or years, but permanent hyperpigmentation is not uncommon. If hyperpigmentation persists despite removal of the heat source and the patient desires further treatment for discoloration, there are few treatment options, none of which are approved by the US Food and Drug Administration for this condition.⁷ There is some evidence for the use of Nd:YAG lasers to reduce hyperpigmentation in EAI.⁶⁹ There have been some reports of treatment using topical hydroquinone and topical tretinoin in an attempt to lighten the skin. If associated hyperkeratosis or other epithelial atypia is present, the use of 5-fluorouracil may show some improvement.⁷⁰ One case report has been published of successful treatment with systemic mesoglycan and topical bioflavonoids.⁷¹ It also is conceivable that medications used to treat postinflammatory hyperpigmentation may be helpful in this condition (eg, kojic acid, arbutin, mild topical steroids, azelaic acid). Patients with darker skin may experience permanent discoloration and may not be good candidates for alternative treatments such as laser therapy due to the risk for inducible hyperpigmentation.⁷

Conclusion

No matter the etiology, EAI usually is a benign skin condition that is treated by removal of the causative heat source. Once a diagnosis is made, the clinician must work with the patient to determine the etiology. Care must be taken to ensure that there are no underlying signs, such as chronic pain or psychiatric illness, that could point to associated conditions. Rarely, sequalae such as cancers have been documented in areas of chronic EAI. Once the heat source is identified and removed, any remaining hyperpigmentation usually will self-resolve over months to years, though this may take longer in patients with darker skin types. If more aggressive treatment is preferred by the patient, laser therapy, topical medications, and oral over-the-counter vitamins have been tried with minimal responses. 

Erythema ab igne (EAI)(also known as toasted skin syndrome) was first described in the British Journal of Dermatology in the 20th century, ¹ though it was known by physicians long before. Reticular netlike skin changes were seen in association with patients who spent extended time directly next to a heat source. This association led to the name of this condition, which literally means “redness by fire.” Indeed, EAI induced by chronic heat exposure has been described across the world for centuries. For example, in the cold regions of northern China, people used to sleep on beds of hot bricks called kang to stay warm at night. The people of India’s Kashmir district carried pots of hot coals called kangri next to the skin under large woven shawls to stay warm. In the past, Irish women often spent much time by a turf- or peat-burning fire. Chronic heat exposure in these cases can lead not only to EAI but also to aggressive types of cancer, often with a latency of 30 years or more. ²

More recently, the invention of home central heating led to a stark decrease in the number of cases associated with combustion-based heat, with a transition to etiologies such as use of hot water bottles, electric blankets, and electric space heaters. Over time, technological advances led to ever-increasing potential causes for EAI, such as laptops or cell phones, car heaters and heated seats, heated blankets,^3,4 infrared lamps for food, and even medical devices such as ultrasound-based heating products and convective temperature management systems for hospitalized patients. As technology evolves, so do the potential causes of EAI, requiring clinicians to diagnose and deduce the cause through a thorough social and medical history as well as a workup on the present illness with considerations for the anatomical location.^5-7 Herein, we describe the etiology of EAI, diagnosis, and treatment options.

Clinical Characteristics

Erythema ab igne begins as mild, transient, and erythematous macules and patches in a reticular pattern that resolve minutes to hours after removal of the heat source. With weeks to months of continued or repeated application of the heat source, the affected area eventually becomes hyperpigmented where there once was erythema (Figures 1 and 2). Sometimes papules, bullae, telangiectasia, and hyperkeratosis also form. The rash usually is asymptomatic, though pain, pruritus, and dysesthesia have been reported.⁷ Dermoscopy of EAI in the hyperpigmented stage can reveal diffuse superficial dark pigmentation, telangiectasia, and mild whitish scaling.⁸ Although the pathogenesis has remained elusive over the years, lesions do seem to be mostly associated with cumulative exposure to heat rather than length of exposure.⁷

Etiology of EAI

Anatomic Location—The affected site depends on the source of heat (Table). Classic examples of this condition include a patient with EAI presenting on the anterior thighs after working in front of a hot oven or a patient with chronic back pain presenting with lower-back EAI secondary to frequent use of a hot water bottle or heating pad.⁷ With evolving technology over the last few decades, new etiologies have become more common—teenagers are presenting with anterior thigh EAI secondary to frequent laptop use^2-29; patients are holding warm cell phones in their pant pockets, leading to unilateral geometric EAI on the anterior thigh (front pocket) or buttock (back pocket)³⁰; plug-in radiators under computer desks are causing EAI on the lower legs^31-34; and automobile seat heaters have been shown to cause EAI on the posterior legs.^5,35-37 Clinicians should consider anatomic location a critical clue for etiology.

Social History—There are rarer and more highly specific causes of EAI than simple heat exposure that can be parsed from a patient’s social history. Occupational exposure has been documented, such as bakers with exposure to ovens, foundry workers with exposure to heated metals, or fast-food workers with chronic exposure to infrared food lamps.^6,7 There also are cultural practices that can cause EAI. For example, the practice of cupping with moxibustion was shown to create a specific pattern in the shape of the cultural tool used.³⁸ When footbaths with Chinese herbal remedies are performed frequently with high heat, they can lead to EAI on the feet with a linear border at the ankles. There also have been reports of kotatsu (heated tables in Japan) leading to lower-body EAI.^39,40 These cultural practices also are more common in patients with darker skin types, which can lead to hyperpigmentation that is difficult to treat, making early diagnosis important.⁷

Medical History—Case reports have shown EAI caused by patients attempting to use heat-based methods for pain relief of an underlying serious disease such as cancer, bowel pathology (abdominal EAI), spinal disc prolapse (midline back EAI),⁴¹ sickle cell anemia, and renal pathology (posterior upper flank EAI).^6,7,40-49 Patients with hypothyroidism or anorexia have been noted to have generalized EAI sparing the face secondary to repeated and extended hot baths or showers.^50-53 One patient with schizophrenia was shown to have associated thermophilia due to a delusion that led the patient to soak in hot baths for long periods of time, leading to EAI.⁵⁴ Finally, all physicians should be aware of iatrogenic causes of EAI, such as use of warming devices, ultrasound-based warming techniques, and laser therapy for lipolysis. Inquire about the patient’s surgical history or intensive care unit stays as well as alternative medicine or chiropractic visits. Obtaining a history of medical procedures can be enlightening when an etiology is not immediately clear.^7,55,56

Diagnosis

Erythema ab igne is a clinical diagnosis based on recognizable cutaneous findings and a clear history of moderate heat exposure. However, when a clinical diagnosis of EAI is not certain (eg, when unable to obtain a clear history from the patient) or when malignant transformation is suspected, a biopsy can be performed. Pathologically, hematoxylin and eosin staining of EAI classically reveals dilated small vascular channels in the superficial dermis, hence a clinically reticular rash; interface dermatitis clinically manifesting as erythema; and pigment incontinence with melanin-laden macrophages consistent with clinical hyperpigmentation. Finally, for unclear reasons, increased numbers of elastic fibers classically are seen in biopsies of EAI.⁷

 

 

Differential Diagnosis

The differential diagnosis for a reticular patch includes livedo reticularis (Figure 3), which usually manifests as a more generalized rash in patients with chronic disease or coagulopathy such as systemic lupus erythematosus, cryoglobulinemia, or Raynaud phenomenon. When differentiating EAI from livedo reticularis or cutis marmorata, consider that both alternative diagnoses are more vascular appearing and are associated with cold exposure rather than heat exposure. In cases that are less reticular, livedo racemosa can be considered in the differential diagnosis. Finally, poikiloderma of Civatte can be reticular, particularly on dermoscopy, but the distribution on the neck with submental sparing should help to distinguish it from EAI unless a heat source around the neck is identified while taking the patient’s history.⁷

In babies, a reticular generalized rash is most likely to be cutis marmorata (Figure 4), which is a physiologic response to cold exposure that resolves with rewarming of the skin. A more serious condition—cutis marmorata telangiectatica congenita (Figure 5)—usually is present at birth, most frequently involves a single extremity, and notably does not resolve with rewarming. This is an important differential for EAI in children because it can be associated with vascular and neurologic anomalies as well as limb asymmetry. Finally, port-wine stains can sometimes be reticular in appearance and can mimic the early erythematous stages of EAI. However, unlike the erythematous stage of EAI, the port-wine stains will be present at birth.⁷

Emerging in 2020, an important differential diagnosis to consider is a cutaneous manifestation of COVID-19 infection. An erythematous, reticular, chilblainlike or transient livedo reticularis–like rash has been described as a cutaneous manifestation of COVID-19. Although the pathophysiology is still being elucidated, it is suspected that this is caused by a major vaso-occlusive crisis secondary to COVID-19–induced thrombotic vasculopathy. Interestingly, the majority of patients with this COVID-related exanthem also displayed symptoms of COVID-19 (eg, fever, cough) at the time of presentation,^57-60 but there also have been cases in patients who were asymptomatic or mildly symptomatic.⁶⁰

In some cases, EAI is an indication to screen for an underlying disease. For example, uncontrolled pain is an opportunity to improve interventions such as modifying the patient’s pain-control regimen, placing a palliative care pain consultation, or checking if the patient has had age-appropriate screenings for malignancy. New focal pain in a patient with a prior diagnosis of cancer may be a sign of a new metastasis. A thermophilic patient leaves opportunity to assess for underlying medical causes such as thyroid abnormalities or social/psychological issues. Geriatric patients who are diagnosed with EAI may need to be assessed for dementia or home safety issues. Patients with a history of diabetes mellitus can unknowingly develop EAI on the lower extremities, which may signal a need to assess the patient for peripheral neuropathy. Patients with gastroparesis secondary to diabetes also may develop EAI on the abdomen secondary to heating pad use for discomfort. These examples are a reminder to consider possible secondary comorbidities in all diagnoses of EAI.⁷ 

Prognosis

Although the prognosis of EAI is excellent if caught early, failure to diagnose this condition can lead to permanent discoloration of the skin and even malignancy.⁶ A rare sequela includes squamous cell carcinoma, most commonly seen in chronic cases of the lower leg, which is likely related to chronic inflammation of the skin.^61-65 Rare cases of poorly differentiated carcinoma,⁶⁶ cutaneous marginal zone lymphoma,⁶⁷ and Merkel cell carcinoma⁶⁸ have been reported. Patients diagnosed with EAI should receive normal periodic surveillance of the skin based on their medical history, though the physician should have an increased suspicion and plan for biopsy of any nodules or ulcerations found on the skin of the affected area.⁷

Treatments

Once the diagnosis of EAI is made, treatment starts with removal of the heat source causing the rash. Because the rash usually is asymptomatic, further treatment typically is not required. The discoloration can resolve over months or years, but permanent hyperpigmentation is not uncommon. If hyperpigmentation persists despite removal of the heat source and the patient desires further treatment for discoloration, there are few treatment options, none of which are approved by the US Food and Drug Administration for this condition.⁷ There is some evidence for the use of Nd:YAG lasers to reduce hyperpigmentation in EAI.⁶⁹ There have been some reports of treatment using topical hydroquinone and topical tretinoin in an attempt to lighten the skin. If associated hyperkeratosis or other epithelial atypia is present, the use of 5-fluorouracil may show some improvement.⁷⁰ One case report has been published of successful treatment with systemic mesoglycan and topical bioflavonoids.⁷¹ It also is conceivable that medications used to treat postinflammatory hyperpigmentation may be helpful in this condition (eg, kojic acid, arbutin, mild topical steroids, azelaic acid). Patients with darker skin may experience permanent discoloration and may not be good candidates for alternative treatments such as laser therapy due to the risk for inducible hyperpigmentation.⁷

Conclusion

No matter the etiology, EAI usually is a benign skin condition that is treated by removal of the causative heat source. Once a diagnosis is made, the clinician must work with the patient to determine the etiology. Care must be taken to ensure that there are no underlying signs, such as chronic pain or psychiatric illness, that could point to associated conditions. Rarely, sequalae such as cancers have been documented in areas of chronic EAI. Once the heat source is identified and removed, any remaining hyperpigmentation usually will self-resolve over months to years, though this may take longer in patients with darker skin types. If more aggressive treatment is preferred by the patient, laser therapy, topical medications, and oral over-the-counter vitamins have been tried with minimal responses. 

Erythema ab igne (EAI)(also known as toasted skin syndrome) was first described in the British Journal of Dermatology in the 20th century, ¹ though it was known by physicians long before. Reticular netlike skin changes were seen in association with patients who spent extended time directly next to a heat source. This association led to the name of this condition, which literally means “redness by fire.” Indeed, EAI induced by chronic heat exposure has been described across the world for centuries. For example, in the cold regions of northern China, people used to sleep on beds of hot bricks called kang to stay warm at night. The people of India’s Kashmir district carried pots of hot coals called kangri next to the skin under large woven shawls to stay warm. In the past, Irish women often spent much time by a turf- or peat-burning fire. Chronic heat exposure in these cases can lead not only to EAI but also to aggressive types of cancer, often with a latency of 30 years or more. ²

More recently, the invention of home central heating led to a stark decrease in the number of cases associated with combustion-based heat, with a transition to etiologies such as use of hot water bottles, electric blankets, and electric space heaters. Over time, technological advances led to ever-increasing potential causes for EAI, such as laptops or cell phones, car heaters and heated seats, heated blankets,^3,4 infrared lamps for food, and even medical devices such as ultrasound-based heating products and convective temperature management systems for hospitalized patients. As technology evolves, so do the potential causes of EAI, requiring clinicians to diagnose and deduce the cause through a thorough social and medical history as well as a workup on the present illness with considerations for the anatomical location.^5-7 Herein, we describe the etiology of EAI, diagnosis, and treatment options.

Clinical Characteristics

Erythema ab igne begins as mild, transient, and erythematous macules and patches in a reticular pattern that resolve minutes to hours after removal of the heat source. With weeks to months of continued or repeated application of the heat source, the affected area eventually becomes hyperpigmented where there once was erythema (Figures 1 and 2). Sometimes papules, bullae, telangiectasia, and hyperkeratosis also form. The rash usually is asymptomatic, though pain, pruritus, and dysesthesia have been reported.⁷ Dermoscopy of EAI in the hyperpigmented stage can reveal diffuse superficial dark pigmentation, telangiectasia, and mild whitish scaling.⁸ Although the pathogenesis has remained elusive over the years, lesions do seem to be mostly associated with cumulative exposure to heat rather than length of exposure.⁷

Etiology of EAI

Anatomic Location—The affected site depends on the source of heat (Table). Classic examples of this condition include a patient with EAI presenting on the anterior thighs after working in front of a hot oven or a patient with chronic back pain presenting with lower-back EAI secondary to frequent use of a hot water bottle or heating pad.⁷ With evolving technology over the last few decades, new etiologies have become more common—teenagers are presenting with anterior thigh EAI secondary to frequent laptop use^2-29; patients are holding warm cell phones in their pant pockets, leading to unilateral geometric EAI on the anterior thigh (front pocket) or buttock (back pocket)³⁰; plug-in radiators under computer desks are causing EAI on the lower legs^31-34; and automobile seat heaters have been shown to cause EAI on the posterior legs.^5,35-37 Clinicians should consider anatomic location a critical clue for etiology.

Social History—There are rarer and more highly specific causes of EAI than simple heat exposure that can be parsed from a patient’s social history. Occupational exposure has been documented, such as bakers with exposure to ovens, foundry workers with exposure to heated metals, or fast-food workers with chronic exposure to infrared food lamps.^6,7 There also are cultural practices that can cause EAI. For example, the practice of cupping with moxibustion was shown to create a specific pattern in the shape of the cultural tool used.³⁸ When footbaths with Chinese herbal remedies are performed frequently with high heat, they can lead to EAI on the feet with a linear border at the ankles. There also have been reports of kotatsu (heated tables in Japan) leading to lower-body EAI.^39,40 These cultural practices also are more common in patients with darker skin types, which can lead to hyperpigmentation that is difficult to treat, making early diagnosis important.⁷

Medical History—Case reports have shown EAI caused by patients attempting to use heat-based methods for pain relief of an underlying serious disease such as cancer, bowel pathology (abdominal EAI), spinal disc prolapse (midline back EAI),⁴¹ sickle cell anemia, and renal pathology (posterior upper flank EAI).^6,7,40-49 Patients with hypothyroidism or anorexia have been noted to have generalized EAI sparing the face secondary to repeated and extended hot baths or showers.^50-53 One patient with schizophrenia was shown to have associated thermophilia due to a delusion that led the patient to soak in hot baths for long periods of time, leading to EAI.⁵⁴ Finally, all physicians should be aware of iatrogenic causes of EAI, such as use of warming devices, ultrasound-based warming techniques, and laser therapy for lipolysis. Inquire about the patient’s surgical history or intensive care unit stays as well as alternative medicine or chiropractic visits. Obtaining a history of medical procedures can be enlightening when an etiology is not immediately clear.^7,55,56

Diagnosis

Erythema ab igne is a clinical diagnosis based on recognizable cutaneous findings and a clear history of moderate heat exposure. However, when a clinical diagnosis of EAI is not certain (eg, when unable to obtain a clear history from the patient) or when malignant transformation is suspected, a biopsy can be performed. Pathologically, hematoxylin and eosin staining of EAI classically reveals dilated small vascular channels in the superficial dermis, hence a clinically reticular rash; interface dermatitis clinically manifesting as erythema; and pigment incontinence with melanin-laden macrophages consistent with clinical hyperpigmentation. Finally, for unclear reasons, increased numbers of elastic fibers classically are seen in biopsies of EAI.⁷

 

 

Differential Diagnosis

The differential diagnosis for a reticular patch includes livedo reticularis (Figure 3), which usually manifests as a more generalized rash in patients with chronic disease or coagulopathy such as systemic lupus erythematosus, cryoglobulinemia, or Raynaud phenomenon. When differentiating EAI from livedo reticularis or cutis marmorata, consider that both alternative diagnoses are more vascular appearing and are associated with cold exposure rather than heat exposure. In cases that are less reticular, livedo racemosa can be considered in the differential diagnosis. Finally, poikiloderma of Civatte can be reticular, particularly on dermoscopy, but the distribution on the neck with submental sparing should help to distinguish it from EAI unless a heat source around the neck is identified while taking the patient’s history.⁷

In babies, a reticular generalized rash is most likely to be cutis marmorata (Figure 4), which is a physiologic response to cold exposure that resolves with rewarming of the skin. A more serious condition—cutis marmorata telangiectatica congenita (Figure 5)—usually is present at birth, most frequently involves a single extremity, and notably does not resolve with rewarming. This is an important differential for EAI in children because it can be associated with vascular and neurologic anomalies as well as limb asymmetry. Finally, port-wine stains can sometimes be reticular in appearance and can mimic the early erythematous stages of EAI. However, unlike the erythematous stage of EAI, the port-wine stains will be present at birth.⁷

Emerging in 2020, an important differential diagnosis to consider is a cutaneous manifestation of COVID-19 infection. An erythematous, reticular, chilblainlike or transient livedo reticularis–like rash has been described as a cutaneous manifestation of COVID-19. Although the pathophysiology is still being elucidated, it is suspected that this is caused by a major vaso-occlusive crisis secondary to COVID-19–induced thrombotic vasculopathy. Interestingly, the majority of patients with this COVID-related exanthem also displayed symptoms of COVID-19 (eg, fever, cough) at the time of presentation,^57-60 but there also have been cases in patients who were asymptomatic or mildly symptomatic.⁶⁰

In some cases, EAI is an indication to screen for an underlying disease. For example, uncontrolled pain is an opportunity to improve interventions such as modifying the patient’s pain-control regimen, placing a palliative care pain consultation, or checking if the patient has had age-appropriate screenings for malignancy. New focal pain in a patient with a prior diagnosis of cancer may be a sign of a new metastasis. A thermophilic patient leaves opportunity to assess for underlying medical causes such as thyroid abnormalities or social/psychological issues. Geriatric patients who are diagnosed with EAI may need to be assessed for dementia or home safety issues. Patients with a history of diabetes mellitus can unknowingly develop EAI on the lower extremities, which may signal a need to assess the patient for peripheral neuropathy. Patients with gastroparesis secondary to diabetes also may develop EAI on the abdomen secondary to heating pad use for discomfort. These examples are a reminder to consider possible secondary comorbidities in all diagnoses of EAI.⁷ 

Prognosis

Although the prognosis of EAI is excellent if caught early, failure to diagnose this condition can lead to permanent discoloration of the skin and even malignancy.⁶ A rare sequela includes squamous cell carcinoma, most commonly seen in chronic cases of the lower leg, which is likely related to chronic inflammation of the skin.^61-65 Rare cases of poorly differentiated carcinoma,⁶⁶ cutaneous marginal zone lymphoma,⁶⁷ and Merkel cell carcinoma⁶⁸ have been reported. Patients diagnosed with EAI should receive normal periodic surveillance of the skin based on their medical history, though the physician should have an increased suspicion and plan for biopsy of any nodules or ulcerations found on the skin of the affected area.⁷

Treatments

Once the diagnosis of EAI is made, treatment starts with removal of the heat source causing the rash. Because the rash usually is asymptomatic, further treatment typically is not required. The discoloration can resolve over months or years, but permanent hyperpigmentation is not uncommon. If hyperpigmentation persists despite removal of the heat source and the patient desires further treatment for discoloration, there are few treatment options, none of which are approved by the US Food and Drug Administration for this condition.⁷ There is some evidence for the use of Nd:YAG lasers to reduce hyperpigmentation in EAI.⁶⁹ There have been some reports of treatment using topical hydroquinone and topical tretinoin in an attempt to lighten the skin. If associated hyperkeratosis or other epithelial atypia is present, the use of 5-fluorouracil may show some improvement.⁷⁰ One case report has been published of successful treatment with systemic mesoglycan and topical bioflavonoids.⁷¹ It also is conceivable that medications used to treat postinflammatory hyperpigmentation may be helpful in this condition (eg, kojic acid, arbutin, mild topical steroids, azelaic acid). Patients with darker skin may experience permanent discoloration and may not be good candidates for alternative treatments such as laser therapy due to the risk for inducible hyperpigmentation.⁷

Conclusion

No matter the etiology, EAI usually is a benign skin condition that is treated by removal of the causative heat source. Once a diagnosis is made, the clinician must work with the patient to determine the etiology. Care must be taken to ensure that there are no underlying signs, such as chronic pain or psychiatric illness, that could point to associated conditions. Rarely, sequalae such as cancers have been documented in areas of chronic EAI. Once the heat source is identified and removed, any remaining hyperpigmentation usually will self-resolve over months to years, though this may take longer in patients with darker skin types. If more aggressive treatment is preferred by the patient, laser therapy, topical medications, and oral over-the-counter vitamins have been tried with minimal responses. 

PHOENIX – Combining a serum containing silymarin with nonablative laser therapy could serve as a promising solution for decreasing inflammation, postinflammatory erythema (PIE), and postinflammatory hyperpigmentation (PIH) associated with acne lesions, results from a prospective, single-center study showed.

“Acne vulgaris is the most common inflammatory dermatosis worldwide, often resulting in sequelae such as scarring, PIE, and PIH,” presenting author Jamie Hu, MD, said at the annual conference of the American Society for Laser Medicine and Surgery, where the study results were presented during an abstract session. “This dyschromia can cause greater psychological distress than the original acne lesions, and disproportionately affects skin of color patients.”

Blemish-prone skin is known to have higher levels of sebum and lower levels of antioxidants, leading to lipid peroxidation and oxidative stress, resulting in proliferation of Cutibacterium acnes and an inflammatory cascade that has recently been implicated in postinflammatory dyschromia and the development of PIE and PIH, noted Dr. Hu, a dermatology resident at the University of Miami. “Therefore, the use of antioxidants presents an opportunity to disrupt blemish and dyschromia,” she said.

One such antioxidant is silymarin, which is derived from the milk thistle plant. Recent studies have demonstrated that silymarin reduces proinflammatory mediators, prevents lipid peroxidation, and presents a new way to target the treatment of both acne and postinflammatory dyschromia.

Dr. Hu’s mentor, Jill S. Waibel, MD, owner and medical director of the Miami Dermatology and Laser Institute, hypothesized that nonablative laser therapy followed by topical application of silymarin would improve acne-associated postinflammatory dyschromia. To test her hunch, she conducted a 12-week, prospective trial in which 24 patients with PIE and/or PIH were randomized to one of two treatment arms: laser treatment with topical antioxidants or laser treatment with vehicle control. Patients received three laser treatments, each 1 month apart. The topical antioxidant used was Silymarin CF, a serum that contains 0.5% silymarin, 0.5% salicylic acid, 15% L-ascorbic acid, and 0.5% ferulic acid. (The study was sponsored by SkinCeuticals, the manufacturer of the serum.)

Laser selection was made primarily on the type of dyschromia, with PIE patients receiving treatment with the pulsed dye laser and PIH patients receiving treatment with the 1,927-nm thulium laser. Patients were treated on days 0, 28, and 56 of the 12-week study, followed by immediate application of topical antioxidants or vehicle control. They were also instructed to apply the assigned topical twice daily for the duration of the study. Patients ranged in age from 21 to 61 years, and 20 had skin types III-IV.

To evaluate efficacy, the researchers conducted blinded clinical assessments with the postacne hyperpigmentation index (PAHPI) and the Global Aesthetic Improvement Scale (GAIS), instrumentation with the Mexameter, a device that captures erythema and melanin index values, and visual diagnostics with optical coherence tomography (OCT).

Dr. Hu reported that at week 12, the PAHPI in the silymarin-plus-laser treatment group fell from an average of 3.18 to 1.74 (a decrease of 1.44), which suggested an improvement trend, compared with the laser treatment–only group, whose PAHPI fell from an average of 3.25 to 1.97 (a decrease of 1.28).

As for the GAIS, a one-time score assessed at the end of the trial, the average score for all patients was 3.24, which translated to “much improved/very much improved.” Patients in the silymarin-plus-laser treatment group had higher average scores compared with patients in the laser treatment–only group (3.35 vs. 3.10, respectively), but the differences did not reach statistical significance.

According to results of the Mexameter assessment, paired t-tests showed that the levels of intralesional melanin decreased significantly for patients in the silymarin-plus-laser treatment group, compared with the laser treatment–only group (P < .05). OCT assessments demonstrated an increase in dermal brightness in both groups, corresponding to an increase in dermal collagen, as well as an increase in blood vessel density.

In an interview at the meeting, Dr. Waibel, subsection chief of dermatology at Baptist Hospital of Miami, said that future studies will focus on long-term follow-up to determine if acne scars can be prevented by combining silymarin with lasers to prevent PIH and PIE. “That would be priceless,” she said. “I believe that the PIH is what causes damage to the collagen, and that damage to the collagen is what causes the scarring. So, if we can prevent or treat PIH, we may be able to prevent scarring.”

This approach, she added, “would decrease the pharmaceutical cost because I think there are many dermatologists who are treating PEI and PIH as active acne. You really have to have a keen eye for understanding the differences and you really have to be looking, because PIE and PIH are flat, whereas active acne consists of either comedones or nodules.”

She noted that in skin of color patients, she has seen PIH persist for 9 or 10 months after treatment with isotretinoin. “It’s not the isotretinoin causing the scars, or even the acne, it’s the prolonged inflammation,” she said.

Catherine M. DiGiorgio, MD, a Boston-based laser and cosmetic dermatologist who was asked to comment on the study, said that patients and dermatologists frequently seek alternatives to hydroquinone for unwanted hyperpigmentation.

Dr. DiGiorgio

Dr. Jalian

“While the study failed to show statistically significant improvement in postinflammatory erythema with concomitant laser and topical therapy versus laser alone, the promising data supporting concurrent use of topicals and fractional lasers for treatment of PIH, particularly in dark skin phototypes, is a clinically impactful contribution to our daily practice,” he said.

Dr. Waibel disclosed that she has conducted clinical trials for many device and pharmaceutical companies including SkinCeuticals. Dr. Hu, Dr. DiGiorgio, and Dr. Jalian were not involved with the study and reported having no relevant disclosures.

PHOENIX – Combining a serum containing silymarin with nonablative laser therapy could serve as a promising solution for decreasing inflammation, postinflammatory erythema (PIE), and postinflammatory hyperpigmentation (PIH) associated with acne lesions, results from a prospective, single-center study showed.

“Acne vulgaris is the most common inflammatory dermatosis worldwide, often resulting in sequelae such as scarring, PIE, and PIH,” presenting author Jamie Hu, MD, said at the annual conference of the American Society for Laser Medicine and Surgery, where the study results were presented during an abstract session. “This dyschromia can cause greater psychological distress than the original acne lesions, and disproportionately affects skin of color patients.”

Blemish-prone skin is known to have higher levels of sebum and lower levels of antioxidants, leading to lipid peroxidation and oxidative stress, resulting in proliferation of Cutibacterium acnes and an inflammatory cascade that has recently been implicated in postinflammatory dyschromia and the development of PIE and PIH, noted Dr. Hu, a dermatology resident at the University of Miami. “Therefore, the use of antioxidants presents an opportunity to disrupt blemish and dyschromia,” she said.

One such antioxidant is silymarin, which is derived from the milk thistle plant. Recent studies have demonstrated that silymarin reduces proinflammatory mediators, prevents lipid peroxidation, and presents a new way to target the treatment of both acne and postinflammatory dyschromia.

Dr. Hu’s mentor, Jill S. Waibel, MD, owner and medical director of the Miami Dermatology and Laser Institute, hypothesized that nonablative laser therapy followed by topical application of silymarin would improve acne-associated postinflammatory dyschromia. To test her hunch, she conducted a 12-week, prospective trial in which 24 patients with PIE and/or PIH were randomized to one of two treatment arms: laser treatment with topical antioxidants or laser treatment with vehicle control. Patients received three laser treatments, each 1 month apart. The topical antioxidant used was Silymarin CF, a serum that contains 0.5% silymarin, 0.5% salicylic acid, 15% L-ascorbic acid, and 0.5% ferulic acid. (The study was sponsored by SkinCeuticals, the manufacturer of the serum.)

Laser selection was made primarily on the type of dyschromia, with PIE patients receiving treatment with the pulsed dye laser and PIH patients receiving treatment with the 1,927-nm thulium laser. Patients were treated on days 0, 28, and 56 of the 12-week study, followed by immediate application of topical antioxidants or vehicle control. They were also instructed to apply the assigned topical twice daily for the duration of the study. Patients ranged in age from 21 to 61 years, and 20 had skin types III-IV.

To evaluate efficacy, the researchers conducted blinded clinical assessments with the postacne hyperpigmentation index (PAHPI) and the Global Aesthetic Improvement Scale (GAIS), instrumentation with the Mexameter, a device that captures erythema and melanin index values, and visual diagnostics with optical coherence tomography (OCT).

Dr. Hu reported that at week 12, the PAHPI in the silymarin-plus-laser treatment group fell from an average of 3.18 to 1.74 (a decrease of 1.44), which suggested an improvement trend, compared with the laser treatment–only group, whose PAHPI fell from an average of 3.25 to 1.97 (a decrease of 1.28).

As for the GAIS, a one-time score assessed at the end of the trial, the average score for all patients was 3.24, which translated to “much improved/very much improved.” Patients in the silymarin-plus-laser treatment group had higher average scores compared with patients in the laser treatment–only group (3.35 vs. 3.10, respectively), but the differences did not reach statistical significance.

According to results of the Mexameter assessment, paired t-tests showed that the levels of intralesional melanin decreased significantly for patients in the silymarin-plus-laser treatment group, compared with the laser treatment–only group (P < .05). OCT assessments demonstrated an increase in dermal brightness in both groups, corresponding to an increase in dermal collagen, as well as an increase in blood vessel density.

In an interview at the meeting, Dr. Waibel, subsection chief of dermatology at Baptist Hospital of Miami, said that future studies will focus on long-term follow-up to determine if acne scars can be prevented by combining silymarin with lasers to prevent PIH and PIE. “That would be priceless,” she said. “I believe that the PIH is what causes damage to the collagen, and that damage to the collagen is what causes the scarring. So, if we can prevent or treat PIH, we may be able to prevent scarring.”

This approach, she added, “would decrease the pharmaceutical cost because I think there are many dermatologists who are treating PEI and PIH as active acne. You really have to have a keen eye for understanding the differences and you really have to be looking, because PIE and PIH are flat, whereas active acne consists of either comedones or nodules.”

She noted that in skin of color patients, she has seen PIH persist for 9 or 10 months after treatment with isotretinoin. “It’s not the isotretinoin causing the scars, or even the acne, it’s the prolonged inflammation,” she said.

Catherine M. DiGiorgio, MD, a Boston-based laser and cosmetic dermatologist who was asked to comment on the study, said that patients and dermatologists frequently seek alternatives to hydroquinone for unwanted hyperpigmentation.

Dr. DiGiorgio

Dr. Jalian

“While the study failed to show statistically significant improvement in postinflammatory erythema with concomitant laser and topical therapy versus laser alone, the promising data supporting concurrent use of topicals and fractional lasers for treatment of PIH, particularly in dark skin phototypes, is a clinically impactful contribution to our daily practice,” he said.

Dr. Waibel disclosed that she has conducted clinical trials for many device and pharmaceutical companies including SkinCeuticals. Dr. Hu, Dr. DiGiorgio, and Dr. Jalian were not involved with the study and reported having no relevant disclosures.

PHOENIX – Combining a serum containing silymarin with nonablative laser therapy could serve as a promising solution for decreasing inflammation, postinflammatory erythema (PIE), and postinflammatory hyperpigmentation (PIH) associated with acne lesions, results from a prospective, single-center study showed.

“Acne vulgaris is the most common inflammatory dermatosis worldwide, often resulting in sequelae such as scarring, PIE, and PIH,” presenting author Jamie Hu, MD, said at the annual conference of the American Society for Laser Medicine and Surgery, where the study results were presented during an abstract session. “This dyschromia can cause greater psychological distress than the original acne lesions, and disproportionately affects skin of color patients.”

Blemish-prone skin is known to have higher levels of sebum and lower levels of antioxidants, leading to lipid peroxidation and oxidative stress, resulting in proliferation of Cutibacterium acnes and an inflammatory cascade that has recently been implicated in postinflammatory dyschromia and the development of PIE and PIH, noted Dr. Hu, a dermatology resident at the University of Miami. “Therefore, the use of antioxidants presents an opportunity to disrupt blemish and dyschromia,” she said.

One such antioxidant is silymarin, which is derived from the milk thistle plant. Recent studies have demonstrated that silymarin reduces proinflammatory mediators, prevents lipid peroxidation, and presents a new way to target the treatment of both acne and postinflammatory dyschromia.

Dr. Hu’s mentor, Jill S. Waibel, MD, owner and medical director of the Miami Dermatology and Laser Institute, hypothesized that nonablative laser therapy followed by topical application of silymarin would improve acne-associated postinflammatory dyschromia. To test her hunch, she conducted a 12-week, prospective trial in which 24 patients with PIE and/or PIH were randomized to one of two treatment arms: laser treatment with topical antioxidants or laser treatment with vehicle control. Patients received three laser treatments, each 1 month apart. The topical antioxidant used was Silymarin CF, a serum that contains 0.5% silymarin, 0.5% salicylic acid, 15% L-ascorbic acid, and 0.5% ferulic acid. (The study was sponsored by SkinCeuticals, the manufacturer of the serum.)

Laser selection was made primarily on the type of dyschromia, with PIE patients receiving treatment with the pulsed dye laser and PIH patients receiving treatment with the 1,927-nm thulium laser. Patients were treated on days 0, 28, and 56 of the 12-week study, followed by immediate application of topical antioxidants or vehicle control. They were also instructed to apply the assigned topical twice daily for the duration of the study. Patients ranged in age from 21 to 61 years, and 20 had skin types III-IV.

To evaluate efficacy, the researchers conducted blinded clinical assessments with the postacne hyperpigmentation index (PAHPI) and the Global Aesthetic Improvement Scale (GAIS), instrumentation with the Mexameter, a device that captures erythema and melanin index values, and visual diagnostics with optical coherence tomography (OCT).

Dr. Hu reported that at week 12, the PAHPI in the silymarin-plus-laser treatment group fell from an average of 3.18 to 1.74 (a decrease of 1.44), which suggested an improvement trend, compared with the laser treatment–only group, whose PAHPI fell from an average of 3.25 to 1.97 (a decrease of 1.28).

As for the GAIS, a one-time score assessed at the end of the trial, the average score for all patients was 3.24, which translated to “much improved/very much improved.” Patients in the silymarin-plus-laser treatment group had higher average scores compared with patients in the laser treatment–only group (3.35 vs. 3.10, respectively), but the differences did not reach statistical significance.

According to results of the Mexameter assessment, paired t-tests showed that the levels of intralesional melanin decreased significantly for patients in the silymarin-plus-laser treatment group, compared with the laser treatment–only group (P < .05). OCT assessments demonstrated an increase in dermal brightness in both groups, corresponding to an increase in dermal collagen, as well as an increase in blood vessel density.

In an interview at the meeting, Dr. Waibel, subsection chief of dermatology at Baptist Hospital of Miami, said that future studies will focus on long-term follow-up to determine if acne scars can be prevented by combining silymarin with lasers to prevent PIH and PIE. “That would be priceless,” she said. “I believe that the PIH is what causes damage to the collagen, and that damage to the collagen is what causes the scarring. So, if we can prevent or treat PIH, we may be able to prevent scarring.”

This approach, she added, “would decrease the pharmaceutical cost because I think there are many dermatologists who are treating PEI and PIH as active acne. You really have to have a keen eye for understanding the differences and you really have to be looking, because PIE and PIH are flat, whereas active acne consists of either comedones or nodules.”

She noted that in skin of color patients, she has seen PIH persist for 9 or 10 months after treatment with isotretinoin. “It’s not the isotretinoin causing the scars, or even the acne, it’s the prolonged inflammation,” she said.

Catherine M. DiGiorgio, MD, a Boston-based laser and cosmetic dermatologist who was asked to comment on the study, said that patients and dermatologists frequently seek alternatives to hydroquinone for unwanted hyperpigmentation.

Dr. DiGiorgio

Dr. Jalian

“While the study failed to show statistically significant improvement in postinflammatory erythema with concomitant laser and topical therapy versus laser alone, the promising data supporting concurrent use of topicals and fractional lasers for treatment of PIH, particularly in dark skin phototypes, is a clinically impactful contribution to our daily practice,” he said.

Dr. Waibel disclosed that she has conducted clinical trials for many device and pharmaceutical companies including SkinCeuticals. Dr. Hu, Dr. DiGiorgio, and Dr. Jalian were not involved with the study and reported having no relevant disclosures.

Liver transplant is an effective therapy for patients with primary liver cancer, and outcomes after transplantation are often superior to surgical resection. But the pool of potential patients is increasing, as transplantation is now emerging as an attractive option for select patients with nonresectable colorectal cancer (CRC) liver metastases, as well as those with intrahepatic cholangiocarcinoma (CCA).

Experts in the field highlighted some of the current challenges and opportunities in transplant oncology during a special session at the ASCO Gastrointestinal Cancers Symposium.
 

Transplant is here to stay

To date, the only curative or potentially curative therapy for patients with CRC liver metastases and intrahepatic CCA has been the combination of systemic therapies and R0 resection, said Gonzalo Sapisochin Cantis, MD, associate professor, department of surgery, University of Toronto.

The new idea is that, for patients with unresectable disease, total hepatectomy followed by a liver transplant may be a promising strategy. “This is a very hot topic in transplant oncology,” he said.

Liver transplantation is already established as the best treatment option for patients with primary hepatocellular carcinoma, which has become the main indication for liver transplantation at many centers.

For patients with CRC metastases and intrahepatic CCA, liver transplantation may help cure some patients by extending the conventional margins of surgical oncology, he suggested. “This is basically going to work in patients who have exclusive liver-restricted disease and not in those with metastatic disease. The efficacy is going to be seen by objective and sustained response to some sort of neoadjuvant therapy.”

However, Dr. Sapisochin emphasized liver transplantation is not an option for every patient. “We’re going to have to have clear inclusion and exclusion criteria that need to be defined a priori.”

Intrahepatic CCA has historically been considered a contraindication for liver transplantation. Surgical resection is the preferred first-line treatment and the only one that is potentially curative, he explained. However, most patients are not candidates for surgery, and even if they do have a resection, many of these patients will experience a recurrence, usually in the liver.

There are some studies that support transplantation in this patient population, including one by Dr. Sapisochin and colleagues. That study looked at patients who were transplanted under the assumption that they had hepatocellular carcinoma but were found to actually have intrahepatic CCA. The recurrence rate at 5 years was 18%, and 5-year survival was 65%.

“We were able to show that those patients with small tumors actually can do very well after transplant, with survivals over 70%-80%, which in this population is a very good outcome,” he said.
 

Transplant for CRC metastases

Unresectable liver metastases from colorectal cancer can also be challenging to treat, he said. Surgical resection is the only potential cure with a combination of systemic chemotherapy, but only a minority of patients are candidates for surgery.

Data supporting transplantation for CRC metastases have been emerging. One trial was conducted by researchers in Norway, who developed the Oslo score for risk stratification. “Those with risk factors had worse outcomes, and obviously, having a large tumor diameter, a high CEA (carcinoembryonic antigen), progressing on chemotherapy, or a short interval between the primary resection and the transplant were risk factors for recurrence,” Dr. Sapisochin said.

The 10-year survival among patients with a low Oslo score was 50%. “We’re talking about patients who had no resection possibility and received a transplant after systemic chemotherapy, and they had a 10-year survival of 50%,” he emphasized.

However, Dr. Sapisochin acknowledged the biggest problem transplant surgeons face is that there are not enough donor organs.

One solution is living donor liver transplantation. “Given that this is an unlimited source, you can utilize this as extended criteria and it adds another graft to the system,” he explained.

“We have a protocol for living donor liver transplantations for patients with colorectal liver metastasis,” Dr. Sapisochin said. “We’ve done seven cases so far with pretty good outcomes. One patient, unfortunately, passed away 39 months after transplant with lung metastases, but the rest are alive with no recurrence.”*
 

More available organs?

R. Mark Ghobrial, MD, PhD, director of the J.C. Walter Jr. Transplant Center at Houston Methodist Hospital, said that, 5 years ago, he was very cautious about liver transplantation for intrahepatic CCA.

He pointed out that, although transplantation for hepatocellular cancer was being done in the 1990s, the results were so poor that a moratorium was placed on the practice. “But now liver transplantation has become the definitive therapy for hepatocellular cancer, and intrahepatic cholangiocarcinoma is going the same way,” he said.

Dr. Ghobrial reiterated that one of the issues in transplantation for oncology patients is the limited supply of available organs, but he believes the landscape for liver transplantation has changed, resulting in more available organs. One factor is that hepatitis C has become curable with the advent of new therapies, and hence, the need for transplantation for patients with this disease has plummeted.

“I’ve done about maybe 800 transplants in the last 5 years. I’ve only transplanted two patients with hepatitis C,” he said. “Now we are doing more transplants for alcoholic liver disease and cancer.”

Improvements in technology are also allowing for more livers to become useable, he pointed out. One example is normothermic machine perfusion, which has entered the clinical arena in the last decade. The technique has shown promising results in improving the quality of marginal organs and increasing the pool of liver grafts.

Another factor that has increased the number of livers available for transplantation is the move to accept organs from circulatory death donors, as well as donations after brain death. “Our transplantation was about 4% of donors after cardiac death, but today this has gone up to almost 16% or 20% of the livers,” Dr. Ghobrial said. “In some centers this has gone up to about 50%.

“Liver transplantation for intrahepatic cholangiocarcinoma and colorectal cancer metastases has come of age for selected patients,” he said.

More caution needed

However, another expert urged some caution, warning that live donation carries risk. Yuman Fong, MD, a surgical oncologist with City of Hope National Medical Center, Duarte, Calif., said that around “1 in 600 live donors die from donation. That is a healthy person dying. This is not a small issue.”

He pointed out that if the criteria for transplant is greatly liberalized, the 5-year survival will not be as high as demonstrated in clinical trials.

Writing about the issue in a recent editorial, Dr. Fong pointed out that cadaveric livers for transplant remain a finite resource and that more than 1,000 patients still die every year on the waiting list for a transplant.

A more reasonable approach would be to advocate for this type of program in regions of the world where cadaveric livers are more plentiful or centers with established living donor transplant programs.

“For us to develop this resource and safeguard patients, family organ donors, and resources, we need to develop what are the best inclusion criteria,” Dr. Fong said. “We have to optimize use of all cadaveric organs and determine if we are willing to transplant borderline organs.”
 

Ethics of transplanting

Ethicist Arthur L. Caplan, PhD, the Drs. William F. and Virginia Connolly Mitty Professor of Bioethics at New York University, said this is an interesting development in the field of liver transplantation. “There have been attempts in the past, and many did not end well, such as with Steve Jobs. But transplantation is always pushing to expand eligibility, and there has also been much success with that.”

However, Dr. Caplan emphasized the new data are innovative and experimental, which may control how many centers will be able to perform liver transplants in these cancer patient populations. “It has to be data driven as we are dealing with an exceedingly scarce source,” he said. “We know that people can do well, but it adds more stress to the supply of organs, and some patients may not do as well.”

He also emphasized that live donation is not a panacea. “Liver donation from a live donor is not the same as live donation for a kidney. It is much riskier and not that common. So not quite the same.”

The bottom line is that livers for transplantation are a scarce resource and transplant may work well in some cancer patients but not others, he emphasized. “Morally, we want to save lives, but not by adding in people who may not do well. If programs try to stretch the criteria, some may try transplants with more marginal organs.”

Dr. Sapisochin has disclosed relationships with Bayer, Roche, Novartis, Integra, AstraZeneca, Chiesi, Evidera, and Stryker. Dr. Ghobrial reported no relevant financial relationships. Dr. Fong has reported being a scientific consultant for Medtronic and Johnson & Johnson and receiving royalties from Merck and Imugene. Dr. Caplan writes a regular column on ethics for Medscape.

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

Correction, 4/28/23 - An earlier version of this article misstated when the patient passed away.

Liver transplant is an effective therapy for patients with primary liver cancer, and outcomes after transplantation are often superior to surgical resection. But the pool of potential patients is increasing, as transplantation is now emerging as an attractive option for select patients with nonresectable colorectal cancer (CRC) liver metastases, as well as those with intrahepatic cholangiocarcinoma (CCA).

Experts in the field highlighted some of the current challenges and opportunities in transplant oncology during a special session at the ASCO Gastrointestinal Cancers Symposium.
 

Transplant is here to stay

To date, the only curative or potentially curative therapy for patients with CRC liver metastases and intrahepatic CCA has been the combination of systemic therapies and R0 resection, said Gonzalo Sapisochin Cantis, MD, associate professor, department of surgery, University of Toronto.

The new idea is that, for patients with unresectable disease, total hepatectomy followed by a liver transplant may be a promising strategy. “This is a very hot topic in transplant oncology,” he said.

Liver transplantation is already established as the best treatment option for patients with primary hepatocellular carcinoma, which has become the main indication for liver transplantation at many centers.

For patients with CRC metastases and intrahepatic CCA, liver transplantation may help cure some patients by extending the conventional margins of surgical oncology, he suggested. “This is basically going to work in patients who have exclusive liver-restricted disease and not in those with metastatic disease. The efficacy is going to be seen by objective and sustained response to some sort of neoadjuvant therapy.”

However, Dr. Sapisochin emphasized liver transplantation is not an option for every patient. “We’re going to have to have clear inclusion and exclusion criteria that need to be defined a priori.”

Intrahepatic CCA has historically been considered a contraindication for liver transplantation. Surgical resection is the preferred first-line treatment and the only one that is potentially curative, he explained. However, most patients are not candidates for surgery, and even if they do have a resection, many of these patients will experience a recurrence, usually in the liver.

There are some studies that support transplantation in this patient population, including one by Dr. Sapisochin and colleagues. That study looked at patients who were transplanted under the assumption that they had hepatocellular carcinoma but were found to actually have intrahepatic CCA. The recurrence rate at 5 years was 18%, and 5-year survival was 65%.

“We were able to show that those patients with small tumors actually can do very well after transplant, with survivals over 70%-80%, which in this population is a very good outcome,” he said.
 

Transplant for CRC metastases

Unresectable liver metastases from colorectal cancer can also be challenging to treat, he said. Surgical resection is the only potential cure with a combination of systemic chemotherapy, but only a minority of patients are candidates for surgery.

Data supporting transplantation for CRC metastases have been emerging. One trial was conducted by researchers in Norway, who developed the Oslo score for risk stratification. “Those with risk factors had worse outcomes, and obviously, having a large tumor diameter, a high CEA (carcinoembryonic antigen), progressing on chemotherapy, or a short interval between the primary resection and the transplant were risk factors for recurrence,” Dr. Sapisochin said.

The 10-year survival among patients with a low Oslo score was 50%. “We’re talking about patients who had no resection possibility and received a transplant after systemic chemotherapy, and they had a 10-year survival of 50%,” he emphasized.

However, Dr. Sapisochin acknowledged the biggest problem transplant surgeons face is that there are not enough donor organs.

One solution is living donor liver transplantation. “Given that this is an unlimited source, you can utilize this as extended criteria and it adds another graft to the system,” he explained.

“We have a protocol for living donor liver transplantations for patients with colorectal liver metastasis,” Dr. Sapisochin said. “We’ve done seven cases so far with pretty good outcomes. One patient, unfortunately, passed away 39 months after transplant with lung metastases, but the rest are alive with no recurrence.”*
 

More available organs?

R. Mark Ghobrial, MD, PhD, director of the J.C. Walter Jr. Transplant Center at Houston Methodist Hospital, said that, 5 years ago, he was very cautious about liver transplantation for intrahepatic CCA.

He pointed out that, although transplantation for hepatocellular cancer was being done in the 1990s, the results were so poor that a moratorium was placed on the practice. “But now liver transplantation has become the definitive therapy for hepatocellular cancer, and intrahepatic cholangiocarcinoma is going the same way,” he said.

Dr. Ghobrial reiterated that one of the issues in transplantation for oncology patients is the limited supply of available organs, but he believes the landscape for liver transplantation has changed, resulting in more available organs. One factor is that hepatitis C has become curable with the advent of new therapies, and hence, the need for transplantation for patients with this disease has plummeted.

“I’ve done about maybe 800 transplants in the last 5 years. I’ve only transplanted two patients with hepatitis C,” he said. “Now we are doing more transplants for alcoholic liver disease and cancer.”

Improvements in technology are also allowing for more livers to become useable, he pointed out. One example is normothermic machine perfusion, which has entered the clinical arena in the last decade. The technique has shown promising results in improving the quality of marginal organs and increasing the pool of liver grafts.

Another factor that has increased the number of livers available for transplantation is the move to accept organs from circulatory death donors, as well as donations after brain death. “Our transplantation was about 4% of donors after cardiac death, but today this has gone up to almost 16% or 20% of the livers,” Dr. Ghobrial said. “In some centers this has gone up to about 50%.

“Liver transplantation for intrahepatic cholangiocarcinoma and colorectal cancer metastases has come of age for selected patients,” he said.

More caution needed

However, another expert urged some caution, warning that live donation carries risk. Yuman Fong, MD, a surgical oncologist with City of Hope National Medical Center, Duarte, Calif., said that around “1 in 600 live donors die from donation. That is a healthy person dying. This is not a small issue.”

He pointed out that if the criteria for transplant is greatly liberalized, the 5-year survival will not be as high as demonstrated in clinical trials.

Writing about the issue in a recent editorial, Dr. Fong pointed out that cadaveric livers for transplant remain a finite resource and that more than 1,000 patients still die every year on the waiting list for a transplant.

A more reasonable approach would be to advocate for this type of program in regions of the world where cadaveric livers are more plentiful or centers with established living donor transplant programs.

“For us to develop this resource and safeguard patients, family organ donors, and resources, we need to develop what are the best inclusion criteria,” Dr. Fong said. “We have to optimize use of all cadaveric organs and determine if we are willing to transplant borderline organs.”
 

Ethics of transplanting

Ethicist Arthur L. Caplan, PhD, the Drs. William F. and Virginia Connolly Mitty Professor of Bioethics at New York University, said this is an interesting development in the field of liver transplantation. “There have been attempts in the past, and many did not end well, such as with Steve Jobs. But transplantation is always pushing to expand eligibility, and there has also been much success with that.”

However, Dr. Caplan emphasized the new data are innovative and experimental, which may control how many centers will be able to perform liver transplants in these cancer patient populations. “It has to be data driven as we are dealing with an exceedingly scarce source,” he said. “We know that people can do well, but it adds more stress to the supply of organs, and some patients may not do as well.”

He also emphasized that live donation is not a panacea. “Liver donation from a live donor is not the same as live donation for a kidney. It is much riskier and not that common. So not quite the same.”

The bottom line is that livers for transplantation are a scarce resource and transplant may work well in some cancer patients but not others, he emphasized. “Morally, we want to save lives, but not by adding in people who may not do well. If programs try to stretch the criteria, some may try transplants with more marginal organs.”

Dr. Sapisochin has disclosed relationships with Bayer, Roche, Novartis, Integra, AstraZeneca, Chiesi, Evidera, and Stryker. Dr. Ghobrial reported no relevant financial relationships. Dr. Fong has reported being a scientific consultant for Medtronic and Johnson & Johnson and receiving royalties from Merck and Imugene. Dr. Caplan writes a regular column on ethics for Medscape.

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

Correction, 4/28/23 - An earlier version of this article misstated when the patient passed away.

Liver transplant is an effective therapy for patients with primary liver cancer, and outcomes after transplantation are often superior to surgical resection. But the pool of potential patients is increasing, as transplantation is now emerging as an attractive option for select patients with nonresectable colorectal cancer (CRC) liver metastases, as well as those with intrahepatic cholangiocarcinoma (CCA).

Experts in the field highlighted some of the current challenges and opportunities in transplant oncology during a special session at the ASCO Gastrointestinal Cancers Symposium.
 

Transplant is here to stay

To date, the only curative or potentially curative therapy for patients with CRC liver metastases and intrahepatic CCA has been the combination of systemic therapies and R0 resection, said Gonzalo Sapisochin Cantis, MD, associate professor, department of surgery, University of Toronto.

The new idea is that, for patients with unresectable disease, total hepatectomy followed by a liver transplant may be a promising strategy. “This is a very hot topic in transplant oncology,” he said.

Liver transplantation is already established as the best treatment option for patients with primary hepatocellular carcinoma, which has become the main indication for liver transplantation at many centers.

For patients with CRC metastases and intrahepatic CCA, liver transplantation may help cure some patients by extending the conventional margins of surgical oncology, he suggested. “This is basically going to work in patients who have exclusive liver-restricted disease and not in those with metastatic disease. The efficacy is going to be seen by objective and sustained response to some sort of neoadjuvant therapy.”

However, Dr. Sapisochin emphasized liver transplantation is not an option for every patient. “We’re going to have to have clear inclusion and exclusion criteria that need to be defined a priori.”

Intrahepatic CCA has historically been considered a contraindication for liver transplantation. Surgical resection is the preferred first-line treatment and the only one that is potentially curative, he explained. However, most patients are not candidates for surgery, and even if they do have a resection, many of these patients will experience a recurrence, usually in the liver.

There are some studies that support transplantation in this patient population, including one by Dr. Sapisochin and colleagues. That study looked at patients who were transplanted under the assumption that they had hepatocellular carcinoma but were found to actually have intrahepatic CCA. The recurrence rate at 5 years was 18%, and 5-year survival was 65%.

“We were able to show that those patients with small tumors actually can do very well after transplant, with survivals over 70%-80%, which in this population is a very good outcome,” he said.
 

Transplant for CRC metastases

Unresectable liver metastases from colorectal cancer can also be challenging to treat, he said. Surgical resection is the only potential cure with a combination of systemic chemotherapy, but only a minority of patients are candidates for surgery.

Data supporting transplantation for CRC metastases have been emerging. One trial was conducted by researchers in Norway, who developed the Oslo score for risk stratification. “Those with risk factors had worse outcomes, and obviously, having a large tumor diameter, a high CEA (carcinoembryonic antigen), progressing on chemotherapy, or a short interval between the primary resection and the transplant were risk factors for recurrence,” Dr. Sapisochin said.

The 10-year survival among patients with a low Oslo score was 50%. “We’re talking about patients who had no resection possibility and received a transplant after systemic chemotherapy, and they had a 10-year survival of 50%,” he emphasized.

However, Dr. Sapisochin acknowledged the biggest problem transplant surgeons face is that there are not enough donor organs.

One solution is living donor liver transplantation. “Given that this is an unlimited source, you can utilize this as extended criteria and it adds another graft to the system,” he explained.

“We have a protocol for living donor liver transplantations for patients with colorectal liver metastasis,” Dr. Sapisochin said. “We’ve done seven cases so far with pretty good outcomes. One patient, unfortunately, passed away 39 months after transplant with lung metastases, but the rest are alive with no recurrence.”*
 

More available organs?

R. Mark Ghobrial, MD, PhD, director of the J.C. Walter Jr. Transplant Center at Houston Methodist Hospital, said that, 5 years ago, he was very cautious about liver transplantation for intrahepatic CCA.

He pointed out that, although transplantation for hepatocellular cancer was being done in the 1990s, the results were so poor that a moratorium was placed on the practice. “But now liver transplantation has become the definitive therapy for hepatocellular cancer, and intrahepatic cholangiocarcinoma is going the same way,” he said.

Dr. Ghobrial reiterated that one of the issues in transplantation for oncology patients is the limited supply of available organs, but he believes the landscape for liver transplantation has changed, resulting in more available organs. One factor is that hepatitis C has become curable with the advent of new therapies, and hence, the need for transplantation for patients with this disease has plummeted.

“I’ve done about maybe 800 transplants in the last 5 years. I’ve only transplanted two patients with hepatitis C,” he said. “Now we are doing more transplants for alcoholic liver disease and cancer.”

Improvements in technology are also allowing for more livers to become useable, he pointed out. One example is normothermic machine perfusion, which has entered the clinical arena in the last decade. The technique has shown promising results in improving the quality of marginal organs and increasing the pool of liver grafts.

Another factor that has increased the number of livers available for transplantation is the move to accept organs from circulatory death donors, as well as donations after brain death. “Our transplantation was about 4% of donors after cardiac death, but today this has gone up to almost 16% or 20% of the livers,” Dr. Ghobrial said. “In some centers this has gone up to about 50%.

“Liver transplantation for intrahepatic cholangiocarcinoma and colorectal cancer metastases has come of age for selected patients,” he said.

More caution needed

However, another expert urged some caution, warning that live donation carries risk. Yuman Fong, MD, a surgical oncologist with City of Hope National Medical Center, Duarte, Calif., said that around “1 in 600 live donors die from donation. That is a healthy person dying. This is not a small issue.”

He pointed out that if the criteria for transplant is greatly liberalized, the 5-year survival will not be as high as demonstrated in clinical trials.

Writing about the issue in a recent editorial, Dr. Fong pointed out that cadaveric livers for transplant remain a finite resource and that more than 1,000 patients still die every year on the waiting list for a transplant.

A more reasonable approach would be to advocate for this type of program in regions of the world where cadaveric livers are more plentiful or centers with established living donor transplant programs.

“For us to develop this resource and safeguard patients, family organ donors, and resources, we need to develop what are the best inclusion criteria,” Dr. Fong said. “We have to optimize use of all cadaveric organs and determine if we are willing to transplant borderline organs.”
 

Ethics of transplanting

Ethicist Arthur L. Caplan, PhD, the Drs. William F. and Virginia Connolly Mitty Professor of Bioethics at New York University, said this is an interesting development in the field of liver transplantation. “There have been attempts in the past, and many did not end well, such as with Steve Jobs. But transplantation is always pushing to expand eligibility, and there has also been much success with that.”

However, Dr. Caplan emphasized the new data are innovative and experimental, which may control how many centers will be able to perform liver transplants in these cancer patient populations. “It has to be data driven as we are dealing with an exceedingly scarce source,” he said. “We know that people can do well, but it adds more stress to the supply of organs, and some patients may not do as well.”

He also emphasized that live donation is not a panacea. “Liver donation from a live donor is not the same as live donation for a kidney. It is much riskier and not that common. So not quite the same.”

The bottom line is that livers for transplantation are a scarce resource and transplant may work well in some cancer patients but not others, he emphasized. “Morally, we want to save lives, but not by adding in people who may not do well. If programs try to stretch the criteria, some may try transplants with more marginal organs.”

Dr. Sapisochin has disclosed relationships with Bayer, Roche, Novartis, Integra, AstraZeneca, Chiesi, Evidera, and Stryker. Dr. Ghobrial reported no relevant financial relationships. Dr. Fong has reported being a scientific consultant for Medtronic and Johnson & Johnson and receiving royalties from Merck and Imugene. Dr. Caplan writes a regular column on ethics for Medscape.

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

Correction, 4/28/23 - An earlier version of this article misstated when the patient passed away.

Having chronic liver disease does not affect outcomes for women who undergo in vitro fertilization (IVF), new research suggests.

The study, published online in the American Journal of Gastroenterology, compared women with and those without chronic liver disease who had normal ovarian reserve and who underwent assisted reproductive technology (ART) treatment in a high-volume fertility practice from 2002 to 2021.

“IVF treatment and pregnancy outcomes were not significantly different compared to controls,” the researchers wrote.

Women with liver disease may experience impaired fertility. For example, women with chronic liver disease, such as hepatitis C virus infection, may have premature ovarian insufficiency, while women with advanced liver disease, cirrhosis, and hepatic decompensation are known to have abnormally low gonadotropin levels.

The prevalence of liver disease in women of reproductive age is rising, leading to “an immediate need for the clinical assessment of reproductive potential in women with chronic liver disease,” the authors wrote.

The literature about ART treatment outcomes for women with liver disease was limited and may not reflect current therapy protocols, researchers found.

“To the best of our knowledge, this study is the largest to date to evaluate IVF efficacy in women with liver disease,” they wrote.
 

Similar outcomes

Researchers identified 295 women with liver disease (mean age, 37.8 ± 5.2 years) who underwent 1,033 contemporary, standard ART treatment cycles. Six patients (2%) had cirrhosis, eight (2.7%) had undergone liver transplantation, and 281 (95.3%) had chronic liver disease, of which viral hepatitis B and C infections were the most prevalent. The final study population consisted of 115 women who underwent 186 IVF cycles, as well as embryo biopsy for genetic testing.

The control group consisted of all the women at the treatment center without liver disease who received contemporary, standard ART treatment because of male factor infertility, which served as an indication that the women had normal ovarian reserve and were considered fertile. These 624 patients underwent 868 IVF cycles with embryo biopsy.

The mean age of the patients with liver disease was significantly higher than that of the control participants. Mean body mass index was also significantly higher for the patients with liver disease, and there were differences in baseline levels of selected hormones, compared with control participants. In addition, among those with liver disease, the number of oocytes retrieved was significantly lower (12.3 ± 7.6 vs. 16.5 ± 8.2; P < .05), as were the number of mature oocytes (9.1 ± 6.2 vs. 12.6 ± 6.7; P < .05), the number of fertilized embryos (7.0 ± 5.2 vs. 9.9 ± 5.9; P < .05), the number of embryos for which biopsy was performed (3.4 ± 2.2 vs. 5.1 ± 3.5; P < .05), and the number of euploid embryos (1.6 ± 1.4 vs. 2.7 ± 2.4; P < .05), compared with control participants.

Among the two groups, there were no statistically significant differences in mature oocyte rate (an indicator of response to controlled ovarian stimulation), fertilization per mature oocyte rate (an indicator of oocyte quality and ability to be fertilized), or embryo ploidy rate (an indicator of genetically normal embryos), as determined by embryo biopsy, the researchers write.

A subanalysis of women who went on to have a single thawed euploid (chromosomally normal) embryo transfer to achieve pregnancy found no statistically significant differences in rates of clinical pregnancy, clinical pregnancy loss, or live births between the liver disease group and the control group.

“Overall, women with chronic liver disease can be counseled that IVF treatment will not significantly differ in response to controlled ovarian stimulation, embryo fertilization rate, or ploidy outcome compared to women without liver disease,” the researchers wrote.
 

Data for patient counseling

The results could change the current common thinking among clinicians that IVF should not be conducted until liver disease is under optimal control, first author Jessica Lee, BS, a student at Icahn School of Medicine at Mount Sinai, New York, said.

“There was a knowledge gap for studies in the United States, and we hope this study will not only help patients with liver disease but also providers with counseling,” she said.

The findings suggest that “even if you have chronic liver disease and it’s not fully optimized, that should not interfere with pursuing IVF,” said principal investigator Tatyana Kushner, MD, an associate professor of medicine in liver diseases at the Icahn School.

Women with liver disease whose fertility is impaired should receive counseling about fertility preservation options earlier to help access fertility care, the researchers write.

The study’s findings are “encouraging,” said Monika Sarkar, MD, associate professor of medicine in gastroenterology at the University of California, San Francisco.

“With rising numbers of young adults with liver disease, it is encouraging to see dedicated studies that address a topic of importance to our patients – namely, their reproductive health,” she said. “The current study nicely expands beyond previous data to include a control population without liver disease.”
 

Differences in oocyte numbers

Although there were no differences in the success rate of embryo transfer, the researchers did see differences in the number of oocytes. Only 37 mature oocytes made it to transfer in the liver disease group, compared with 609 in the control group, noted Dr. Sarkar, who was not involved with the study.

“The challenge of ART is less at the level of embryo transfer, which is very successful once a euploid embryo is achieved, but rather at the earlier step of retrieval of mature oocytes,” Dr. Sarkar said. “Here, the authors found that patients with liver disease had a significantly lower number of oocytes retrieved, number of mature oocytes, and lower number of fertilized embryos.”

The data suggest that fewer eggs are retrieved per cycle from patients with liver disease, “which ultimately will lower the success per cycle,” Dr. Sarkar said.

“This suggests that referring women with chronic liver disease to ART sooner may help to optimize outcomes,” she added. “Larger data evaluating ability to achieve mature oocytes and subsequent fertilization will also be key for determining whether ART success differs by presence, severity, and type of liver disease.”

As more research on ART outcomes in women with liver disease is conducted, subspecialists in gastrointestinal and liver disease may gain confidence in counseling patients, Dr. Sarkar said.

Ms. Lee, Dr. Kushner, and Dr. Sarkar report no relevant financial relationships.

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

Having chronic liver disease does not affect outcomes for women who undergo in vitro fertilization (IVF), new research suggests.

The study, published online in the American Journal of Gastroenterology, compared women with and those without chronic liver disease who had normal ovarian reserve and who underwent assisted reproductive technology (ART) treatment in a high-volume fertility practice from 2002 to 2021.

“IVF treatment and pregnancy outcomes were not significantly different compared to controls,” the researchers wrote.

Women with liver disease may experience impaired fertility. For example, women with chronic liver disease, such as hepatitis C virus infection, may have premature ovarian insufficiency, while women with advanced liver disease, cirrhosis, and hepatic decompensation are known to have abnormally low gonadotropin levels.

The prevalence of liver disease in women of reproductive age is rising, leading to “an immediate need for the clinical assessment of reproductive potential in women with chronic liver disease,” the authors wrote.

The literature about ART treatment outcomes for women with liver disease was limited and may not reflect current therapy protocols, researchers found.

“To the best of our knowledge, this study is the largest to date to evaluate IVF efficacy in women with liver disease,” they wrote.
 

Similar outcomes

Researchers identified 295 women with liver disease (mean age, 37.8 ± 5.2 years) who underwent 1,033 contemporary, standard ART treatment cycles. Six patients (2%) had cirrhosis, eight (2.7%) had undergone liver transplantation, and 281 (95.3%) had chronic liver disease, of which viral hepatitis B and C infections were the most prevalent. The final study population consisted of 115 women who underwent 186 IVF cycles, as well as embryo biopsy for genetic testing.

The control group consisted of all the women at the treatment center without liver disease who received contemporary, standard ART treatment because of male factor infertility, which served as an indication that the women had normal ovarian reserve and were considered fertile. These 624 patients underwent 868 IVF cycles with embryo biopsy.

The mean age of the patients with liver disease was significantly higher than that of the control participants. Mean body mass index was also significantly higher for the patients with liver disease, and there were differences in baseline levels of selected hormones, compared with control participants. In addition, among those with liver disease, the number of oocytes retrieved was significantly lower (12.3 ± 7.6 vs. 16.5 ± 8.2; P < .05), as were the number of mature oocytes (9.1 ± 6.2 vs. 12.6 ± 6.7; P < .05), the number of fertilized embryos (7.0 ± 5.2 vs. 9.9 ± 5.9; P < .05), the number of embryos for which biopsy was performed (3.4 ± 2.2 vs. 5.1 ± 3.5; P < .05), and the number of euploid embryos (1.6 ± 1.4 vs. 2.7 ± 2.4; P < .05), compared with control participants.

Among the two groups, there were no statistically significant differences in mature oocyte rate (an indicator of response to controlled ovarian stimulation), fertilization per mature oocyte rate (an indicator of oocyte quality and ability to be fertilized), or embryo ploidy rate (an indicator of genetically normal embryos), as determined by embryo biopsy, the researchers write.

A subanalysis of women who went on to have a single thawed euploid (chromosomally normal) embryo transfer to achieve pregnancy found no statistically significant differences in rates of clinical pregnancy, clinical pregnancy loss, or live births between the liver disease group and the control group.

“Overall, women with chronic liver disease can be counseled that IVF treatment will not significantly differ in response to controlled ovarian stimulation, embryo fertilization rate, or ploidy outcome compared to women without liver disease,” the researchers wrote.
 

Data for patient counseling

The results could change the current common thinking among clinicians that IVF should not be conducted until liver disease is under optimal control, first author Jessica Lee, BS, a student at Icahn School of Medicine at Mount Sinai, New York, said.

“There was a knowledge gap for studies in the United States, and we hope this study will not only help patients with liver disease but also providers with counseling,” she said.

The findings suggest that “even if you have chronic liver disease and it’s not fully optimized, that should not interfere with pursuing IVF,” said principal investigator Tatyana Kushner, MD, an associate professor of medicine in liver diseases at the Icahn School.

Women with liver disease whose fertility is impaired should receive counseling about fertility preservation options earlier to help access fertility care, the researchers write.

The study’s findings are “encouraging,” said Monika Sarkar, MD, associate professor of medicine in gastroenterology at the University of California, San Francisco.

“With rising numbers of young adults with liver disease, it is encouraging to see dedicated studies that address a topic of importance to our patients – namely, their reproductive health,” she said. “The current study nicely expands beyond previous data to include a control population without liver disease.”
 

Differences in oocyte numbers

Although there were no differences in the success rate of embryo transfer, the researchers did see differences in the number of oocytes. Only 37 mature oocytes made it to transfer in the liver disease group, compared with 609 in the control group, noted Dr. Sarkar, who was not involved with the study.

“The challenge of ART is less at the level of embryo transfer, which is very successful once a euploid embryo is achieved, but rather at the earlier step of retrieval of mature oocytes,” Dr. Sarkar said. “Here, the authors found that patients with liver disease had a significantly lower number of oocytes retrieved, number of mature oocytes, and lower number of fertilized embryos.”

The data suggest that fewer eggs are retrieved per cycle from patients with liver disease, “which ultimately will lower the success per cycle,” Dr. Sarkar said.

“This suggests that referring women with chronic liver disease to ART sooner may help to optimize outcomes,” she added. “Larger data evaluating ability to achieve mature oocytes and subsequent fertilization will also be key for determining whether ART success differs by presence, severity, and type of liver disease.”

As more research on ART outcomes in women with liver disease is conducted, subspecialists in gastrointestinal and liver disease may gain confidence in counseling patients, Dr. Sarkar said.

Ms. Lee, Dr. Kushner, and Dr. Sarkar report no relevant financial relationships.

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

Having chronic liver disease does not affect outcomes for women who undergo in vitro fertilization (IVF), new research suggests.

The study, published online in the American Journal of Gastroenterology, compared women with and those without chronic liver disease who had normal ovarian reserve and who underwent assisted reproductive technology (ART) treatment in a high-volume fertility practice from 2002 to 2021.

“IVF treatment and pregnancy outcomes were not significantly different compared to controls,” the researchers wrote.

Women with liver disease may experience impaired fertility. For example, women with chronic liver disease, such as hepatitis C virus infection, may have premature ovarian insufficiency, while women with advanced liver disease, cirrhosis, and hepatic decompensation are known to have abnormally low gonadotropin levels.

The prevalence of liver disease in women of reproductive age is rising, leading to “an immediate need for the clinical assessment of reproductive potential in women with chronic liver disease,” the authors wrote.

The literature about ART treatment outcomes for women with liver disease was limited and may not reflect current therapy protocols, researchers found.

“To the best of our knowledge, this study is the largest to date to evaluate IVF efficacy in women with liver disease,” they wrote.
 

Similar outcomes

Researchers identified 295 women with liver disease (mean age, 37.8 ± 5.2 years) who underwent 1,033 contemporary, standard ART treatment cycles. Six patients (2%) had cirrhosis, eight (2.7%) had undergone liver transplantation, and 281 (95.3%) had chronic liver disease, of which viral hepatitis B and C infections were the most prevalent. The final study population consisted of 115 women who underwent 186 IVF cycles, as well as embryo biopsy for genetic testing.

The control group consisted of all the women at the treatment center without liver disease who received contemporary, standard ART treatment because of male factor infertility, which served as an indication that the women had normal ovarian reserve and were considered fertile. These 624 patients underwent 868 IVF cycles with embryo biopsy.

The mean age of the patients with liver disease was significantly higher than that of the control participants. Mean body mass index was also significantly higher for the patients with liver disease, and there were differences in baseline levels of selected hormones, compared with control participants. In addition, among those with liver disease, the number of oocytes retrieved was significantly lower (12.3 ± 7.6 vs. 16.5 ± 8.2; P < .05), as were the number of mature oocytes (9.1 ± 6.2 vs. 12.6 ± 6.7; P < .05), the number of fertilized embryos (7.0 ± 5.2 vs. 9.9 ± 5.9; P < .05), the number of embryos for which biopsy was performed (3.4 ± 2.2 vs. 5.1 ± 3.5; P < .05), and the number of euploid embryos (1.6 ± 1.4 vs. 2.7 ± 2.4; P < .05), compared with control participants.

Among the two groups, there were no statistically significant differences in mature oocyte rate (an indicator of response to controlled ovarian stimulation), fertilization per mature oocyte rate (an indicator of oocyte quality and ability to be fertilized), or embryo ploidy rate (an indicator of genetically normal embryos), as determined by embryo biopsy, the researchers write.

A subanalysis of women who went on to have a single thawed euploid (chromosomally normal) embryo transfer to achieve pregnancy found no statistically significant differences in rates of clinical pregnancy, clinical pregnancy loss, or live births between the liver disease group and the control group.

“Overall, women with chronic liver disease can be counseled that IVF treatment will not significantly differ in response to controlled ovarian stimulation, embryo fertilization rate, or ploidy outcome compared to women without liver disease,” the researchers wrote.
 

Data for patient counseling

The results could change the current common thinking among clinicians that IVF should not be conducted until liver disease is under optimal control, first author Jessica Lee, BS, a student at Icahn School of Medicine at Mount Sinai, New York, said.

“There was a knowledge gap for studies in the United States, and we hope this study will not only help patients with liver disease but also providers with counseling,” she said.

The findings suggest that “even if you have chronic liver disease and it’s not fully optimized, that should not interfere with pursuing IVF,” said principal investigator Tatyana Kushner, MD, an associate professor of medicine in liver diseases at the Icahn School.

Women with liver disease whose fertility is impaired should receive counseling about fertility preservation options earlier to help access fertility care, the researchers write.

The study’s findings are “encouraging,” said Monika Sarkar, MD, associate professor of medicine in gastroenterology at the University of California, San Francisco.

“With rising numbers of young adults with liver disease, it is encouraging to see dedicated studies that address a topic of importance to our patients – namely, their reproductive health,” she said. “The current study nicely expands beyond previous data to include a control population without liver disease.”
 

Differences in oocyte numbers

Although there were no differences in the success rate of embryo transfer, the researchers did see differences in the number of oocytes. Only 37 mature oocytes made it to transfer in the liver disease group, compared with 609 in the control group, noted Dr. Sarkar, who was not involved with the study.

“The challenge of ART is less at the level of embryo transfer, which is very successful once a euploid embryo is achieved, but rather at the earlier step of retrieval of mature oocytes,” Dr. Sarkar said. “Here, the authors found that patients with liver disease had a significantly lower number of oocytes retrieved, number of mature oocytes, and lower number of fertilized embryos.”

The data suggest that fewer eggs are retrieved per cycle from patients with liver disease, “which ultimately will lower the success per cycle,” Dr. Sarkar said.

“This suggests that referring women with chronic liver disease to ART sooner may help to optimize outcomes,” she added. “Larger data evaluating ability to achieve mature oocytes and subsequent fertilization will also be key for determining whether ART success differs by presence, severity, and type of liver disease.”

As more research on ART outcomes in women with liver disease is conducted, subspecialists in gastrointestinal and liver disease may gain confidence in counseling patients, Dr. Sarkar said.

Ms. Lee, Dr. Kushner, and Dr. Sarkar report no relevant financial relationships.

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

Key clinical point: Rheumatoid arthritis (RA) is associated with a significant increase in the risk for ischemic heart disease (IHD) and myocardial infarction (MI), and managing RA activity may reduce the risk for cardiovascular diseases.

Major finding: RA is significantly associated with an increased risk for IHD (odds ratio [OR] 1.0006; P  =  .001551915) and MI (OR 1.0458; P  =  .001636), but not arrhythmia and atrial fibrillation.

Study details: Findings are from a two-sample Mendelian randomization study including patients and matched control individuals for RA (n = 14,361 and n = 43,923, respectively), MI (n = 12,801 and n = 187,840, respectively), IHD (n = 5861 and n = 457,149, respectively), atrial fibrillation (n = 60,620 and n = 970,216, respectively), and arrhythmia (n = 2545 and n = 460,388, respectively).

Disclosures: This study was supported by the Young Talent Development Plan of Changzhou Health Commission, China, and other sources. The authors declared no conflicts of interest.

Source: Wang M et al. Relationship between rheumatoid arthritis and cardiovascular comorbidity, causation or co-occurrence: A Mendelian randomization study. Front Cardiovasc Med. 2023;10:1099861 (Mar 17). Doi: 10.3389/fcvm.2023.1099861

Key clinical point: Rheumatoid arthritis (RA) is associated with a significant increase in the risk for ischemic heart disease (IHD) and myocardial infarction (MI), and managing RA activity may reduce the risk for cardiovascular diseases.

Major finding: RA is significantly associated with an increased risk for IHD (odds ratio [OR] 1.0006; P  =  .001551915) and MI (OR 1.0458; P  =  .001636), but not arrhythmia and atrial fibrillation.

Study details: Findings are from a two-sample Mendelian randomization study including patients and matched control individuals for RA (n = 14,361 and n = 43,923, respectively), MI (n = 12,801 and n = 187,840, respectively), IHD (n = 5861 and n = 457,149, respectively), atrial fibrillation (n = 60,620 and n = 970,216, respectively), and arrhythmia (n = 2545 and n = 460,388, respectively).

Disclosures: This study was supported by the Young Talent Development Plan of Changzhou Health Commission, China, and other sources. The authors declared no conflicts of interest.

Source: Wang M et al. Relationship between rheumatoid arthritis and cardiovascular comorbidity, causation or co-occurrence: A Mendelian randomization study. Front Cardiovasc Med. 2023;10:1099861 (Mar 17). Doi: 10.3389/fcvm.2023.1099861

Key clinical point: Rheumatoid arthritis (RA) is associated with a significant increase in the risk for ischemic heart disease (IHD) and myocardial infarction (MI), and managing RA activity may reduce the risk for cardiovascular diseases.

Major finding: RA is significantly associated with an increased risk for IHD (odds ratio [OR] 1.0006; P  =  .001551915) and MI (OR 1.0458; P  =  .001636), but not arrhythmia and atrial fibrillation.

Study details: Findings are from a two-sample Mendelian randomization study including patients and matched control individuals for RA (n = 14,361 and n = 43,923, respectively), MI (n = 12,801 and n = 187,840, respectively), IHD (n = 5861 and n = 457,149, respectively), atrial fibrillation (n = 60,620 and n = 970,216, respectively), and arrhythmia (n = 2545 and n = 460,388, respectively).

Disclosures: This study was supported by the Young Talent Development Plan of Changzhou Health Commission, China, and other sources. The authors declared no conflicts of interest.

Source: Wang M et al. Relationship between rheumatoid arthritis and cardiovascular comorbidity, causation or co-occurrence: A Mendelian randomization study. Front Cardiovasc Med. 2023;10:1099861 (Mar 17). Doi: 10.3389/fcvm.2023.1099861

Key clinical point: Mortality risk varied with time and increased only during the second not the first decade after the diagnosis of rheumatoid arthritis (RA), with respiratory diseases potentially surpassing cardiovascular diseases as major attributable factors.

Major finding: Increase in mortality was observed at 20 years (standardized mortality ratio [SMR] 1.49; P < .001) but not during the first 10 years (P  =  .44) after RA diagnosis, with pneumonia (cause-specific SMR 5.22; 95% CI 2.26-10.29) and interstitial lung disease (cause-specific SMR 7.64; 95% CI 2.98-14.69) being major contributors.

Study details: Findings are from an analysis of 1895 patients with RA from the Australian Rheumatology Association Database (ARAD) registry who received biologic, targeted synthetic, or conventional synthetic disease-modifying antirheumatic drugs.

Disclosures: ARAD received support through the Australian Rheumatology Association from various sources. Three authors declared receiving grants, funding, or honoraria from different sources unrelated to this study.

Source: Black RJ et al. Mortality estimates and excess mortality in rheumatoid arthritis. Rheumatology (Oxford). 2023 (Mar 15). Doi: 10.1093/rheumatology/kead106

Key clinical point: Mortality risk varied with time and increased only during the second not the first decade after the diagnosis of rheumatoid arthritis (RA), with respiratory diseases potentially surpassing cardiovascular diseases as major attributable factors.

Major finding: Increase in mortality was observed at 20 years (standardized mortality ratio [SMR] 1.49; P < .001) but not during the first 10 years (P  =  .44) after RA diagnosis, with pneumonia (cause-specific SMR 5.22; 95% CI 2.26-10.29) and interstitial lung disease (cause-specific SMR 7.64; 95% CI 2.98-14.69) being major contributors.

Study details: Findings are from an analysis of 1895 patients with RA from the Australian Rheumatology Association Database (ARAD) registry who received biologic, targeted synthetic, or conventional synthetic disease-modifying antirheumatic drugs.

Disclosures: ARAD received support through the Australian Rheumatology Association from various sources. Three authors declared receiving grants, funding, or honoraria from different sources unrelated to this study.

Source: Black RJ et al. Mortality estimates and excess mortality in rheumatoid arthritis. Rheumatology (Oxford). 2023 (Mar 15). Doi: 10.1093/rheumatology/kead106

Key clinical point: Mortality risk varied with time and increased only during the second not the first decade after the diagnosis of rheumatoid arthritis (RA), with respiratory diseases potentially surpassing cardiovascular diseases as major attributable factors.

Major finding: Increase in mortality was observed at 20 years (standardized mortality ratio [SMR] 1.49; P < .001) but not during the first 10 years (P  =  .44) after RA diagnosis, with pneumonia (cause-specific SMR 5.22; 95% CI 2.26-10.29) and interstitial lung disease (cause-specific SMR 7.64; 95% CI 2.98-14.69) being major contributors.

Study details: Findings are from an analysis of 1895 patients with RA from the Australian Rheumatology Association Database (ARAD) registry who received biologic, targeted synthetic, or conventional synthetic disease-modifying antirheumatic drugs.

Disclosures: ARAD received support through the Australian Rheumatology Association from various sources. Three authors declared receiving grants, funding, or honoraria from different sources unrelated to this study.

Source: Black RJ et al. Mortality estimates and excess mortality in rheumatoid arthritis. Rheumatology (Oxford). 2023 (Mar 15). Doi: 10.1093/rheumatology/kead106

Key clinical point: Rheumatoid arthritis (RA) was significantly associated with an increased risk for bronchial asthma, allergic rhinitis, and sinusitis, and a notable interrelation was observed between the presence of asthma and obesity in patients with RA.

Major finding: Presence of RA significantly increased the risk for asthma (odds ratio [OR] 2.32; 95% CI 1.51-3.57), allergic rhinitis (OR 1.51; 95% CI 1.08-2.10), and sinusitis (OR 1.64; 95% CI 1.08-2.50) in the whole cohort and the prevalence of obesity in patients with asthma (64.0% vs 40.2%; P  =  .034).

Study details: This population-based cross-sectional study included 14,272 participants, of which 334 had RA.

Disclosures: This study was supported by the National Research Foundation of Korea grant funded by the Korean Government. The authors declared no conflicts of interest.

Source: Kim JG et al. Association of rheumatoid arthritis with bronchial asthma and asthma-related comorbidities: A population-based national surveillance study. Front Med (Lausanne). 2023;10:1006290 (Mar 10). Doi: 10.3389/fmed.2023.1006290

Key clinical point: Rheumatoid arthritis (RA) was significantly associated with an increased risk for bronchial asthma, allergic rhinitis, and sinusitis, and a notable interrelation was observed between the presence of asthma and obesity in patients with RA.

Major finding: Presence of RA significantly increased the risk for asthma (odds ratio [OR] 2.32; 95% CI 1.51-3.57), allergic rhinitis (OR 1.51; 95% CI 1.08-2.10), and sinusitis (OR 1.64; 95% CI 1.08-2.50) in the whole cohort and the prevalence of obesity in patients with asthma (64.0% vs 40.2%; P  =  .034).

Study details: This population-based cross-sectional study included 14,272 participants, of which 334 had RA.

Disclosures: This study was supported by the National Research Foundation of Korea grant funded by the Korean Government. The authors declared no conflicts of interest.

Source: Kim JG et al. Association of rheumatoid arthritis with bronchial asthma and asthma-related comorbidities: A population-based national surveillance study. Front Med (Lausanne). 2023;10:1006290 (Mar 10). Doi: 10.3389/fmed.2023.1006290

Key clinical point: Rheumatoid arthritis (RA) was significantly associated with an increased risk for bronchial asthma, allergic rhinitis, and sinusitis, and a notable interrelation was observed between the presence of asthma and obesity in patients with RA.

Major finding: Presence of RA significantly increased the risk for asthma (odds ratio [OR] 2.32; 95% CI 1.51-3.57), allergic rhinitis (OR 1.51; 95% CI 1.08-2.10), and sinusitis (OR 1.64; 95% CI 1.08-2.50) in the whole cohort and the prevalence of obesity in patients with asthma (64.0% vs 40.2%; P  =  .034).

Study details: This population-based cross-sectional study included 14,272 participants, of which 334 had RA.

Disclosures: This study was supported by the National Research Foundation of Korea grant funded by the Korean Government. The authors declared no conflicts of interest.

Source: Kim JG et al. Association of rheumatoid arthritis with bronchial asthma and asthma-related comorbidities: A population-based national surveillance study. Front Med (Lausanne). 2023;10:1006290 (Mar 10). Doi: 10.3389/fmed.2023.1006290

Key clinical point: Abatacept with or without conventional synthetic disease-modifying antirheumatic drugs (csDMARD) demonstrated better efficacy and favorable safety outcomes compared with placebo, csDMARD, or other biologic DMARD (bDMARD) in patients with rheumatoid arthritis (RA).

Major finding: Patients treated with abatacept with or without csDMARD vs placebo, csDMARD, or other bDMARD were more likely to achieve American College of Rheumatology (ACR) 20 (relative risk [RR] 1.57; 95% CI 1.27-1.93), ACR50 (RR 1.84; 95% CI 1.38-2.44), and ACR70 (RR 2.36; 95% CI 1.60-3.47) responses, as well as were less likely to experience adverse events (RR 0.93; 95% CI 0.84-1.03).

Study details: Findings are from a systematic review and meta-analysis of 13 randomized controlled trials including 5978 patients with RA who were randomly assigned to receive abatacept alone, abatacept with csDMARD, placebo, csDMARD, or other bDMARD.

Disclosures: This study was supported by the National Key R&D Program of China. The authors did not report conflicts of interest.

Source: Ahamada MM and Wu X. Analysis of efficacy and safety of abatacept for rheumatoid arthritis: Systematic review and meta-analysis. Clin Exp Rheumatol. 2023 (Mar 7). Doi: 10.55563/clinexprheumatol/2xjg0d

Key clinical point: Abatacept with or without conventional synthetic disease-modifying antirheumatic drugs (csDMARD) demonstrated better efficacy and favorable safety outcomes compared with placebo, csDMARD, or other biologic DMARD (bDMARD) in patients with rheumatoid arthritis (RA).

Major finding: Patients treated with abatacept with or without csDMARD vs placebo, csDMARD, or other bDMARD were more likely to achieve American College of Rheumatology (ACR) 20 (relative risk [RR] 1.57; 95% CI 1.27-1.93), ACR50 (RR 1.84; 95% CI 1.38-2.44), and ACR70 (RR 2.36; 95% CI 1.60-3.47) responses, as well as were less likely to experience adverse events (RR 0.93; 95% CI 0.84-1.03).

Study details: Findings are from a systematic review and meta-analysis of 13 randomized controlled trials including 5978 patients with RA who were randomly assigned to receive abatacept alone, abatacept with csDMARD, placebo, csDMARD, or other bDMARD.

Disclosures: This study was supported by the National Key R&D Program of China. The authors did not report conflicts of interest.

Source: Ahamada MM and Wu X. Analysis of efficacy and safety of abatacept for rheumatoid arthritis: Systematic review and meta-analysis. Clin Exp Rheumatol. 2023 (Mar 7). Doi: 10.55563/clinexprheumatol/2xjg0d

Key clinical point: Abatacept with or without conventional synthetic disease-modifying antirheumatic drugs (csDMARD) demonstrated better efficacy and favorable safety outcomes compared with placebo, csDMARD, or other biologic DMARD (bDMARD) in patients with rheumatoid arthritis (RA).

Major finding: Patients treated with abatacept with or without csDMARD vs placebo, csDMARD, or other bDMARD were more likely to achieve American College of Rheumatology (ACR) 20 (relative risk [RR] 1.57; 95% CI 1.27-1.93), ACR50 (RR 1.84; 95% CI 1.38-2.44), and ACR70 (RR 2.36; 95% CI 1.60-3.47) responses, as well as were less likely to experience adverse events (RR 0.93; 95% CI 0.84-1.03).

Study details: Findings are from a systematic review and meta-analysis of 13 randomized controlled trials including 5978 patients with RA who were randomly assigned to receive abatacept alone, abatacept with csDMARD, placebo, csDMARD, or other bDMARD.

Disclosures: This study was supported by the National Key R&D Program of China. The authors did not report conflicts of interest.

Source: Ahamada MM and Wu X. Analysis of efficacy and safety of abatacept for rheumatoid arthritis: Systematic review and meta-analysis. Clin Exp Rheumatol. 2023 (Mar 7). Doi: 10.55563/clinexprheumatol/2xjg0d

Key clinical point: Factors like age ≥65 years or current or former smoking accounted for excess risk with tofacitinib vs tumor necrosis factor inhibitor (TNFi) use in patients with rheumatoid arthritis (RA).

Major finding: Tofacitinib vs TNFi significantly increased the risk for malignancies (hazard ratio [HR] 1.55; 95% CI 1.05-2.30), venous thromboembolism (HR 5.19; 95% CI 1.86-14.46), and all-cause death (HR 2.24; 95% CI 1.20-4.19) among patients who were ≥65 years old or ever smokers, but not among those aged <65 years and never smokers.

Study details: Findings are from a post hoc analysis of the ORAL Surveillance trial including patients with RA (n = 4362) treated with tofacitinib or TNFi and an exploratory analysis of RA, PsA, and ulcerative colitis (UC) development programs including tofacitinib-exposed patients with RA (n = 7964), psoriatic arthritis (n = 783), and UC (n = 1157).

Disclosures: This study was sponsored by Pfizer Inc. Six authors declared being employees and stockholders of Pfizer. Two authors declared receiving speaking, consulting, or lecture fees or research grants from Pfizer and other sources.

Source: Kristensen LE et al. Identification of two tofacitinib subpopulations with different relative risk versus TNF inhibitors: An analysis of the open label, randomised controlled study ORAL Surveillance. Ann Rheum Dis. 2023 (Mar 17). Doi: 10.1136/ard-2022-223715

Key clinical point: Factors like age ≥65 years or current or former smoking accounted for excess risk with tofacitinib vs tumor necrosis factor inhibitor (TNFi) use in patients with rheumatoid arthritis (RA).

Major finding: Tofacitinib vs TNFi significantly increased the risk for malignancies (hazard ratio [HR] 1.55; 95% CI 1.05-2.30), venous thromboembolism (HR 5.19; 95% CI 1.86-14.46), and all-cause death (HR 2.24; 95% CI 1.20-4.19) among patients who were ≥65 years old or ever smokers, but not among those aged <65 years and never smokers.

Study details: Findings are from a post hoc analysis of the ORAL Surveillance trial including patients with RA (n = 4362) treated with tofacitinib or TNFi and an exploratory analysis of RA, PsA, and ulcerative colitis (UC) development programs including tofacitinib-exposed patients with RA (n = 7964), psoriatic arthritis (n = 783), and UC (n = 1157).

Disclosures: This study was sponsored by Pfizer Inc. Six authors declared being employees and stockholders of Pfizer. Two authors declared receiving speaking, consulting, or lecture fees or research grants from Pfizer and other sources.

Source: Kristensen LE et al. Identification of two tofacitinib subpopulations with different relative risk versus TNF inhibitors: An analysis of the open label, randomised controlled study ORAL Surveillance. Ann Rheum Dis. 2023 (Mar 17). Doi: 10.1136/ard-2022-223715

Key clinical point: Factors like age ≥65 years or current or former smoking accounted for excess risk with tofacitinib vs tumor necrosis factor inhibitor (TNFi) use in patients with rheumatoid arthritis (RA).

Major finding: Tofacitinib vs TNFi significantly increased the risk for malignancies (hazard ratio [HR] 1.55; 95% CI 1.05-2.30), venous thromboembolism (HR 5.19; 95% CI 1.86-14.46), and all-cause death (HR 2.24; 95% CI 1.20-4.19) among patients who were ≥65 years old or ever smokers, but not among those aged <65 years and never smokers.

Study details: Findings are from a post hoc analysis of the ORAL Surveillance trial including patients with RA (n = 4362) treated with tofacitinib or TNFi and an exploratory analysis of RA, PsA, and ulcerative colitis (UC) development programs including tofacitinib-exposed patients with RA (n = 7964), psoriatic arthritis (n = 783), and UC (n = 1157).

Disclosures: This study was sponsored by Pfizer Inc. Six authors declared being employees and stockholders of Pfizer. Two authors declared receiving speaking, consulting, or lecture fees or research grants from Pfizer and other sources.

Source: Kristensen LE et al. Identification of two tofacitinib subpopulations with different relative risk versus TNF inhibitors: An analysis of the open label, randomised controlled study ORAL Surveillance. Ann Rheum Dis. 2023 (Mar 17). Doi: 10.1136/ard-2022-223715