A swallowable, vibrating capsule improved symptoms among patients with chronic idiopathic constipation in a phase 3 multicenter, randomized, controlled trial. The method represents a mechanical approach to the treatment of constipation.

The swallowable pill acts by vibrating during passage through the gut, where it is thought to augment colonic biorhythm and peristalsis. Traditional treatments for constipation generally increase motility or secretion.

“That’s how we have been managing constipation since time immemorial. Now we have come up with this novel approach, where there’s a pill that is designed to increase local oscillations, and probably induce local contractions of the colon to mimic what happens normally,” said Satish Rao, MD, PhD, who presented the results of the trial at the annual Digestive Disease Week^® (DDW).

“We’re now seeing that local stimulation works, and the other neat thing seems to be a lack of side effects, which is really a huge plus. I think it will benefit people with both occasional or chronic constipation,” said Dr. Rao, professor of medicine at Medical College of Georgia, Augusta.

The capsules activate for two stimulation cycles, each lasting for about 2 hours. The cycle includes 3 seconds of vibration followed by 16 seconds of rest.

The researchers conducted a study with two active arms and a placebo. It included 312 patients age 22 or older who had an average of between 1 and 2.5 spontaneous bowel movements (SBM) per week.

Treatment lasted for 8 weeks, with patients ingesting a capsule between 9 and 10 p.m. In one treatment group, the device was activated at 6 a.m., and in the other group at about 2 p.m.

The placebo and treatment groups had similar baseline characteristics, except for a longer duration of constipation in the treatment groups (17.9 versus 14.5 years; P = .0253). In an intention-to-treat analysis, the treatment groups were more likely to achieve an increase of one complete SBM per week (39.26% versus 22.15%; P < .0001) and an increase of two complete SBMs per week (22.7% versus 11.41%; P < .0006).

The capsules also improved straining score, stool consistency, and quality of life. There was no significant difference between treatment and placebo groups with respect to bloating or rescue medication use.

The product had few adverse effects. The most common was a vibrating sensation or discomfort (11.0%, versus none in the placebo group).

Dr. Rao expects that the treatment could be widely applicable since many constipation patients don’t gain sufficient benefit from existing treatments, or find side effects intolerable.

Another benefit is that the therapy’s mimicry of natural cycles appears to grant patients more control of bowel movements. Laxatives and other pharmaceutical interventions may prompt the patient to go to the bathroom within an hour or two, but patients in the trial reported bowel movements at predictable times.

However, he noted that the pill is nondissolvable, which would make it contraindicated for patients who have had previous gut surgeries or narrowing of the gut. He noted that the sponsoring company, Vibrant Gastro, expects to obtain Food and Drug Administration approval by the end of 2022.

The results of the study were well received. “I think it’s an exciting new approach for managing patients with chronic constipation. It was a large sample size, and the treatment seems to be well tolerated. It may offer a promising option for patients who have not responded to many other medications,” said Adil E. Bharucha, MD, who comoderated the session where the research was presented.

However, he pointed out that the presentation did not indicate how many of the patients had previously tried other therapies. “We’d like to see the full paper, which will provide a better understanding of the role of this treatment in practice down the road,” said Dr. Bharucha, professor of medicine in the division of gastroenterology and hepatology and director of the office of clinical trials at Mayo Clinic, Rochester, Minn.

The capsule may not work for everyone, said Dr. Bharucha. He suspects that many refractory patients have an issue with pelvic floor muscles, which may restrict stool evacuation. “You wouldn’t expect those people to respond optimally to a laxative and I suspect perhaps not to a capsule, either. I think defecatory disorders are substantially underdiagnosed in patients who don’t respond to laxatives,” said Dr. Bharucha.

Asked why the capsule might benefit patients who don’t improve with laxatives, Dr. Bharucha responded: “I think we need more studies to understand how the capsule works.”

Dr. Rao consults for Vibrant Gastro. Dr. Bharucha has no relevant financial disclosures.

A swallowable, vibrating capsule improved symptoms among patients with chronic idiopathic constipation in a phase 3 multicenter, randomized, controlled trial. The method represents a mechanical approach to the treatment of constipation.

The swallowable pill acts by vibrating during passage through the gut, where it is thought to augment colonic biorhythm and peristalsis. Traditional treatments for constipation generally increase motility or secretion.

“That’s how we have been managing constipation since time immemorial. Now we have come up with this novel approach, where there’s a pill that is designed to increase local oscillations, and probably induce local contractions of the colon to mimic what happens normally,” said Satish Rao, MD, PhD, who presented the results of the trial at the annual Digestive Disease Week^® (DDW).

“We’re now seeing that local stimulation works, and the other neat thing seems to be a lack of side effects, which is really a huge plus. I think it will benefit people with both occasional or chronic constipation,” said Dr. Rao, professor of medicine at Medical College of Georgia, Augusta.

The capsules activate for two stimulation cycles, each lasting for about 2 hours. The cycle includes 3 seconds of vibration followed by 16 seconds of rest.

The researchers conducted a study with two active arms and a placebo. It included 312 patients age 22 or older who had an average of between 1 and 2.5 spontaneous bowel movements (SBM) per week.

Treatment lasted for 8 weeks, with patients ingesting a capsule between 9 and 10 p.m. In one treatment group, the device was activated at 6 a.m., and in the other group at about 2 p.m.

The placebo and treatment groups had similar baseline characteristics, except for a longer duration of constipation in the treatment groups (17.9 versus 14.5 years; P = .0253). In an intention-to-treat analysis, the treatment groups were more likely to achieve an increase of one complete SBM per week (39.26% versus 22.15%; P < .0001) and an increase of two complete SBMs per week (22.7% versus 11.41%; P < .0006).

The capsules also improved straining score, stool consistency, and quality of life. There was no significant difference between treatment and placebo groups with respect to bloating or rescue medication use.

The product had few adverse effects. The most common was a vibrating sensation or discomfort (11.0%, versus none in the placebo group).

Dr. Rao expects that the treatment could be widely applicable since many constipation patients don’t gain sufficient benefit from existing treatments, or find side effects intolerable.

Another benefit is that the therapy’s mimicry of natural cycles appears to grant patients more control of bowel movements. Laxatives and other pharmaceutical interventions may prompt the patient to go to the bathroom within an hour or two, but patients in the trial reported bowel movements at predictable times.

However, he noted that the pill is nondissolvable, which would make it contraindicated for patients who have had previous gut surgeries or narrowing of the gut. He noted that the sponsoring company, Vibrant Gastro, expects to obtain Food and Drug Administration approval by the end of 2022.

The results of the study were well received. “I think it’s an exciting new approach for managing patients with chronic constipation. It was a large sample size, and the treatment seems to be well tolerated. It may offer a promising option for patients who have not responded to many other medications,” said Adil E. Bharucha, MD, who comoderated the session where the research was presented.

However, he pointed out that the presentation did not indicate how many of the patients had previously tried other therapies. “We’d like to see the full paper, which will provide a better understanding of the role of this treatment in practice down the road,” said Dr. Bharucha, professor of medicine in the division of gastroenterology and hepatology and director of the office of clinical trials at Mayo Clinic, Rochester, Minn.

The capsule may not work for everyone, said Dr. Bharucha. He suspects that many refractory patients have an issue with pelvic floor muscles, which may restrict stool evacuation. “You wouldn’t expect those people to respond optimally to a laxative and I suspect perhaps not to a capsule, either. I think defecatory disorders are substantially underdiagnosed in patients who don’t respond to laxatives,” said Dr. Bharucha.

Asked why the capsule might benefit patients who don’t improve with laxatives, Dr. Bharucha responded: “I think we need more studies to understand how the capsule works.”

Dr. Rao consults for Vibrant Gastro. Dr. Bharucha has no relevant financial disclosures.

A swallowable, vibrating capsule improved symptoms among patients with chronic idiopathic constipation in a phase 3 multicenter, randomized, controlled trial. The method represents a mechanical approach to the treatment of constipation.

The swallowable pill acts by vibrating during passage through the gut, where it is thought to augment colonic biorhythm and peristalsis. Traditional treatments for constipation generally increase motility or secretion.

“That’s how we have been managing constipation since time immemorial. Now we have come up with this novel approach, where there’s a pill that is designed to increase local oscillations, and probably induce local contractions of the colon to mimic what happens normally,” said Satish Rao, MD, PhD, who presented the results of the trial at the annual Digestive Disease Week^® (DDW).

“We’re now seeing that local stimulation works, and the other neat thing seems to be a lack of side effects, which is really a huge plus. I think it will benefit people with both occasional or chronic constipation,” said Dr. Rao, professor of medicine at Medical College of Georgia, Augusta.

The capsules activate for two stimulation cycles, each lasting for about 2 hours. The cycle includes 3 seconds of vibration followed by 16 seconds of rest.

The researchers conducted a study with two active arms and a placebo. It included 312 patients age 22 or older who had an average of between 1 and 2.5 spontaneous bowel movements (SBM) per week.

Treatment lasted for 8 weeks, with patients ingesting a capsule between 9 and 10 p.m. In one treatment group, the device was activated at 6 a.m., and in the other group at about 2 p.m.

The placebo and treatment groups had similar baseline characteristics, except for a longer duration of constipation in the treatment groups (17.9 versus 14.5 years; P = .0253). In an intention-to-treat analysis, the treatment groups were more likely to achieve an increase of one complete SBM per week (39.26% versus 22.15%; P < .0001) and an increase of two complete SBMs per week (22.7% versus 11.41%; P < .0006).

The capsules also improved straining score, stool consistency, and quality of life. There was no significant difference between treatment and placebo groups with respect to bloating or rescue medication use.

The product had few adverse effects. The most common was a vibrating sensation or discomfort (11.0%, versus none in the placebo group).

Dr. Rao expects that the treatment could be widely applicable since many constipation patients don’t gain sufficient benefit from existing treatments, or find side effects intolerable.

Another benefit is that the therapy’s mimicry of natural cycles appears to grant patients more control of bowel movements. Laxatives and other pharmaceutical interventions may prompt the patient to go to the bathroom within an hour or two, but patients in the trial reported bowel movements at predictable times.

However, he noted that the pill is nondissolvable, which would make it contraindicated for patients who have had previous gut surgeries or narrowing of the gut. He noted that the sponsoring company, Vibrant Gastro, expects to obtain Food and Drug Administration approval by the end of 2022.

The results of the study were well received. “I think it’s an exciting new approach for managing patients with chronic constipation. It was a large sample size, and the treatment seems to be well tolerated. It may offer a promising option for patients who have not responded to many other medications,” said Adil E. Bharucha, MD, who comoderated the session where the research was presented.

However, he pointed out that the presentation did not indicate how many of the patients had previously tried other therapies. “We’d like to see the full paper, which will provide a better understanding of the role of this treatment in practice down the road,” said Dr. Bharucha, professor of medicine in the division of gastroenterology and hepatology and director of the office of clinical trials at Mayo Clinic, Rochester, Minn.

The capsule may not work for everyone, said Dr. Bharucha. He suspects that many refractory patients have an issue with pelvic floor muscles, which may restrict stool evacuation. “You wouldn’t expect those people to respond optimally to a laxative and I suspect perhaps not to a capsule, either. I think defecatory disorders are substantially underdiagnosed in patients who don’t respond to laxatives,” said Dr. Bharucha.

Asked why the capsule might benefit patients who don’t improve with laxatives, Dr. Bharucha responded: “I think we need more studies to understand how the capsule works.”

Dr. Rao consults for Vibrant Gastro. Dr. Bharucha has no relevant financial disclosures.

To the Editor:

Wolf isotopic response describes the development of a skin disorder at the site of another healed and unrelated skin disease. Skin disorders presenting as isotopic responses have included inflammatory, malignant, granulomatous, and infectious processes. Discoid lupus erythematosus (DLE) is a rare isotopic response. We report a cutaneous lupus erythematosus–like isotopic response that presented at the site of a recent herpes zoster infection in a liver transplant recipient.

A 74-year-old immunocompromised woman was referred to the dermatology clinic for evaluation of a rash on the right leg. She was being treated with maintenance valganciclovir due to cytomegalovirus viremia, as well as tacrolimus, azathioprine, and prednisone following liver transplantation due to autoimmune hepatitis for 8 months prior to presentation. Eighteen days prior to the current presentation, she was clinically diagnosed with herpes zoster. As the grouped vesicles from the herpes zoster resolved, she developed pink scaly papules in the same distribution as the original vesicular eruption.

Physical examination revealed numerous erythematous, 2- to 3-mm, scaly papules that coalesced into small plaques with serous crusts; they originated above the supragluteal cleft and extended rightward in the L3 and L4 dermatomes to the right knee (Figure 1). A 3-mm punch biopsy specimen was obtained from the right anterior thigh. Histologic analysis revealed interface lymphocytic inflammation with squamatization of basal keratinocytes, basement membrane thickening, and follicular plugging by keratin (Figure 2). There was a moderately intense perivascular and periadnexal inflammatory infiltrate of mature lymphocytes with rare eosinophils within the papillary and superficial reticular dermis. There was no evidence of a viral cytopathic effect, and an immunohistochemical stain for varicella-zoster virus protein was negative. The histologic findings were suggestive of cutaneous involvement by DLE. A diagnosis of a cutaneous lupus erythematosus–like Wolf isotopic response was made, and the patient’s rash resolved with the use of triamcinolone cream 0.1% applied twice daily for 2 weeks. At 6-week follow-up, there were postinflammatory pigmentation changes at the sites of the prior rash and persistent postherpetic neuralgia. Recent antinuclear antibody screening was negative, coupled with the patient’s lack of systemic symptoms and quick resolution of rash, indicating that additional testing for systemic lupus was not warranted.

Wolf isotopic response describes the occurrence of a new skin disorder at the site of a previously healed and unrelated skin disorder. The second disease may appear within days to years after the primary disease subsides and is clearly differentiated from the isomorphic response of the Koebner phenomenon, which describes an established skin disorder appearing at a previously uninvolved anatomic site following trauma.¹ As in our case, the initial cutaneous eruption resulting in a subsequent Wolf isotopic response frequently is herpes zoster and less commonly is herpes simplex virus.² The most common reported isotopic response is a granulomatous reaction.² Rare reports of leukemic infiltration, lymphoma, lichen planus, morphea, reactive perforating collagenosis, psoriasis, discoid lupus, lichen simplex chronicus, contact dermatitis, xanthomatous changes, malignant tumors, cutaneous graft-vs-host disease, pityriasis rosea, erythema annulare centrifugum, and other infectious-based isotopic responses exist.^2-6

Our patient presented with Wolf isotopic response that histologically mimicked DLE. A PubMed search of articles indexed for MEDLINE using the terms isotopic response and lupus revealed only 3 cases of cutaneous lupus erythematosus presenting as an isotopic response in the English-language literature. One of those cases occurred in a patient with preexisting systemic lupus erythematosus, making a diagnosis of Koebner isomorphic phenomenon more appropriate than an isotopic response at the site of prior herpes zoster infection.⁷ The remaining 2 cases were clinically defined DLE lesions occurring at sites of prior infection—cutaneous leishmaniasis and herpes zoster—in patients without a prior history of cutaneous or systemic lupus erythematosus.^8,9 The latter case of DLE-like isotopic response occurring after herpes zoster infection was further complicated by local injections at the zoster site for herpes-related local pain. Injection sites are reported as a distinct nidus for Wolf isotopic response.⁹

The pathogenesis of Wolf isotopic response is unclear. Possible explanations include local interactions between persistent viral particles at prior herpes infection sites, vascular injury, neural injury, and an altered immune response.^1,5,6,10 The destruction of sensory nerve fibers by herpesviruses cause the release of neuropeptides that then modulate the local immune system and angiogenic responses.^5,6 Our patient’s immunocompromised state may have further propagated a local altered immune cell infiltrate at the site of the isotopic response. Despite its unclear etiology, Wolf isotopic response should be considered in the differential diagnosis for any patient who presents with a dermatomal eruption at the site of a prior cutaneous infection, particularly after infection with herpes zoster. Treatment with topical or intralesional corticosteroids usually suffices for inflammatory-based isotopic responses with an excellent prognosis.¹¹

We present a case of a cutaneous lupus erythematosus–like isotopic response that occurred at the site of a recent herpes zoster eruption in an immunocompromised patient without prior history of systemic or cutaneous lupus erythematosus. Clinical recognition of Wolf isotopic response is important for accurate histopathologic diagnosis and management. Continued investigation into the underlying pathogenesis should be performed to fully understand and better treat this process.

To the Editor:

Wolf isotopic response describes the development of a skin disorder at the site of another healed and unrelated skin disease. Skin disorders presenting as isotopic responses have included inflammatory, malignant, granulomatous, and infectious processes. Discoid lupus erythematosus (DLE) is a rare isotopic response. We report a cutaneous lupus erythematosus–like isotopic response that presented at the site of a recent herpes zoster infection in a liver transplant recipient.

A 74-year-old immunocompromised woman was referred to the dermatology clinic for evaluation of a rash on the right leg. She was being treated with maintenance valganciclovir due to cytomegalovirus viremia, as well as tacrolimus, azathioprine, and prednisone following liver transplantation due to autoimmune hepatitis for 8 months prior to presentation. Eighteen days prior to the current presentation, she was clinically diagnosed with herpes zoster. As the grouped vesicles from the herpes zoster resolved, she developed pink scaly papules in the same distribution as the original vesicular eruption.

Physical examination revealed numerous erythematous, 2- to 3-mm, scaly papules that coalesced into small plaques with serous crusts; they originated above the supragluteal cleft and extended rightward in the L3 and L4 dermatomes to the right knee (Figure 1). A 3-mm punch biopsy specimen was obtained from the right anterior thigh. Histologic analysis revealed interface lymphocytic inflammation with squamatization of basal keratinocytes, basement membrane thickening, and follicular plugging by keratin (Figure 2). There was a moderately intense perivascular and periadnexal inflammatory infiltrate of mature lymphocytes with rare eosinophils within the papillary and superficial reticular dermis. There was no evidence of a viral cytopathic effect, and an immunohistochemical stain for varicella-zoster virus protein was negative. The histologic findings were suggestive of cutaneous involvement by DLE. A diagnosis of a cutaneous lupus erythematosus–like Wolf isotopic response was made, and the patient’s rash resolved with the use of triamcinolone cream 0.1% applied twice daily for 2 weeks. At 6-week follow-up, there were postinflammatory pigmentation changes at the sites of the prior rash and persistent postherpetic neuralgia. Recent antinuclear antibody screening was negative, coupled with the patient’s lack of systemic symptoms and quick resolution of rash, indicating that additional testing for systemic lupus was not warranted.

Wolf isotopic response describes the occurrence of a new skin disorder at the site of a previously healed and unrelated skin disorder. The second disease may appear within days to years after the primary disease subsides and is clearly differentiated from the isomorphic response of the Koebner phenomenon, which describes an established skin disorder appearing at a previously uninvolved anatomic site following trauma.¹ As in our case, the initial cutaneous eruption resulting in a subsequent Wolf isotopic response frequently is herpes zoster and less commonly is herpes simplex virus.² The most common reported isotopic response is a granulomatous reaction.² Rare reports of leukemic infiltration, lymphoma, lichen planus, morphea, reactive perforating collagenosis, psoriasis, discoid lupus, lichen simplex chronicus, contact dermatitis, xanthomatous changes, malignant tumors, cutaneous graft-vs-host disease, pityriasis rosea, erythema annulare centrifugum, and other infectious-based isotopic responses exist.^2-6

Our patient presented with Wolf isotopic response that histologically mimicked DLE. A PubMed search of articles indexed for MEDLINE using the terms isotopic response and lupus revealed only 3 cases of cutaneous lupus erythematosus presenting as an isotopic response in the English-language literature. One of those cases occurred in a patient with preexisting systemic lupus erythematosus, making a diagnosis of Koebner isomorphic phenomenon more appropriate than an isotopic response at the site of prior herpes zoster infection.⁷ The remaining 2 cases were clinically defined DLE lesions occurring at sites of prior infection—cutaneous leishmaniasis and herpes zoster—in patients without a prior history of cutaneous or systemic lupus erythematosus.^8,9 The latter case of DLE-like isotopic response occurring after herpes zoster infection was further complicated by local injections at the zoster site for herpes-related local pain. Injection sites are reported as a distinct nidus for Wolf isotopic response.⁹

The pathogenesis of Wolf isotopic response is unclear. Possible explanations include local interactions between persistent viral particles at prior herpes infection sites, vascular injury, neural injury, and an altered immune response.^1,5,6,10 The destruction of sensory nerve fibers by herpesviruses cause the release of neuropeptides that then modulate the local immune system and angiogenic responses.^5,6 Our patient’s immunocompromised state may have further propagated a local altered immune cell infiltrate at the site of the isotopic response. Despite its unclear etiology, Wolf isotopic response should be considered in the differential diagnosis for any patient who presents with a dermatomal eruption at the site of a prior cutaneous infection, particularly after infection with herpes zoster. Treatment with topical or intralesional corticosteroids usually suffices for inflammatory-based isotopic responses with an excellent prognosis.¹¹

We present a case of a cutaneous lupus erythematosus–like isotopic response that occurred at the site of a recent herpes zoster eruption in an immunocompromised patient without prior history of systemic or cutaneous lupus erythematosus. Clinical recognition of Wolf isotopic response is important for accurate histopathologic diagnosis and management. Continued investigation into the underlying pathogenesis should be performed to fully understand and better treat this process.

To the Editor:

Wolf isotopic response describes the development of a skin disorder at the site of another healed and unrelated skin disease. Skin disorders presenting as isotopic responses have included inflammatory, malignant, granulomatous, and infectious processes. Discoid lupus erythematosus (DLE) is a rare isotopic response. We report a cutaneous lupus erythematosus–like isotopic response that presented at the site of a recent herpes zoster infection in a liver transplant recipient.

A 74-year-old immunocompromised woman was referred to the dermatology clinic for evaluation of a rash on the right leg. She was being treated with maintenance valganciclovir due to cytomegalovirus viremia, as well as tacrolimus, azathioprine, and prednisone following liver transplantation due to autoimmune hepatitis for 8 months prior to presentation. Eighteen days prior to the current presentation, she was clinically diagnosed with herpes zoster. As the grouped vesicles from the herpes zoster resolved, she developed pink scaly papules in the same distribution as the original vesicular eruption.

Physical examination revealed numerous erythematous, 2- to 3-mm, scaly papules that coalesced into small plaques with serous crusts; they originated above the supragluteal cleft and extended rightward in the L3 and L4 dermatomes to the right knee (Figure 1). A 3-mm punch biopsy specimen was obtained from the right anterior thigh. Histologic analysis revealed interface lymphocytic inflammation with squamatization of basal keratinocytes, basement membrane thickening, and follicular plugging by keratin (Figure 2). There was a moderately intense perivascular and periadnexal inflammatory infiltrate of mature lymphocytes with rare eosinophils within the papillary and superficial reticular dermis. There was no evidence of a viral cytopathic effect, and an immunohistochemical stain for varicella-zoster virus protein was negative. The histologic findings were suggestive of cutaneous involvement by DLE. A diagnosis of a cutaneous lupus erythematosus–like Wolf isotopic response was made, and the patient’s rash resolved with the use of triamcinolone cream 0.1% applied twice daily for 2 weeks. At 6-week follow-up, there were postinflammatory pigmentation changes at the sites of the prior rash and persistent postherpetic neuralgia. Recent antinuclear antibody screening was negative, coupled with the patient’s lack of systemic symptoms and quick resolution of rash, indicating that additional testing for systemic lupus was not warranted.

Wolf isotopic response describes the occurrence of a new skin disorder at the site of a previously healed and unrelated skin disorder. The second disease may appear within days to years after the primary disease subsides and is clearly differentiated from the isomorphic response of the Koebner phenomenon, which describes an established skin disorder appearing at a previously uninvolved anatomic site following trauma.¹ As in our case, the initial cutaneous eruption resulting in a subsequent Wolf isotopic response frequently is herpes zoster and less commonly is herpes simplex virus.² The most common reported isotopic response is a granulomatous reaction.² Rare reports of leukemic infiltration, lymphoma, lichen planus, morphea, reactive perforating collagenosis, psoriasis, discoid lupus, lichen simplex chronicus, contact dermatitis, xanthomatous changes, malignant tumors, cutaneous graft-vs-host disease, pityriasis rosea, erythema annulare centrifugum, and other infectious-based isotopic responses exist.^2-6

Our patient presented with Wolf isotopic response that histologically mimicked DLE. A PubMed search of articles indexed for MEDLINE using the terms isotopic response and lupus revealed only 3 cases of cutaneous lupus erythematosus presenting as an isotopic response in the English-language literature. One of those cases occurred in a patient with preexisting systemic lupus erythematosus, making a diagnosis of Koebner isomorphic phenomenon more appropriate than an isotopic response at the site of prior herpes zoster infection.⁷ The remaining 2 cases were clinically defined DLE lesions occurring at sites of prior infection—cutaneous leishmaniasis and herpes zoster—in patients without a prior history of cutaneous or systemic lupus erythematosus.^8,9 The latter case of DLE-like isotopic response occurring after herpes zoster infection was further complicated by local injections at the zoster site for herpes-related local pain. Injection sites are reported as a distinct nidus for Wolf isotopic response.⁹

The pathogenesis of Wolf isotopic response is unclear. Possible explanations include local interactions between persistent viral particles at prior herpes infection sites, vascular injury, neural injury, and an altered immune response.^1,5,6,10 The destruction of sensory nerve fibers by herpesviruses cause the release of neuropeptides that then modulate the local immune system and angiogenic responses.^5,6 Our patient’s immunocompromised state may have further propagated a local altered immune cell infiltrate at the site of the isotopic response. Despite its unclear etiology, Wolf isotopic response should be considered in the differential diagnosis for any patient who presents with a dermatomal eruption at the site of a prior cutaneous infection, particularly after infection with herpes zoster. Treatment with topical or intralesional corticosteroids usually suffices for inflammatory-based isotopic responses with an excellent prognosis.¹¹

We present a case of a cutaneous lupus erythematosus–like isotopic response that occurred at the site of a recent herpes zoster eruption in an immunocompromised patient without prior history of systemic or cutaneous lupus erythematosus. Clinical recognition of Wolf isotopic response is important for accurate histopathologic diagnosis and management. Continued investigation into the underlying pathogenesis should be performed to fully understand and better treat this process.

Regulators and the nation’s largest physician organization took separate steps in recent days to prepare for expected authorization of use of COVID-19 vaccines in children younger than age 6.

The Food and Drug Administration on May 23 announced its Vaccines and Related Biological Products Advisory Committee will meet June 15 to discuss expanding the use of COVID vaccines from Pfizer and Moderna.

The panel will examine a request from Pfizer and its partner BioNTech for an emergency use authorization (EUA) of its vaccine to cover children ages 6 months through 4 years. The EUA expansion for the Moderna shot would cover children ages 6 months through 5 years, the FDA said.

Many parents and physicians have been urging regulators to clear COVID shots for young children, among whom rates of infection are high.

The American Medical Association in February announced an update of its Current Procedural Terminology (CPT) to prepare for an eventual FDA clearance of the Pfizer-BioNTech shot for children aged 6 months to younger than 5 years. On May 19, the association announced a new CPT update to prepare for FDA clearance for use of the Moderna COVID-19 vaccine for children 6 months through 5 years.

“Extending COVID-19 vaccination protection to approximately 18 million young children will significantly reduce their risk of COVID-19 infection, hospitalization, and death, and give their parents incredible peace of mind,” Gerald Harmon, MD, AMA’s president, said in a statement. “We strongly urge all parents to get their infants and toddlers vaccinated as soon as they are eligible for a COVID-19 vaccine.”

Both the Moderna and the Pfizer-BioNTech COVID vaccines would be given to these young children in low doses.

On May 23, Pfizer announced results from a phase 2/3 trial evaluating a series of three shots of its vaccine in children ages 6 months to younger than 5 years.

Vaccine efficacy, which was a secondary endpoint in this study, was 80.3% in this age group, Pfizer said. The analysis was based on 10 symptomatic cases of COVID-19. The trial’s protocol specifies a formal analysis will be performed when at least 21 cases have accrued from 7 days after the third dose. The company said it would share final data on the effectiveness of the vaccine once the results are available.

Moderna on April 28 issued a statement with details about testing of its vaccine in young children. Vaccine efficacy was estimated at about 51% for children aged 6 months to younger than 2 years and 37% for the children aged 2 years to younger than 6. Paul Burton, MD, Moderna’s chief medical officer, spoke about this rate during a May 1 appearance on CBS’ Face the Nation.

“What it means for parents, for caregivers, is that if they give the Moderna vaccine to these little kids, they would basically cut in half the risk of that child getting symptomatic COVID,” Dr. Burton said in the interview. “Now, the number, 50%, I know is often lower than we are used to seeing with our vaccine, but it’s because this study was conducted during a time of Omicron.”

The FDA’s vaccine advisory committee also will meet on June 14 discuss potential use under an EUA of Moderna’s COVID vaccine for children and teenagers aged 6-17 years. The Pfizer-BioNTech vaccine already is authorized under an EUA for people aged 5 years and older.

The FDA has to date granted both conditional clearances, or EUAs, and regular approvals for COVID vaccines.

EUAs are meant to be temporary, allowing for rapid introduction of medicines in response to public health crises such as the pandemic. The FDA also uses EUAs to provide initial clearances of additional indications for products, as would be the case with the authorizations Moderna and Pfizer-BioNTech are seeking for their COVID vaccines.

Companies that want to continue to sell EUA-cleared products or promote EUA-cleared indications beyond the time of the public health crisis must seek regular approvals.

The FDA cleared the Pfizer-BioNTech and Moderna COVID vaccines under EUAs in December 2020. The agency then granted a regular approval for the Pfizer-BioNTech vaccine for people ages 16 and older in August 2021 based on more robust data. Regular approval for the Moderna vaccine for people ages 18 and older followed in January 2022.
 

Varied reactions among parents

Attitudes in the United States about pediatric COVID vaccines are far from uniform.

The initial uptake has disappointed physicians and researchers, who have been urging wider use of the COVID vaccination among children and teens for whom the FDA already has granted a clearance. Many parents are hesitating to bring their children for the COVID vaccines, according to the Centers for Disease Control and Prevention. Only 35.4% of children ages 5-11 had received at least one dose of a COVID vaccine, CDC staff said during a meeting.

Yet many other parents are demanding this medicine for their young children, urging the FDA to move quickly to clear COVID shots.

A private Facebook group called “Protect Their Future: A Call to Action for COVID Vaccines in Kids <5” boasts about 6,200 members. Many parents and physicians have used Twitter in recent months to press for a speedy review of COVID vaccines for the youngest children, often using the hashtag #immunizeunder5s. A group called Protect Their Future, which uses @ImmunizeUnder5s as its Twitter handle, had 5,288 followers as of the afternoon of May 23.

A special panel of the House of Representatives, the Select Subcommittee on the Coronavirus Crisis, on May 23 joined those tweeting about the need to soon authorize COVID vaccines for very young children.

“Parents have been waiting many months for vaccines for their young children,” the subcommittee tweeted. “They deserve to hear from @US_FDA why this lengthy process has been in children’s best interests.”

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

Regulators and the nation’s largest physician organization took separate steps in recent days to prepare for expected authorization of use of COVID-19 vaccines in children younger than age 6.

The Food and Drug Administration on May 23 announced its Vaccines and Related Biological Products Advisory Committee will meet June 15 to discuss expanding the use of COVID vaccines from Pfizer and Moderna.

The panel will examine a request from Pfizer and its partner BioNTech for an emergency use authorization (EUA) of its vaccine to cover children ages 6 months through 4 years. The EUA expansion for the Moderna shot would cover children ages 6 months through 5 years, the FDA said.

Many parents and physicians have been urging regulators to clear COVID shots for young children, among whom rates of infection are high.

The American Medical Association in February announced an update of its Current Procedural Terminology (CPT) to prepare for an eventual FDA clearance of the Pfizer-BioNTech shot for children aged 6 months to younger than 5 years. On May 19, the association announced a new CPT update to prepare for FDA clearance for use of the Moderna COVID-19 vaccine for children 6 months through 5 years.

“Extending COVID-19 vaccination protection to approximately 18 million young children will significantly reduce their risk of COVID-19 infection, hospitalization, and death, and give their parents incredible peace of mind,” Gerald Harmon, MD, AMA’s president, said in a statement. “We strongly urge all parents to get their infants and toddlers vaccinated as soon as they are eligible for a COVID-19 vaccine.”

Both the Moderna and the Pfizer-BioNTech COVID vaccines would be given to these young children in low doses.

On May 23, Pfizer announced results from a phase 2/3 trial evaluating a series of three shots of its vaccine in children ages 6 months to younger than 5 years.

Vaccine efficacy, which was a secondary endpoint in this study, was 80.3% in this age group, Pfizer said. The analysis was based on 10 symptomatic cases of COVID-19. The trial’s protocol specifies a formal analysis will be performed when at least 21 cases have accrued from 7 days after the third dose. The company said it would share final data on the effectiveness of the vaccine once the results are available.

Moderna on April 28 issued a statement with details about testing of its vaccine in young children. Vaccine efficacy was estimated at about 51% for children aged 6 months to younger than 2 years and 37% for the children aged 2 years to younger than 6. Paul Burton, MD, Moderna’s chief medical officer, spoke about this rate during a May 1 appearance on CBS’ Face the Nation.

“What it means for parents, for caregivers, is that if they give the Moderna vaccine to these little kids, they would basically cut in half the risk of that child getting symptomatic COVID,” Dr. Burton said in the interview. “Now, the number, 50%, I know is often lower than we are used to seeing with our vaccine, but it’s because this study was conducted during a time of Omicron.”

The FDA’s vaccine advisory committee also will meet on June 14 discuss potential use under an EUA of Moderna’s COVID vaccine for children and teenagers aged 6-17 years. The Pfizer-BioNTech vaccine already is authorized under an EUA for people aged 5 years and older.

The FDA has to date granted both conditional clearances, or EUAs, and regular approvals for COVID vaccines.

EUAs are meant to be temporary, allowing for rapid introduction of medicines in response to public health crises such as the pandemic. The FDA also uses EUAs to provide initial clearances of additional indications for products, as would be the case with the authorizations Moderna and Pfizer-BioNTech are seeking for their COVID vaccines.

Companies that want to continue to sell EUA-cleared products or promote EUA-cleared indications beyond the time of the public health crisis must seek regular approvals.

The FDA cleared the Pfizer-BioNTech and Moderna COVID vaccines under EUAs in December 2020. The agency then granted a regular approval for the Pfizer-BioNTech vaccine for people ages 16 and older in August 2021 based on more robust data. Regular approval for the Moderna vaccine for people ages 18 and older followed in January 2022.
 

Varied reactions among parents

Attitudes in the United States about pediatric COVID vaccines are far from uniform.

The initial uptake has disappointed physicians and researchers, who have been urging wider use of the COVID vaccination among children and teens for whom the FDA already has granted a clearance. Many parents are hesitating to bring their children for the COVID vaccines, according to the Centers for Disease Control and Prevention. Only 35.4% of children ages 5-11 had received at least one dose of a COVID vaccine, CDC staff said during a meeting.

Yet many other parents are demanding this medicine for their young children, urging the FDA to move quickly to clear COVID shots.

A private Facebook group called “Protect Their Future: A Call to Action for COVID Vaccines in Kids <5” boasts about 6,200 members. Many parents and physicians have used Twitter in recent months to press for a speedy review of COVID vaccines for the youngest children, often using the hashtag #immunizeunder5s. A group called Protect Their Future, which uses @ImmunizeUnder5s as its Twitter handle, had 5,288 followers as of the afternoon of May 23.

A special panel of the House of Representatives, the Select Subcommittee on the Coronavirus Crisis, on May 23 joined those tweeting about the need to soon authorize COVID vaccines for very young children.

“Parents have been waiting many months for vaccines for their young children,” the subcommittee tweeted. “They deserve to hear from @US_FDA why this lengthy process has been in children’s best interests.”

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

Regulators and the nation’s largest physician organization took separate steps in recent days to prepare for expected authorization of use of COVID-19 vaccines in children younger than age 6.

The Food and Drug Administration on May 23 announced its Vaccines and Related Biological Products Advisory Committee will meet June 15 to discuss expanding the use of COVID vaccines from Pfizer and Moderna.

The panel will examine a request from Pfizer and its partner BioNTech for an emergency use authorization (EUA) of its vaccine to cover children ages 6 months through 4 years. The EUA expansion for the Moderna shot would cover children ages 6 months through 5 years, the FDA said.

Many parents and physicians have been urging regulators to clear COVID shots for young children, among whom rates of infection are high.

The American Medical Association in February announced an update of its Current Procedural Terminology (CPT) to prepare for an eventual FDA clearance of the Pfizer-BioNTech shot for children aged 6 months to younger than 5 years. On May 19, the association announced a new CPT update to prepare for FDA clearance for use of the Moderna COVID-19 vaccine for children 6 months through 5 years.

“Extending COVID-19 vaccination protection to approximately 18 million young children will significantly reduce their risk of COVID-19 infection, hospitalization, and death, and give their parents incredible peace of mind,” Gerald Harmon, MD, AMA’s president, said in a statement. “We strongly urge all parents to get their infants and toddlers vaccinated as soon as they are eligible for a COVID-19 vaccine.”

Both the Moderna and the Pfizer-BioNTech COVID vaccines would be given to these young children in low doses.

On May 23, Pfizer announced results from a phase 2/3 trial evaluating a series of three shots of its vaccine in children ages 6 months to younger than 5 years.

Vaccine efficacy, which was a secondary endpoint in this study, was 80.3% in this age group, Pfizer said. The analysis was based on 10 symptomatic cases of COVID-19. The trial’s protocol specifies a formal analysis will be performed when at least 21 cases have accrued from 7 days after the third dose. The company said it would share final data on the effectiveness of the vaccine once the results are available.

Moderna on April 28 issued a statement with details about testing of its vaccine in young children. Vaccine efficacy was estimated at about 51% for children aged 6 months to younger than 2 years and 37% for the children aged 2 years to younger than 6. Paul Burton, MD, Moderna’s chief medical officer, spoke about this rate during a May 1 appearance on CBS’ Face the Nation.

“What it means for parents, for caregivers, is that if they give the Moderna vaccine to these little kids, they would basically cut in half the risk of that child getting symptomatic COVID,” Dr. Burton said in the interview. “Now, the number, 50%, I know is often lower than we are used to seeing with our vaccine, but it’s because this study was conducted during a time of Omicron.”

The FDA’s vaccine advisory committee also will meet on June 14 discuss potential use under an EUA of Moderna’s COVID vaccine for children and teenagers aged 6-17 years. The Pfizer-BioNTech vaccine already is authorized under an EUA for people aged 5 years and older.

The FDA has to date granted both conditional clearances, or EUAs, and regular approvals for COVID vaccines.

EUAs are meant to be temporary, allowing for rapid introduction of medicines in response to public health crises such as the pandemic. The FDA also uses EUAs to provide initial clearances of additional indications for products, as would be the case with the authorizations Moderna and Pfizer-BioNTech are seeking for their COVID vaccines.

Companies that want to continue to sell EUA-cleared products or promote EUA-cleared indications beyond the time of the public health crisis must seek regular approvals.

The FDA cleared the Pfizer-BioNTech and Moderna COVID vaccines under EUAs in December 2020. The agency then granted a regular approval for the Pfizer-BioNTech vaccine for people ages 16 and older in August 2021 based on more robust data. Regular approval for the Moderna vaccine for people ages 18 and older followed in January 2022.
 

Varied reactions among parents

Attitudes in the United States about pediatric COVID vaccines are far from uniform.

The initial uptake has disappointed physicians and researchers, who have been urging wider use of the COVID vaccination among children and teens for whom the FDA already has granted a clearance. Many parents are hesitating to bring their children for the COVID vaccines, according to the Centers for Disease Control and Prevention. Only 35.4% of children ages 5-11 had received at least one dose of a COVID vaccine, CDC staff said during a meeting.

Yet many other parents are demanding this medicine for their young children, urging the FDA to move quickly to clear COVID shots.

A private Facebook group called “Protect Their Future: A Call to Action for COVID Vaccines in Kids <5” boasts about 6,200 members. Many parents and physicians have used Twitter in recent months to press for a speedy review of COVID vaccines for the youngest children, often using the hashtag #immunizeunder5s. A group called Protect Their Future, which uses @ImmunizeUnder5s as its Twitter handle, had 5,288 followers as of the afternoon of May 23.

A special panel of the House of Representatives, the Select Subcommittee on the Coronavirus Crisis, on May 23 joined those tweeting about the need to soon authorize COVID vaccines for very young children.

“Parents have been waiting many months for vaccines for their young children,” the subcommittee tweeted. “They deserve to hear from @US_FDA why this lengthy process has been in children’s best interests.”

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

Intravenous thrombolysis (IVT) for acute stroke appears safe for patients who have recently received direct oral anticoagulant (DOAC) therapy, a new observational study suggests, prompting researchers to ask whether guidelines that restrict its use should be updated.

Researchers found that DOAC users were significantly less likely to develop symptomatic intracerebral hemorrhage (sICH) after IVT, and there was no difference in functional independence at 3 months, compared with patients who received IVT but who did not receive DOAC.

“At the moment, the guidelines really pose a barrier and stop sign in front of the most important medical reperfusion therapy, which is thrombolysis,” said principal investigator Jan Purrucker, MD, professor of neurology at Heidelberg University Hospital.

“The main question we have to answer is, is IVT safe in patients with acute ischemic stroke who were pretreated with direct oral anticoagulants or not?”

The findings were presented at the European Stroke Organisation Conference (ESOC) 2022, Lyon, France.
 

A ‘daily clinical problem’

As many as 20% of patients with atrial fibrillation experience ischemic stroke while receiving DOAC therapy. Reperfusion therapy with intravenous alteplase is considered standard of care for acute ischemic stroke, but current guidelines recommend against the use of IVT for patients who have recently received a DOAC, owing to safety concerns that researchers say are not backed by strong clinical evidence.

A recent study found no significant difference in sICH among patients who received IV alteplase for acute ischemic stroke within 7 days of receiving therapy with non–vitamin K antagonist oral anticoagulants.

“In our daily clinical practice, we face a lot of patients who have received oral anticoagulation, many with atrial fibrillation, but a lot of other indicators as well, and they suffer from ischemic stroke,” Dr. Purrucker said. “They usually are ineligible for medical reperfusion therapy because of quite strict guideline recommendations at the moment. This is a daily clinical problem.”

Dr. Purrucker and colleagues in New Zealand and Switzerland launched an international, observational, multicenter cohort study to examine the issue.

Researchers collected data on patients with ischemic stroke who had last received DOAC therapy 48 hours or less before the event or whose last intake was unknown and who had received IVT. They included 20,448 patients, 830 of whom were receiving DOAC therapy at the time of stroke onset.

Among the DOAC users, 30% received DOAC reversal prior to IVT, 27% had their DOAC level measured, and 42% received IVT without reversal treatment or knowledge of DOAC levels.

Overall, 4.5% of patients developed sICH. Compared with the control group, DOAC users were half as likely to develop sICH (adjusted odds ratio, 0.47; P = .003).

There was no significant difference between groups in independent outcome at 3 months, defined as a Modified Rankin Scale score of 1 to 3 (aOR, 1.21; 95% confidence interval, 0.99-1.49).

This finding held across patient subgroups, including patients for whom selection methods differed and patients with very recent intake of less than 12 hours.

“The question is whether we are so confident in these data that we would change our clinical practice now,” Dr. Purrucker said.
 

Infrastructure needed

While the findings are promising, more data are needed to strengthen the argument for revising current IVT guidelines, said Ho-Yan Yvonne Chun, PhD, honorary senior clinical lecturer with the Centre for Clinical Brain Sciences at the University of Edinburgh and a consultant in stroke medicine for NHS Lothian and Borders General Hospital, who commented on the findings.

“The study sample are a highly selected group of patients from selected centers that have the infrastructure to offer DOAC level checking and DOAC reversal,” Dr. Chun said. “The selected centers are not representative of the majority of hospitals that offer IVT to stroke patients with acute stroke.”

Most hospitals lack the equipment necessary to test DOAC levels and don’t have immediate access to DOAC reversal agents, Dr. Chun said. In those centers, she added, the administration of IVT could be delayed, which might affect clinical outcomes.

“Infrastructure needs to be in place to ensure timely delivery of IVT to these patients,” Dr. Chun added. “This means that in real-world practice, hospitals need to have right logistical pathway in place in order to provide timely DOAC level checking and DOAC reversal agents.”

Dr. Chun added that “large pragmatic clinical trials, preferably multicentered, are needed to provide the definitive evidence on the safety and effectiveness of using these approaches to select patients with prior DOAC use for IVT.”

But such a study may not be feasible, Dr. Purrucker said. Among the hurdles he noted are the large sample size needed for such a trial, uncertainty regarding funding, and patient selection bias, resulting from the fact that such studies would likely exclude patients eligible for mechanical thrombectomy or those eligible for reversal treatment.

In light of earlier studies, including preclinical data that support the safety of DOACs in IVT, and these new data, Dr. Purrucker said he hopes a change in guidelines might be taken up in the future.

“But it should be good academic practice to first let the results be externally evaluated, for example, during the manuscript submission process,” he said. “But once published, guideline working groups will have to evaluate the recent and new evidence and might reconsider previous recommendations.”

The study received no commercial funding. Dr. Purrucker and Dr. Chun reported no relevant financial relationships.

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

Intravenous thrombolysis (IVT) for acute stroke appears safe for patients who have recently received direct oral anticoagulant (DOAC) therapy, a new observational study suggests, prompting researchers to ask whether guidelines that restrict its use should be updated.

Researchers found that DOAC users were significantly less likely to develop symptomatic intracerebral hemorrhage (sICH) after IVT, and there was no difference in functional independence at 3 months, compared with patients who received IVT but who did not receive DOAC.

“At the moment, the guidelines really pose a barrier and stop sign in front of the most important medical reperfusion therapy, which is thrombolysis,” said principal investigator Jan Purrucker, MD, professor of neurology at Heidelberg University Hospital.

“The main question we have to answer is, is IVT safe in patients with acute ischemic stroke who were pretreated with direct oral anticoagulants or not?”

The findings were presented at the European Stroke Organisation Conference (ESOC) 2022, Lyon, France.
 

A ‘daily clinical problem’

As many as 20% of patients with atrial fibrillation experience ischemic stroke while receiving DOAC therapy. Reperfusion therapy with intravenous alteplase is considered standard of care for acute ischemic stroke, but current guidelines recommend against the use of IVT for patients who have recently received a DOAC, owing to safety concerns that researchers say are not backed by strong clinical evidence.

A recent study found no significant difference in sICH among patients who received IV alteplase for acute ischemic stroke within 7 days of receiving therapy with non–vitamin K antagonist oral anticoagulants.

“In our daily clinical practice, we face a lot of patients who have received oral anticoagulation, many with atrial fibrillation, but a lot of other indicators as well, and they suffer from ischemic stroke,” Dr. Purrucker said. “They usually are ineligible for medical reperfusion therapy because of quite strict guideline recommendations at the moment. This is a daily clinical problem.”

Dr. Purrucker and colleagues in New Zealand and Switzerland launched an international, observational, multicenter cohort study to examine the issue.

Researchers collected data on patients with ischemic stroke who had last received DOAC therapy 48 hours or less before the event or whose last intake was unknown and who had received IVT. They included 20,448 patients, 830 of whom were receiving DOAC therapy at the time of stroke onset.

Among the DOAC users, 30% received DOAC reversal prior to IVT, 27% had their DOAC level measured, and 42% received IVT without reversal treatment or knowledge of DOAC levels.

Overall, 4.5% of patients developed sICH. Compared with the control group, DOAC users were half as likely to develop sICH (adjusted odds ratio, 0.47; P = .003).

There was no significant difference between groups in independent outcome at 3 months, defined as a Modified Rankin Scale score of 1 to 3 (aOR, 1.21; 95% confidence interval, 0.99-1.49).

This finding held across patient subgroups, including patients for whom selection methods differed and patients with very recent intake of less than 12 hours.

“The question is whether we are so confident in these data that we would change our clinical practice now,” Dr. Purrucker said.
 

Infrastructure needed

While the findings are promising, more data are needed to strengthen the argument for revising current IVT guidelines, said Ho-Yan Yvonne Chun, PhD, honorary senior clinical lecturer with the Centre for Clinical Brain Sciences at the University of Edinburgh and a consultant in stroke medicine for NHS Lothian and Borders General Hospital, who commented on the findings.

“The study sample are a highly selected group of patients from selected centers that have the infrastructure to offer DOAC level checking and DOAC reversal,” Dr. Chun said. “The selected centers are not representative of the majority of hospitals that offer IVT to stroke patients with acute stroke.”

Most hospitals lack the equipment necessary to test DOAC levels and don’t have immediate access to DOAC reversal agents, Dr. Chun said. In those centers, she added, the administration of IVT could be delayed, which might affect clinical outcomes.

“Infrastructure needs to be in place to ensure timely delivery of IVT to these patients,” Dr. Chun added. “This means that in real-world practice, hospitals need to have right logistical pathway in place in order to provide timely DOAC level checking and DOAC reversal agents.”

Dr. Chun added that “large pragmatic clinical trials, preferably multicentered, are needed to provide the definitive evidence on the safety and effectiveness of using these approaches to select patients with prior DOAC use for IVT.”

But such a study may not be feasible, Dr. Purrucker said. Among the hurdles he noted are the large sample size needed for such a trial, uncertainty regarding funding, and patient selection bias, resulting from the fact that such studies would likely exclude patients eligible for mechanical thrombectomy or those eligible for reversal treatment.

In light of earlier studies, including preclinical data that support the safety of DOACs in IVT, and these new data, Dr. Purrucker said he hopes a change in guidelines might be taken up in the future.

“But it should be good academic practice to first let the results be externally evaluated, for example, during the manuscript submission process,” he said. “But once published, guideline working groups will have to evaluate the recent and new evidence and might reconsider previous recommendations.”

The study received no commercial funding. Dr. Purrucker and Dr. Chun reported no relevant financial relationships.

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

Intravenous thrombolysis (IVT) for acute stroke appears safe for patients who have recently received direct oral anticoagulant (DOAC) therapy, a new observational study suggests, prompting researchers to ask whether guidelines that restrict its use should be updated.

Researchers found that DOAC users were significantly less likely to develop symptomatic intracerebral hemorrhage (sICH) after IVT, and there was no difference in functional independence at 3 months, compared with patients who received IVT but who did not receive DOAC.

“At the moment, the guidelines really pose a barrier and stop sign in front of the most important medical reperfusion therapy, which is thrombolysis,” said principal investigator Jan Purrucker, MD, professor of neurology at Heidelberg University Hospital.

“The main question we have to answer is, is IVT safe in patients with acute ischemic stroke who were pretreated with direct oral anticoagulants or not?”

The findings were presented at the European Stroke Organisation Conference (ESOC) 2022, Lyon, France.
 

A ‘daily clinical problem’

As many as 20% of patients with atrial fibrillation experience ischemic stroke while receiving DOAC therapy. Reperfusion therapy with intravenous alteplase is considered standard of care for acute ischemic stroke, but current guidelines recommend against the use of IVT for patients who have recently received a DOAC, owing to safety concerns that researchers say are not backed by strong clinical evidence.

A recent study found no significant difference in sICH among patients who received IV alteplase for acute ischemic stroke within 7 days of receiving therapy with non–vitamin K antagonist oral anticoagulants.

“In our daily clinical practice, we face a lot of patients who have received oral anticoagulation, many with atrial fibrillation, but a lot of other indicators as well, and they suffer from ischemic stroke,” Dr. Purrucker said. “They usually are ineligible for medical reperfusion therapy because of quite strict guideline recommendations at the moment. This is a daily clinical problem.”

Dr. Purrucker and colleagues in New Zealand and Switzerland launched an international, observational, multicenter cohort study to examine the issue.

Researchers collected data on patients with ischemic stroke who had last received DOAC therapy 48 hours or less before the event or whose last intake was unknown and who had received IVT. They included 20,448 patients, 830 of whom were receiving DOAC therapy at the time of stroke onset.

Among the DOAC users, 30% received DOAC reversal prior to IVT, 27% had their DOAC level measured, and 42% received IVT without reversal treatment or knowledge of DOAC levels.

Overall, 4.5% of patients developed sICH. Compared with the control group, DOAC users were half as likely to develop sICH (adjusted odds ratio, 0.47; P = .003).

There was no significant difference between groups in independent outcome at 3 months, defined as a Modified Rankin Scale score of 1 to 3 (aOR, 1.21; 95% confidence interval, 0.99-1.49).

This finding held across patient subgroups, including patients for whom selection methods differed and patients with very recent intake of less than 12 hours.

“The question is whether we are so confident in these data that we would change our clinical practice now,” Dr. Purrucker said.
 

Infrastructure needed

While the findings are promising, more data are needed to strengthen the argument for revising current IVT guidelines, said Ho-Yan Yvonne Chun, PhD, honorary senior clinical lecturer with the Centre for Clinical Brain Sciences at the University of Edinburgh and a consultant in stroke medicine for NHS Lothian and Borders General Hospital, who commented on the findings.

“The study sample are a highly selected group of patients from selected centers that have the infrastructure to offer DOAC level checking and DOAC reversal,” Dr. Chun said. “The selected centers are not representative of the majority of hospitals that offer IVT to stroke patients with acute stroke.”

Most hospitals lack the equipment necessary to test DOAC levels and don’t have immediate access to DOAC reversal agents, Dr. Chun said. In those centers, she added, the administration of IVT could be delayed, which might affect clinical outcomes.

“Infrastructure needs to be in place to ensure timely delivery of IVT to these patients,” Dr. Chun added. “This means that in real-world practice, hospitals need to have right logistical pathway in place in order to provide timely DOAC level checking and DOAC reversal agents.”

Dr. Chun added that “large pragmatic clinical trials, preferably multicentered, are needed to provide the definitive evidence on the safety and effectiveness of using these approaches to select patients with prior DOAC use for IVT.”

But such a study may not be feasible, Dr. Purrucker said. Among the hurdles he noted are the large sample size needed for such a trial, uncertainty regarding funding, and patient selection bias, resulting from the fact that such studies would likely exclude patients eligible for mechanical thrombectomy or those eligible for reversal treatment.

In light of earlier studies, including preclinical data that support the safety of DOACs in IVT, and these new data, Dr. Purrucker said he hopes a change in guidelines might be taken up in the future.

“But it should be good academic practice to first let the results be externally evaluated, for example, during the manuscript submission process,” he said. “But once published, guideline working groups will have to evaluate the recent and new evidence and might reconsider previous recommendations.”

The study received no commercial funding. Dr. Purrucker and Dr. Chun reported no relevant financial relationships.

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

A federal sting operation led to the recent conviction of a Texas physician assistant on charges of illegally prescribing a total of $3 million in drugs to patients at two “pill mill” clinics in Houston and helping others do the same.

The May 20 conviction of Charles Thompson, 76, of Houston, was based on charges of distributing more than 1.2 million opioid pills to thousands of individuals posing as patients at two pain management clinics, according to the U.S. Department of Justice.

Thompson’s conviction was the latest legal action in a string of cases involving the operation, including a doctor convicted in March who worked with Thompson at the West Parker Medical Clinic. Internist James Pierre, MD, 52, faces charges of unlawfully prescribing more than $1 million worth of opioid hydrocodone, according to federal officials.

Thompson also worked at Priority Wellness Clinic. Six people have pled guilty in connection with their conduct at West Parker or Priority Wellness, the justice department reported.

From June 2015 through July 2016, while Thompson was at West Parker, he helped Dr. Pierre unlawfully prescribe hydrocodone and the muscle relaxant carisoprodol, a combination of controlled substances for pain management known as the “Las Vegas cocktail,” to people in the sting operations pretending to be patients, authorities stated.

Thompson also distributed unlawful prescriptions for carisoprodol. So-called “runners” brought numerous people to pose as patients at West Parker and paid the clinic about $220 to $500 in cash for each visit that resulted in prescriptions for dangerous drugs. Throughout the scheme, West Parker pocketed about $1.75 million from prescriptions; Thompson was paid more than $208,000.

According to authorities, Thompson also helped others illegally prescribe controlled substances, including hydrocodone and oxycodone, from May to July 2017 at Priority Wellness, which opened in December 2016 after West Parker closed.

Priority Wellness reportedly operated as a pill mill similar to West Parker’s. Runners brought people posing as patients to Priority Wellness and paid the clinic between $300 and $600. The cost depended on whether the purported patient received a prescription for hydrocodone or oxycodone, almost always prescribed in combination with carisoprodol, authorities said. Throughout the scheme, Priority Wellness made about $1.1 million, and Thompson made between $700 and $900 a day.

He was convicted of one count of conspiracy to unlawfully distribute and dispense controlled substances and seven counts of unlawfully distributing and dispensing controlled substances in connection with his conduct at West Parker. For his conduct at Priority Wellness, he was convicted of one count of conspiracy to unlawfully distribute and dispense controlled substances and one count of unlawfully distributing and dispensing controlled substances.

He faces up to 20 years in prison for each count of conviction with sentencing scheduled for Oct. 3.

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

A federal sting operation led to the recent conviction of a Texas physician assistant on charges of illegally prescribing a total of $3 million in drugs to patients at two “pill mill” clinics in Houston and helping others do the same.

The May 20 conviction of Charles Thompson, 76, of Houston, was based on charges of distributing more than 1.2 million opioid pills to thousands of individuals posing as patients at two pain management clinics, according to the U.S. Department of Justice.

Thompson’s conviction was the latest legal action in a string of cases involving the operation, including a doctor convicted in March who worked with Thompson at the West Parker Medical Clinic. Internist James Pierre, MD, 52, faces charges of unlawfully prescribing more than $1 million worth of opioid hydrocodone, according to federal officials.

Thompson also worked at Priority Wellness Clinic. Six people have pled guilty in connection with their conduct at West Parker or Priority Wellness, the justice department reported.

From June 2015 through July 2016, while Thompson was at West Parker, he helped Dr. Pierre unlawfully prescribe hydrocodone and the muscle relaxant carisoprodol, a combination of controlled substances for pain management known as the “Las Vegas cocktail,” to people in the sting operations pretending to be patients, authorities stated.

Thompson also distributed unlawful prescriptions for carisoprodol. So-called “runners” brought numerous people to pose as patients at West Parker and paid the clinic about $220 to $500 in cash for each visit that resulted in prescriptions for dangerous drugs. Throughout the scheme, West Parker pocketed about $1.75 million from prescriptions; Thompson was paid more than $208,000.

According to authorities, Thompson also helped others illegally prescribe controlled substances, including hydrocodone and oxycodone, from May to July 2017 at Priority Wellness, which opened in December 2016 after West Parker closed.

Priority Wellness reportedly operated as a pill mill similar to West Parker’s. Runners brought people posing as patients to Priority Wellness and paid the clinic between $300 and $600. The cost depended on whether the purported patient received a prescription for hydrocodone or oxycodone, almost always prescribed in combination with carisoprodol, authorities said. Throughout the scheme, Priority Wellness made about $1.1 million, and Thompson made between $700 and $900 a day.

He was convicted of one count of conspiracy to unlawfully distribute and dispense controlled substances and seven counts of unlawfully distributing and dispensing controlled substances in connection with his conduct at West Parker. For his conduct at Priority Wellness, he was convicted of one count of conspiracy to unlawfully distribute and dispense controlled substances and one count of unlawfully distributing and dispensing controlled substances.

He faces up to 20 years in prison for each count of conviction with sentencing scheduled for Oct. 3.

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

A federal sting operation led to the recent conviction of a Texas physician assistant on charges of illegally prescribing a total of $3 million in drugs to patients at two “pill mill” clinics in Houston and helping others do the same.

The May 20 conviction of Charles Thompson, 76, of Houston, was based on charges of distributing more than 1.2 million opioid pills to thousands of individuals posing as patients at two pain management clinics, according to the U.S. Department of Justice.

Thompson’s conviction was the latest legal action in a string of cases involving the operation, including a doctor convicted in March who worked with Thompson at the West Parker Medical Clinic. Internist James Pierre, MD, 52, faces charges of unlawfully prescribing more than $1 million worth of opioid hydrocodone, according to federal officials.

Thompson also worked at Priority Wellness Clinic. Six people have pled guilty in connection with their conduct at West Parker or Priority Wellness, the justice department reported.

From June 2015 through July 2016, while Thompson was at West Parker, he helped Dr. Pierre unlawfully prescribe hydrocodone and the muscle relaxant carisoprodol, a combination of controlled substances for pain management known as the “Las Vegas cocktail,” to people in the sting operations pretending to be patients, authorities stated.

Thompson also distributed unlawful prescriptions for carisoprodol. So-called “runners” brought numerous people to pose as patients at West Parker and paid the clinic about $220 to $500 in cash for each visit that resulted in prescriptions for dangerous drugs. Throughout the scheme, West Parker pocketed about $1.75 million from prescriptions; Thompson was paid more than $208,000.

According to authorities, Thompson also helped others illegally prescribe controlled substances, including hydrocodone and oxycodone, from May to July 2017 at Priority Wellness, which opened in December 2016 after West Parker closed.

Priority Wellness reportedly operated as a pill mill similar to West Parker’s. Runners brought people posing as patients to Priority Wellness and paid the clinic between $300 and $600. The cost depended on whether the purported patient received a prescription for hydrocodone or oxycodone, almost always prescribed in combination with carisoprodol, authorities said. Throughout the scheme, Priority Wellness made about $1.1 million, and Thompson made between $700 and $900 a day.

He was convicted of one count of conspiracy to unlawfully distribute and dispense controlled substances and seven counts of unlawfully distributing and dispensing controlled substances in connection with his conduct at West Parker. For his conduct at Priority Wellness, he was convicted of one count of conspiracy to unlawfully distribute and dispense controlled substances and one count of unlawfully distributing and dispensing controlled substances.

He faces up to 20 years in prison for each count of conviction with sentencing scheduled for Oct. 3.

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

Chronic lymphocytic leukemia (CLL) patients aged 65 years and older who were treated with ibrutinib showed sustained progression-free and overall survival benefits up to 8 years later, based on follow-up data from the RESONATE-2 trial.

“This trial led to the first-line approval of ibrutinib for CLL patients,” lead author Paul M. Barr, MD, of the University of Rochester (N.Y.), said in an interview. “It is important to follow these patients long-term to understand the expected duration of response/disease control and to monitor for late toxicity,” he said “The data are useful in guiding clinicians who treat CLL and patients being treated with single agent BTK inhibitors,” he noted.

In the initial RESONATE-2, a phase 3, open-label study, 269 adults aged 65 years and older who were previously untreated for CLL or small lymphocytic leukemia were randomized to ibrutinib or the standard of care, chlorambucil. Patients received 420 mg of ibrutinib once daily until disease progression or unacceptable toxicity (136 patients) or up to 12 cycles of 0.5-0.8 mg/kg of chlorambucil (133 patients).

The long-term outcome data were published in Blood Advances.

Overall, at a median of 83 months’ follow-up, progression-free survival was significantly higher for ibrutinib patients than for chlorambucil patients (hazard ratio 0.154).

At 7 years, progression-free survival was 59% in the ibrutinib group vs. 9% in the chlorambucil group.

Notably, progression-free survival benefits with ibrutinib also were higher for patients with high-risk genomic features, identified as del(11q) and unmutated immunoglobulin heavy-chain variable region gene (IGHV).

Complete data were available for 54 patients with del(11q) and 118 with unmutated IGHV. In this subset of patients, progression-free survival rates at 7 years were significantly higher for those treated with ibrutinib vs. chlorambucil who had del(11q) or unmutated IGHV (52% vs. 0% and 58% vs. 2%, respectively).

Approximately 42% of patients with chronic lymphocytic leukemia treated with ibrutinib remained on the therapy at up to 8 years, with a median follow-up of 7.4 years. Overall survival at 7 years was 78% for ibrutinib; overall survival data were not collected for chlorambucil for patients with progressive disease after the median of 5 years, as these patients were eligible to switch to ibrutinib in a long-term extension study or exit the study.

Adverse events prompted reduction of ibrutinib in 30 patients and dose holding for at least 7 days in 79 patients. However, dose modification resolved or improved the adverse events in 85% of the patients with held doses and 90% of those with reduced doses.

The overall prevalence of adverse events was similar to previous follow-up data at 5 years. No new safety signals were observed during the longer study period. The rate of treatment discontinuation because of adverse events was highest in the first year.

“We have been surprised at how long the remissions have lasted with ibrutinib,” said Dr. Barr. “Even with up to 8 years of follow-up, we have yet to reach the median progression free-survival,” he noted.

“These data, in combination with other data sets, highlight the impact that ibrutinib and other BTK inhibitors have had in treating CLL,” said Dr. Barr. “Patients are living longer and avoiding the side effects of chemotherapy in the era of novel agent use,” he said.

However, research gaps remain, Dr. Barr noted. “We need to continue following these patients over time given the length of the remissions. Additionally, we need to continue investigating novel combinations,” he said. Such studies will help us understand the benefit of fixed durations regimens compared to single agent BTK inhibitors,” he emphasized.
 

Safety and efficacy remain promising

“Ibrutinib was approved for the treatment of CLL, but only in the relapsed setting,” Susan M. O’Brien, MD, of the University of California, Irvine, said in an interview. “This trial was important because it led to the approval of ibrutinib in the front-line setting, making it the first, and at the time, only, small molecule that could be used upfront,” said Dr. O’Brien, who was not involved with the study.

“The initial results were certainly not surprising, as given the efficacy of ibrutinib in the relapsed setting, it seemed likely that it would produce a longer PFS than chlorambucil,” said Dr. O’Brien. “What may not have been expected though, is the incredible durability of these responses with ibrutinib,” she noted.

The clinical implications of the long-term data are that ibrutinib is producing “very durable remissions with continuous therapy,” Dr. O’Brien said. “There are no late safety signals and most side effects diminish with time. However, hypertension and atrial fibrillation continue to occur, so continued monitoring of blood pressure in these patients is important,” she emphasized.

Minor, but annoying, side effects are not infrequent early on with ibrutinib and may present a barrier to use for some patients, Dr. O’Brien said. “Some side effects may be overcome with temporary pauses of drug or dose reduction,” she noted. However, “it is important for patients to be aware that most of these side effects will completely abate with time,” she added.  

“The main limitation of this trial was that the comparison was to a rather weak chemotherapy agent, albeit it one frequently used in older patients, particularly in Europe,” said Dr. O’Brien. “Nevertheless, two subsequent trials comparing ibrutinib (with or without rituximab) with either BR [bendamustine/rituximab] or FCR [fludarabine/cyclophosphamide/rituximab] showed a longer PFS with ibrutinib, as compared to that seen with either chemoimmunotherapy regimen,” she said.

The study was supported by Pharmacyclics LLC, an AbbVie company. Dr. Barr collaborated with sponsor AbbVie on the study design, and disclosed relationships with companies including AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Genentech, Gilead, Janssen, MEI Pharma, Merck, Morphosys, Pharmacyclics LLC (an AbbVie company), Seattle Genetics, and TG Therapeutics. Dr. O’Brien had no relevant financial conflicts to disclose.

Chronic lymphocytic leukemia (CLL) patients aged 65 years and older who were treated with ibrutinib showed sustained progression-free and overall survival benefits up to 8 years later, based on follow-up data from the RESONATE-2 trial.

“This trial led to the first-line approval of ibrutinib for CLL patients,” lead author Paul M. Barr, MD, of the University of Rochester (N.Y.), said in an interview. “It is important to follow these patients long-term to understand the expected duration of response/disease control and to monitor for late toxicity,” he said “The data are useful in guiding clinicians who treat CLL and patients being treated with single agent BTK inhibitors,” he noted.

In the initial RESONATE-2, a phase 3, open-label study, 269 adults aged 65 years and older who were previously untreated for CLL or small lymphocytic leukemia were randomized to ibrutinib or the standard of care, chlorambucil. Patients received 420 mg of ibrutinib once daily until disease progression or unacceptable toxicity (136 patients) or up to 12 cycles of 0.5-0.8 mg/kg of chlorambucil (133 patients).

The long-term outcome data were published in Blood Advances.

Overall, at a median of 83 months’ follow-up, progression-free survival was significantly higher for ibrutinib patients than for chlorambucil patients (hazard ratio 0.154).

At 7 years, progression-free survival was 59% in the ibrutinib group vs. 9% in the chlorambucil group.

Notably, progression-free survival benefits with ibrutinib also were higher for patients with high-risk genomic features, identified as del(11q) and unmutated immunoglobulin heavy-chain variable region gene (IGHV).

Complete data were available for 54 patients with del(11q) and 118 with unmutated IGHV. In this subset of patients, progression-free survival rates at 7 years were significantly higher for those treated with ibrutinib vs. chlorambucil who had del(11q) or unmutated IGHV (52% vs. 0% and 58% vs. 2%, respectively).

Approximately 42% of patients with chronic lymphocytic leukemia treated with ibrutinib remained on the therapy at up to 8 years, with a median follow-up of 7.4 years. Overall survival at 7 years was 78% for ibrutinib; overall survival data were not collected for chlorambucil for patients with progressive disease after the median of 5 years, as these patients were eligible to switch to ibrutinib in a long-term extension study or exit the study.

Adverse events prompted reduction of ibrutinib in 30 patients and dose holding for at least 7 days in 79 patients. However, dose modification resolved or improved the adverse events in 85% of the patients with held doses and 90% of those with reduced doses.

The overall prevalence of adverse events was similar to previous follow-up data at 5 years. No new safety signals were observed during the longer study period. The rate of treatment discontinuation because of adverse events was highest in the first year.

“We have been surprised at how long the remissions have lasted with ibrutinib,” said Dr. Barr. “Even with up to 8 years of follow-up, we have yet to reach the median progression free-survival,” he noted.

“These data, in combination with other data sets, highlight the impact that ibrutinib and other BTK inhibitors have had in treating CLL,” said Dr. Barr. “Patients are living longer and avoiding the side effects of chemotherapy in the era of novel agent use,” he said.

However, research gaps remain, Dr. Barr noted. “We need to continue following these patients over time given the length of the remissions. Additionally, we need to continue investigating novel combinations,” he said. Such studies will help us understand the benefit of fixed durations regimens compared to single agent BTK inhibitors,” he emphasized.
 

Safety and efficacy remain promising

“Ibrutinib was approved for the treatment of CLL, but only in the relapsed setting,” Susan M. O’Brien, MD, of the University of California, Irvine, said in an interview. “This trial was important because it led to the approval of ibrutinib in the front-line setting, making it the first, and at the time, only, small molecule that could be used upfront,” said Dr. O’Brien, who was not involved with the study.

“The initial results were certainly not surprising, as given the efficacy of ibrutinib in the relapsed setting, it seemed likely that it would produce a longer PFS than chlorambucil,” said Dr. O’Brien. “What may not have been expected though, is the incredible durability of these responses with ibrutinib,” she noted.

The clinical implications of the long-term data are that ibrutinib is producing “very durable remissions with continuous therapy,” Dr. O’Brien said. “There are no late safety signals and most side effects diminish with time. However, hypertension and atrial fibrillation continue to occur, so continued monitoring of blood pressure in these patients is important,” she emphasized.

Minor, but annoying, side effects are not infrequent early on with ibrutinib and may present a barrier to use for some patients, Dr. O’Brien said. “Some side effects may be overcome with temporary pauses of drug or dose reduction,” she noted. However, “it is important for patients to be aware that most of these side effects will completely abate with time,” she added.  

“The main limitation of this trial was that the comparison was to a rather weak chemotherapy agent, albeit it one frequently used in older patients, particularly in Europe,” said Dr. O’Brien. “Nevertheless, two subsequent trials comparing ibrutinib (with or without rituximab) with either BR [bendamustine/rituximab] or FCR [fludarabine/cyclophosphamide/rituximab] showed a longer PFS with ibrutinib, as compared to that seen with either chemoimmunotherapy regimen,” she said.

The study was supported by Pharmacyclics LLC, an AbbVie company. Dr. Barr collaborated with sponsor AbbVie on the study design, and disclosed relationships with companies including AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Genentech, Gilead, Janssen, MEI Pharma, Merck, Morphosys, Pharmacyclics LLC (an AbbVie company), Seattle Genetics, and TG Therapeutics. Dr. O’Brien had no relevant financial conflicts to disclose.

Chronic lymphocytic leukemia (CLL) patients aged 65 years and older who were treated with ibrutinib showed sustained progression-free and overall survival benefits up to 8 years later, based on follow-up data from the RESONATE-2 trial.

“This trial led to the first-line approval of ibrutinib for CLL patients,” lead author Paul M. Barr, MD, of the University of Rochester (N.Y.), said in an interview. “It is important to follow these patients long-term to understand the expected duration of response/disease control and to monitor for late toxicity,” he said “The data are useful in guiding clinicians who treat CLL and patients being treated with single agent BTK inhibitors,” he noted.

In the initial RESONATE-2, a phase 3, open-label study, 269 adults aged 65 years and older who were previously untreated for CLL or small lymphocytic leukemia were randomized to ibrutinib or the standard of care, chlorambucil. Patients received 420 mg of ibrutinib once daily until disease progression or unacceptable toxicity (136 patients) or up to 12 cycles of 0.5-0.8 mg/kg of chlorambucil (133 patients).

The long-term outcome data were published in Blood Advances.

Overall, at a median of 83 months’ follow-up, progression-free survival was significantly higher for ibrutinib patients than for chlorambucil patients (hazard ratio 0.154).

At 7 years, progression-free survival was 59% in the ibrutinib group vs. 9% in the chlorambucil group.

Notably, progression-free survival benefits with ibrutinib also were higher for patients with high-risk genomic features, identified as del(11q) and unmutated immunoglobulin heavy-chain variable region gene (IGHV).

Complete data were available for 54 patients with del(11q) and 118 with unmutated IGHV. In this subset of patients, progression-free survival rates at 7 years were significantly higher for those treated with ibrutinib vs. chlorambucil who had del(11q) or unmutated IGHV (52% vs. 0% and 58% vs. 2%, respectively).

Approximately 42% of patients with chronic lymphocytic leukemia treated with ibrutinib remained on the therapy at up to 8 years, with a median follow-up of 7.4 years. Overall survival at 7 years was 78% for ibrutinib; overall survival data were not collected for chlorambucil for patients with progressive disease after the median of 5 years, as these patients were eligible to switch to ibrutinib in a long-term extension study or exit the study.

Adverse events prompted reduction of ibrutinib in 30 patients and dose holding for at least 7 days in 79 patients. However, dose modification resolved or improved the adverse events in 85% of the patients with held doses and 90% of those with reduced doses.

The overall prevalence of adverse events was similar to previous follow-up data at 5 years. No new safety signals were observed during the longer study period. The rate of treatment discontinuation because of adverse events was highest in the first year.

“We have been surprised at how long the remissions have lasted with ibrutinib,” said Dr. Barr. “Even with up to 8 years of follow-up, we have yet to reach the median progression free-survival,” he noted.

“These data, in combination with other data sets, highlight the impact that ibrutinib and other BTK inhibitors have had in treating CLL,” said Dr. Barr. “Patients are living longer and avoiding the side effects of chemotherapy in the era of novel agent use,” he said.

However, research gaps remain, Dr. Barr noted. “We need to continue following these patients over time given the length of the remissions. Additionally, we need to continue investigating novel combinations,” he said. Such studies will help us understand the benefit of fixed durations regimens compared to single agent BTK inhibitors,” he emphasized.
 

Safety and efficacy remain promising

“Ibrutinib was approved for the treatment of CLL, but only in the relapsed setting,” Susan M. O’Brien, MD, of the University of California, Irvine, said in an interview. “This trial was important because it led to the approval of ibrutinib in the front-line setting, making it the first, and at the time, only, small molecule that could be used upfront,” said Dr. O’Brien, who was not involved with the study.

“The initial results were certainly not surprising, as given the efficacy of ibrutinib in the relapsed setting, it seemed likely that it would produce a longer PFS than chlorambucil,” said Dr. O’Brien. “What may not have been expected though, is the incredible durability of these responses with ibrutinib,” she noted.

The clinical implications of the long-term data are that ibrutinib is producing “very durable remissions with continuous therapy,” Dr. O’Brien said. “There are no late safety signals and most side effects diminish with time. However, hypertension and atrial fibrillation continue to occur, so continued monitoring of blood pressure in these patients is important,” she emphasized.

Minor, but annoying, side effects are not infrequent early on with ibrutinib and may present a barrier to use for some patients, Dr. O’Brien said. “Some side effects may be overcome with temporary pauses of drug or dose reduction,” she noted. However, “it is important for patients to be aware that most of these side effects will completely abate with time,” she added.  

“The main limitation of this trial was that the comparison was to a rather weak chemotherapy agent, albeit it one frequently used in older patients, particularly in Europe,” said Dr. O’Brien. “Nevertheless, two subsequent trials comparing ibrutinib (with or without rituximab) with either BR [bendamustine/rituximab] or FCR [fludarabine/cyclophosphamide/rituximab] showed a longer PFS with ibrutinib, as compared to that seen with either chemoimmunotherapy regimen,” she said.

The study was supported by Pharmacyclics LLC, an AbbVie company. Dr. Barr collaborated with sponsor AbbVie on the study design, and disclosed relationships with companies including AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Genentech, Gilead, Janssen, MEI Pharma, Merck, Morphosys, Pharmacyclics LLC (an AbbVie company), Seattle Genetics, and TG Therapeutics. Dr. O’Brien had no relevant financial conflicts to disclose.

The Diagnosis: Granulomatous Cheilitis

A punch biopsy of the lip revealed a noncaseating microgranuloma in the submucosa with modest submucosal vascular ectasia and perivascular lymphoplasmacytic infiltrates (Figure). Comprehensive metabolic panel, complete blood cell count, angiotensinconverting enzyme (ACE) levels, and inflammatory markers (ie, erythrocyte sedimentation rate, C-reactive protein) all were within reference range. A serum environmental allergen test was negative except for ragweed. Levels of complements—C1 esterase inhibitor (C1-INH) antigen and function, C1q, C3, and C4—and antinuclear antibodies all were normal. Chest radiography was unremarkable. In lieu of a colonoscopy, a fecal calprotectin obtained by gastroenterology was normal. Given the clinical presentation and histopathologic findings, a diagnosis of granulomatous cheilitis (GC) was made.

Granulomatous cheilitis (also known as Miescher cheilitis) is an idiopathic condition characterized by recurrent or persistent swelling of one or both lips. Granulomatous cheilitis usually is an isolated finding but can occur in the setting of Melkersson-Rosenthal syndrome, which refers to a triad of orofacial swelling, facial paralysis, and fissured tongue. Orofacial granulomatosis is a unifying term for any orofacial swelling associated with histologic findings of noncaseating granulomas without evidence of a systemic disease.

Granulomatous cheilitis is a rare disease that most commonly occurs in young adults without any sex predilection.¹ The etiology still is unknown, but genetic predisposition, idiopathic influx of inflammatory cells, sensitivity to food or dental materials, and infections have been implicated.² Granulomatous cheilitis initially presents as soft, nonerythematous, nontender swelling affecting one or both lips. The first episode usually resolves in hours or days, but the frequency and duration of the attacks may increase until the swelling becomes persistent and indurated.³ Granulomatous cheilitis often is a diagnosis of exclusion. A tissue biopsy may show noncaseating epithelioid and multinucleated giant cells with associated lymphedema and fibrosis⁴; however, histologic findings may be nonspecific, especially early in the disease course, and may be indistinguishable from those of other granulomatous diseases such as sarcoidosis and Crohn disease (CD).⁵

Lip swelling may be an oral manifestation of CD. Compared with GC, however, CD more commonly is associated with ulcerations, buccal sulcus involvement, abnormalities in complete blood cell count such as anemia and thrombocytosis, and elevated C-reactive protein and erythrocyte sedimentation rate. Although infrequent, GC may coincide with or precede the onset of CD.⁶ Thus, a detailed gastrointestinal history and appropriate laboratory tests are needed to rule out undiagnosed CD. Nevertheless, performing a routine colonoscopy in the absence of gastrointestinal symptoms is debated.^7,8

Sarcoidosis is a systemic granulomatous disease that can have oral involvement in the form of edema, nodules, or ulcers. Oral sarcoidosis usually occurs in patients with chronic multisystemic sarcoidosis and likely is accompanied by pulmonary manifestations such as hilar adenopathy and infiltrates on chest radiography, which are found in more than 90% of patients with sarcoidosis.^9,10 A diagnosis of sarcoidosis is additionally supported by other organ involvement such as the joints, skin, or eyes, as well as elevated ACE and calcium levels.

Foreign bodies are another source of granulomatous inflammation and may present with nonspecific findings of swelling, masses, erythema, pain, or ulceration in oral tissues.¹¹ Foreign body reactions to dental materials, retained sutures, and cosmetic fillers have been reported.^12-14 In many cases, the foreign material is evident on biopsy.

Angioedema may mimic GC and should be excluded before more extensive testing is done, as it can result in life-threatening respiratory compromise. Numerous etiologies of angioedema have been identified including allergens, acquired or hereditary C1-INH deficiency, nonsteroidal anti-inflammatory drugs, ACE inhibitors, autoimmune disorders, and chronic infections.¹⁵ Patients with angioedema may have abnormalities in C4 and C1-INH levels or report certain medication use, allergen exposure, or family history of unexplained recurrent swellings or gastrointestinal symptoms.

There currently is no established treatment of GC due to the unclear etiology and unpredictable clinical course that can lead to spontaneous remissions or frequent recurrences. Corticosteroids administered systemically, intralesionally, or topically have been the mainstay treatment of GC.² In particular, intralesional injections have been reported as effective in reducing swelling and preventing recurrences in several studies.^16,17 Numerous other treatments have been reported in the literature with inconsistent outcomes, including antibiotics such as minocycline, metronidazole, and roxithromycin; clofazimine; thalidomide; immunomodulators such as tumor necrosis factor inhibitors and methotrexate; fumaric acid esters; and cheiloplasty in severe cases.16 Our patient showed near-complete resolution of the lip swelling after a single intralesional injection of 0.5 cc of triamcinolone acetonide 5 mg/mL. The patient has since received 5 additional maintenance injections of 0.1 to 0.2 cc of triamcinolone acetonide 2.5 to 5 mg/mL spaced 2 to 4 months apart with excellent control of the lip swelling, which the patient feels has resolved. We anticipate that repeated injections and monitoring of recurrences may be required for long-term remission.

The Diagnosis: Granulomatous Cheilitis

A punch biopsy of the lip revealed a noncaseating microgranuloma in the submucosa with modest submucosal vascular ectasia and perivascular lymphoplasmacytic infiltrates (Figure). Comprehensive metabolic panel, complete blood cell count, angiotensinconverting enzyme (ACE) levels, and inflammatory markers (ie, erythrocyte sedimentation rate, C-reactive protein) all were within reference range. A serum environmental allergen test was negative except for ragweed. Levels of complements—C1 esterase inhibitor (C1-INH) antigen and function, C1q, C3, and C4—and antinuclear antibodies all were normal. Chest radiography was unremarkable. In lieu of a colonoscopy, a fecal calprotectin obtained by gastroenterology was normal. Given the clinical presentation and histopathologic findings, a diagnosis of granulomatous cheilitis (GC) was made.

Granulomatous cheilitis (also known as Miescher cheilitis) is an idiopathic condition characterized by recurrent or persistent swelling of one or both lips. Granulomatous cheilitis usually is an isolated finding but can occur in the setting of Melkersson-Rosenthal syndrome, which refers to a triad of orofacial swelling, facial paralysis, and fissured tongue. Orofacial granulomatosis is a unifying term for any orofacial swelling associated with histologic findings of noncaseating granulomas without evidence of a systemic disease.

Granulomatous cheilitis is a rare disease that most commonly occurs in young adults without any sex predilection.¹ The etiology still is unknown, but genetic predisposition, idiopathic influx of inflammatory cells, sensitivity to food or dental materials, and infections have been implicated.² Granulomatous cheilitis initially presents as soft, nonerythematous, nontender swelling affecting one or both lips. The first episode usually resolves in hours or days, but the frequency and duration of the attacks may increase until the swelling becomes persistent and indurated.³ Granulomatous cheilitis often is a diagnosis of exclusion. A tissue biopsy may show noncaseating epithelioid and multinucleated giant cells with associated lymphedema and fibrosis⁴; however, histologic findings may be nonspecific, especially early in the disease course, and may be indistinguishable from those of other granulomatous diseases such as sarcoidosis and Crohn disease (CD).⁵

Lip swelling may be an oral manifestation of CD. Compared with GC, however, CD more commonly is associated with ulcerations, buccal sulcus involvement, abnormalities in complete blood cell count such as anemia and thrombocytosis, and elevated C-reactive protein and erythrocyte sedimentation rate. Although infrequent, GC may coincide with or precede the onset of CD.⁶ Thus, a detailed gastrointestinal history and appropriate laboratory tests are needed to rule out undiagnosed CD. Nevertheless, performing a routine colonoscopy in the absence of gastrointestinal symptoms is debated.^7,8

Sarcoidosis is a systemic granulomatous disease that can have oral involvement in the form of edema, nodules, or ulcers. Oral sarcoidosis usually occurs in patients with chronic multisystemic sarcoidosis and likely is accompanied by pulmonary manifestations such as hilar adenopathy and infiltrates on chest radiography, which are found in more than 90% of patients with sarcoidosis.^9,10 A diagnosis of sarcoidosis is additionally supported by other organ involvement such as the joints, skin, or eyes, as well as elevated ACE and calcium levels.

Foreign bodies are another source of granulomatous inflammation and may present with nonspecific findings of swelling, masses, erythema, pain, or ulceration in oral tissues.¹¹ Foreign body reactions to dental materials, retained sutures, and cosmetic fillers have been reported.^12-14 In many cases, the foreign material is evident on biopsy.

Angioedema may mimic GC and should be excluded before more extensive testing is done, as it can result in life-threatening respiratory compromise. Numerous etiologies of angioedema have been identified including allergens, acquired or hereditary C1-INH deficiency, nonsteroidal anti-inflammatory drugs, ACE inhibitors, autoimmune disorders, and chronic infections.¹⁵ Patients with angioedema may have abnormalities in C4 and C1-INH levels or report certain medication use, allergen exposure, or family history of unexplained recurrent swellings or gastrointestinal symptoms.

There currently is no established treatment of GC due to the unclear etiology and unpredictable clinical course that can lead to spontaneous remissions or frequent recurrences. Corticosteroids administered systemically, intralesionally, or topically have been the mainstay treatment of GC.² In particular, intralesional injections have been reported as effective in reducing swelling and preventing recurrences in several studies.^16,17 Numerous other treatments have been reported in the literature with inconsistent outcomes, including antibiotics such as minocycline, metronidazole, and roxithromycin; clofazimine; thalidomide; immunomodulators such as tumor necrosis factor inhibitors and methotrexate; fumaric acid esters; and cheiloplasty in severe cases.16 Our patient showed near-complete resolution of the lip swelling after a single intralesional injection of 0.5 cc of triamcinolone acetonide 5 mg/mL. The patient has since received 5 additional maintenance injections of 0.1 to 0.2 cc of triamcinolone acetonide 2.5 to 5 mg/mL spaced 2 to 4 months apart with excellent control of the lip swelling, which the patient feels has resolved. We anticipate that repeated injections and monitoring of recurrences may be required for long-term remission.

The Diagnosis: Granulomatous Cheilitis

A punch biopsy of the lip revealed a noncaseating microgranuloma in the submucosa with modest submucosal vascular ectasia and perivascular lymphoplasmacytic infiltrates (Figure). Comprehensive metabolic panel, complete blood cell count, angiotensinconverting enzyme (ACE) levels, and inflammatory markers (ie, erythrocyte sedimentation rate, C-reactive protein) all were within reference range. A serum environmental allergen test was negative except for ragweed. Levels of complements—C1 esterase inhibitor (C1-INH) antigen and function, C1q, C3, and C4—and antinuclear antibodies all were normal. Chest radiography was unremarkable. In lieu of a colonoscopy, a fecal calprotectin obtained by gastroenterology was normal. Given the clinical presentation and histopathologic findings, a diagnosis of granulomatous cheilitis (GC) was made.

Granulomatous cheilitis (also known as Miescher cheilitis) is an idiopathic condition characterized by recurrent or persistent swelling of one or both lips. Granulomatous cheilitis usually is an isolated finding but can occur in the setting of Melkersson-Rosenthal syndrome, which refers to a triad of orofacial swelling, facial paralysis, and fissured tongue. Orofacial granulomatosis is a unifying term for any orofacial swelling associated with histologic findings of noncaseating granulomas without evidence of a systemic disease.

Granulomatous cheilitis is a rare disease that most commonly occurs in young adults without any sex predilection.¹ The etiology still is unknown, but genetic predisposition, idiopathic influx of inflammatory cells, sensitivity to food or dental materials, and infections have been implicated.² Granulomatous cheilitis initially presents as soft, nonerythematous, nontender swelling affecting one or both lips. The first episode usually resolves in hours or days, but the frequency and duration of the attacks may increase until the swelling becomes persistent and indurated.³ Granulomatous cheilitis often is a diagnosis of exclusion. A tissue biopsy may show noncaseating epithelioid and multinucleated giant cells with associated lymphedema and fibrosis⁴; however, histologic findings may be nonspecific, especially early in the disease course, and may be indistinguishable from those of other granulomatous diseases such as sarcoidosis and Crohn disease (CD).⁵

Lip swelling may be an oral manifestation of CD. Compared with GC, however, CD more commonly is associated with ulcerations, buccal sulcus involvement, abnormalities in complete blood cell count such as anemia and thrombocytosis, and elevated C-reactive protein and erythrocyte sedimentation rate. Although infrequent, GC may coincide with or precede the onset of CD.⁶ Thus, a detailed gastrointestinal history and appropriate laboratory tests are needed to rule out undiagnosed CD. Nevertheless, performing a routine colonoscopy in the absence of gastrointestinal symptoms is debated.^7,8

Sarcoidosis is a systemic granulomatous disease that can have oral involvement in the form of edema, nodules, or ulcers. Oral sarcoidosis usually occurs in patients with chronic multisystemic sarcoidosis and likely is accompanied by pulmonary manifestations such as hilar adenopathy and infiltrates on chest radiography, which are found in more than 90% of patients with sarcoidosis.^9,10 A diagnosis of sarcoidosis is additionally supported by other organ involvement such as the joints, skin, or eyes, as well as elevated ACE and calcium levels.

Foreign bodies are another source of granulomatous inflammation and may present with nonspecific findings of swelling, masses, erythema, pain, or ulceration in oral tissues.¹¹ Foreign body reactions to dental materials, retained sutures, and cosmetic fillers have been reported.^12-14 In many cases, the foreign material is evident on biopsy.

Angioedema may mimic GC and should be excluded before more extensive testing is done, as it can result in life-threatening respiratory compromise. Numerous etiologies of angioedema have been identified including allergens, acquired or hereditary C1-INH deficiency, nonsteroidal anti-inflammatory drugs, ACE inhibitors, autoimmune disorders, and chronic infections.¹⁵ Patients with angioedema may have abnormalities in C4 and C1-INH levels or report certain medication use, allergen exposure, or family history of unexplained recurrent swellings or gastrointestinal symptoms.

There currently is no established treatment of GC due to the unclear etiology and unpredictable clinical course that can lead to spontaneous remissions or frequent recurrences. Corticosteroids administered systemically, intralesionally, or topically have been the mainstay treatment of GC.² In particular, intralesional injections have been reported as effective in reducing swelling and preventing recurrences in several studies.^16,17 Numerous other treatments have been reported in the literature with inconsistent outcomes, including antibiotics such as minocycline, metronidazole, and roxithromycin; clofazimine; thalidomide; immunomodulators such as tumor necrosis factor inhibitors and methotrexate; fumaric acid esters; and cheiloplasty in severe cases.16 Our patient showed near-complete resolution of the lip swelling after a single intralesional injection of 0.5 cc of triamcinolone acetonide 5 mg/mL. The patient has since received 5 additional maintenance injections of 0.1 to 0.2 cc of triamcinolone acetonide 2.5 to 5 mg/mL spaced 2 to 4 months apart with excellent control of the lip swelling, which the patient feels has resolved. We anticipate that repeated injections and monitoring of recurrences may be required for long-term remission.

The Food and Drug Administration has approved tapinarof cream, 1%, a steroid-free topical cream applied once a day, for the treatment of mild, moderate, or severe plaque psoriasis in adults, the manufacturer announced.

Tapinarof is an aryl hydrocarbon receptor agonist and is the first FDA-approved steroid-free topical medication in this class, according to a press release from the manufacturer, Dermavant.

Approval was based on results of three studies in a phase 3 clinical trial program (PSOARING 1, PSOARING 2), and an open-label extension study, (PSOARING 3), the company release said. In PSOARING 1 and 2, approximately 1,000 adults aged 18-75 years (median age, 51 years) with plaque psoriasis were randomized to once-daily topical tapinarof or placebo for up to 12 weeks; 85% were White and 57% were men. The study findings were published in the New England Journal of Medicine in December 2021.

The primary endpoint for both trials was the proportion of patients who achieved Physician Global Assessment (PGA) scores score of “clear” (0) or “almost clear” (1) and improvement of at least two grades from baseline.

After 12 weeks, 36% of the patients in PSOARING 1 and 40% in PSOARING 2 who received tapinarof met the primary outcome, compared with 6% of patients on placebo (P < .001 for both studies). Of these, a total of 73 patients from both studies who achieved PGA scores of 0 were entered in PSOARING 3, a 40-week open-label extension study, in which they stopped tapinarof treatment and retained PGA scores of 0 or 1 for approximately 4 months off treatment. An additional 312 patients who were enrolled in the PSOARING 3 extension study achieved PGA scores of 0 at least once during the study period, with “remittive” effects lasting a mean of 130 days off of treatment.

In addition, patients who received tapinarof in the PSOARING 1 and 2 studies showed significant improvement from baseline, compared with patients on placebo, across a range of secondary endpoints including a 75% or greater improvement in Psoriasis Area and Severity Index score (PASI 75).

In PSOARING 1, and 2, respectively, 36.1% and 47.6% of those on tapinarof achieved a PASI 75 response at week 12, compared with 10.2% and 6.9% of those on the vehicle (P < .001 for both).

Across all three studies, the majority adverse events were mild to moderate, and limited to the application site.

The most common adverse events reported by patients in the tapinarof groups were folliculitis, nasopharyngitis, and contact dermatitis. Headaches were more common among those treated with tapinarof than those on vehicle in the studies (3.8% vs. 2.4% in PSOARING 1, and 3.8% vs. 0.6% in PSOARING 2), leading to only three treatment discontinuations.

At the end of the PSOARING 3 study (at either week 40 or early termination), 599 participants responded to satisfaction questionnaires. Of these, 83.6% said they were satisfied with the results of tapinarof treatment, and 81.7% said it was more effective than previous topical treatments they had used, according to the company’s release.

Tapinarof cream can be used on all areas of the body, including the face, skin folds, neck, genitalia, anal crux, inflammatory areas, and axillae, according to the company release.

Full prescribing information is available here.

The Food and Drug Administration has approved tapinarof cream, 1%, a steroid-free topical cream applied once a day, for the treatment of mild, moderate, or severe plaque psoriasis in adults, the manufacturer announced.

Tapinarof is an aryl hydrocarbon receptor agonist and is the first FDA-approved steroid-free topical medication in this class, according to a press release from the manufacturer, Dermavant.

Approval was based on results of three studies in a phase 3 clinical trial program (PSOARING 1, PSOARING 2), and an open-label extension study, (PSOARING 3), the company release said. In PSOARING 1 and 2, approximately 1,000 adults aged 18-75 years (median age, 51 years) with plaque psoriasis were randomized to once-daily topical tapinarof or placebo for up to 12 weeks; 85% were White and 57% were men. The study findings were published in the New England Journal of Medicine in December 2021.

The primary endpoint for both trials was the proportion of patients who achieved Physician Global Assessment (PGA) scores score of “clear” (0) or “almost clear” (1) and improvement of at least two grades from baseline.

After 12 weeks, 36% of the patients in PSOARING 1 and 40% in PSOARING 2 who received tapinarof met the primary outcome, compared with 6% of patients on placebo (P < .001 for both studies). Of these, a total of 73 patients from both studies who achieved PGA scores of 0 were entered in PSOARING 3, a 40-week open-label extension study, in which they stopped tapinarof treatment and retained PGA scores of 0 or 1 for approximately 4 months off treatment. An additional 312 patients who were enrolled in the PSOARING 3 extension study achieved PGA scores of 0 at least once during the study period, with “remittive” effects lasting a mean of 130 days off of treatment.

In addition, patients who received tapinarof in the PSOARING 1 and 2 studies showed significant improvement from baseline, compared with patients on placebo, across a range of secondary endpoints including a 75% or greater improvement in Psoriasis Area and Severity Index score (PASI 75).

In PSOARING 1, and 2, respectively, 36.1% and 47.6% of those on tapinarof achieved a PASI 75 response at week 12, compared with 10.2% and 6.9% of those on the vehicle (P < .001 for both).

Across all three studies, the majority adverse events were mild to moderate, and limited to the application site.

The most common adverse events reported by patients in the tapinarof groups were folliculitis, nasopharyngitis, and contact dermatitis. Headaches were more common among those treated with tapinarof than those on vehicle in the studies (3.8% vs. 2.4% in PSOARING 1, and 3.8% vs. 0.6% in PSOARING 2), leading to only three treatment discontinuations.

At the end of the PSOARING 3 study (at either week 40 or early termination), 599 participants responded to satisfaction questionnaires. Of these, 83.6% said they were satisfied with the results of tapinarof treatment, and 81.7% said it was more effective than previous topical treatments they had used, according to the company’s release.

Tapinarof cream can be used on all areas of the body, including the face, skin folds, neck, genitalia, anal crux, inflammatory areas, and axillae, according to the company release.

Full prescribing information is available here.

The Food and Drug Administration has approved tapinarof cream, 1%, a steroid-free topical cream applied once a day, for the treatment of mild, moderate, or severe plaque psoriasis in adults, the manufacturer announced.

Tapinarof is an aryl hydrocarbon receptor agonist and is the first FDA-approved steroid-free topical medication in this class, according to a press release from the manufacturer, Dermavant.

Approval was based on results of three studies in a phase 3 clinical trial program (PSOARING 1, PSOARING 2), and an open-label extension study, (PSOARING 3), the company release said. In PSOARING 1 and 2, approximately 1,000 adults aged 18-75 years (median age, 51 years) with plaque psoriasis were randomized to once-daily topical tapinarof or placebo for up to 12 weeks; 85% were White and 57% were men. The study findings were published in the New England Journal of Medicine in December 2021.

The primary endpoint for both trials was the proportion of patients who achieved Physician Global Assessment (PGA) scores score of “clear” (0) or “almost clear” (1) and improvement of at least two grades from baseline.

After 12 weeks, 36% of the patients in PSOARING 1 and 40% in PSOARING 2 who received tapinarof met the primary outcome, compared with 6% of patients on placebo (P < .001 for both studies). Of these, a total of 73 patients from both studies who achieved PGA scores of 0 were entered in PSOARING 3, a 40-week open-label extension study, in which they stopped tapinarof treatment and retained PGA scores of 0 or 1 for approximately 4 months off treatment. An additional 312 patients who were enrolled in the PSOARING 3 extension study achieved PGA scores of 0 at least once during the study period, with “remittive” effects lasting a mean of 130 days off of treatment.

In addition, patients who received tapinarof in the PSOARING 1 and 2 studies showed significant improvement from baseline, compared with patients on placebo, across a range of secondary endpoints including a 75% or greater improvement in Psoriasis Area and Severity Index score (PASI 75).

In PSOARING 1, and 2, respectively, 36.1% and 47.6% of those on tapinarof achieved a PASI 75 response at week 12, compared with 10.2% and 6.9% of those on the vehicle (P < .001 for both).

Across all three studies, the majority adverse events were mild to moderate, and limited to the application site.

The most common adverse events reported by patients in the tapinarof groups were folliculitis, nasopharyngitis, and contact dermatitis. Headaches were more common among those treated with tapinarof than those on vehicle in the studies (3.8% vs. 2.4% in PSOARING 1, and 3.8% vs. 0.6% in PSOARING 2), leading to only three treatment discontinuations.

At the end of the PSOARING 3 study (at either week 40 or early termination), 599 participants responded to satisfaction questionnaires. Of these, 83.6% said they were satisfied with the results of tapinarof treatment, and 81.7% said it was more effective than previous topical treatments they had used, according to the company’s release.

Tapinarof cream can be used on all areas of the body, including the face, skin folds, neck, genitalia, anal crux, inflammatory areas, and axillae, according to the company release.

Full prescribing information is available here.

SAN DIEGO – Video and text messaging may not increase the proportion of people with inflammatory bowel disease (IBD) who get influenza vaccinations.

Although patients who received the messages expressed greater intention to get the vaccinations in a trial of the two methods, they didn’t follow through and get the shots, said Keren Appel, MD, a pediatric gastroenterologist at Children’s Hospital of Orange County in Orange, Calif.

“We found there was no difference in the uptake of the influenza vaccine between the two groups,” she said in an interview. Dr. Appel, who participated in the research while at Cedars-Sinai Medical Center in Los Angeles, presented the finding at the annual Digestive Diseases Week^® (DDW) 2022.

People with IBD run an increased risk of complications such as infection, bone fractures, and cancer, said Dr. Appel. Previous research has suggested many people with IBD lack understanding or awareness or are skeptical of immunizations.

A previous trial with text-based email reminders did not result in more immunizations, according to Dr. Appel, so she and her colleagues decided to try promoting health prevention with videos. With feedback from patients, they created a series of animations encouraging patients to get influenza, pneumococcal, and zoster vaccinations and screening for bone health and skin cancer.

They randomly assigned 511 to receive videos and 545 patients to receive texts as a control group. After 6 months, 345 patients remained in the text group and 322 remained in the video group. The two groups had similar demographics, health status, and preventive health behaviors. They were mostly educated White women whose IBD was in remission.

The percentage of those who got flu vaccines increased from 59% (for the 2018-2019 season) to 63% (for the 2019-2020 flu season) in the group that watched the videos. However this change did not quite reach statistical significance (P = .07). The change in the text group, from 55% to 57%, was also not significant (P = .23).

The subjects did express more intention to get flu vaccines. The percentage with this intention increased from 59 to 75 in the video group, and from 55 to 72 in the text group. Both changes were statistically significant (P < .001).

Intentions to receive pneumonia and shingles vaccines, and bone and skin cancer screening, were not statistically different between the groups.

The researchers looked at age, immunosuppression, gender, and education to see if these factors could predict who was most likely to get the flu vaccine, but the only significant predictor was having received a previous flu shot.

Dr. Appel speculated that the videos might have been more effective in a more racially diverse, less educated population, or one where fewer people had previously received vaccinations.

“While we didn’t see a difference in this study, I think it opens up a lot of other questions that we can explore and answer,” she said. “It’s possible that patients may not have a one size fits all on their response. Some may respond better to video. Some may respond to text. Some may need more frequent reminders. Some might need to hear it from their doctor directly.”

Session comoderator Alyse Bedell, PhD, an assistant professor of psychiatry and behavioral neuroscience at the University of Chicago, agreed that a different patient population might have responded differently. “A population that may have lower access to educational resources, or has less educational attainment, or may have fewer people in their communities that are already receiving vaccines – those I think are going to be the populations where we’re going to be more likely to see the effects of an intervention like this,” she said in an interview.

Neither Dr. Appel nor Dr. Bedell reported any relevant financial interests. The study was funded by Pfizer.

SAN DIEGO – Video and text messaging may not increase the proportion of people with inflammatory bowel disease (IBD) who get influenza vaccinations.

Although patients who received the messages expressed greater intention to get the vaccinations in a trial of the two methods, they didn’t follow through and get the shots, said Keren Appel, MD, a pediatric gastroenterologist at Children’s Hospital of Orange County in Orange, Calif.

“We found there was no difference in the uptake of the influenza vaccine between the two groups,” she said in an interview. Dr. Appel, who participated in the research while at Cedars-Sinai Medical Center in Los Angeles, presented the finding at the annual Digestive Diseases Week^® (DDW) 2022.

People with IBD run an increased risk of complications such as infection, bone fractures, and cancer, said Dr. Appel. Previous research has suggested many people with IBD lack understanding or awareness or are skeptical of immunizations.

A previous trial with text-based email reminders did not result in more immunizations, according to Dr. Appel, so she and her colleagues decided to try promoting health prevention with videos. With feedback from patients, they created a series of animations encouraging patients to get influenza, pneumococcal, and zoster vaccinations and screening for bone health and skin cancer.

They randomly assigned 511 to receive videos and 545 patients to receive texts as a control group. After 6 months, 345 patients remained in the text group and 322 remained in the video group. The two groups had similar demographics, health status, and preventive health behaviors. They were mostly educated White women whose IBD was in remission.

The percentage of those who got flu vaccines increased from 59% (for the 2018-2019 season) to 63% (for the 2019-2020 flu season) in the group that watched the videos. However this change did not quite reach statistical significance (P = .07). The change in the text group, from 55% to 57%, was also not significant (P = .23).

The subjects did express more intention to get flu vaccines. The percentage with this intention increased from 59 to 75 in the video group, and from 55 to 72 in the text group. Both changes were statistically significant (P < .001).

Intentions to receive pneumonia and shingles vaccines, and bone and skin cancer screening, were not statistically different between the groups.

The researchers looked at age, immunosuppression, gender, and education to see if these factors could predict who was most likely to get the flu vaccine, but the only significant predictor was having received a previous flu shot.

Dr. Appel speculated that the videos might have been more effective in a more racially diverse, less educated population, or one where fewer people had previously received vaccinations.

“While we didn’t see a difference in this study, I think it opens up a lot of other questions that we can explore and answer,” she said. “It’s possible that patients may not have a one size fits all on their response. Some may respond better to video. Some may respond to text. Some may need more frequent reminders. Some might need to hear it from their doctor directly.”

Session comoderator Alyse Bedell, PhD, an assistant professor of psychiatry and behavioral neuroscience at the University of Chicago, agreed that a different patient population might have responded differently. “A population that may have lower access to educational resources, or has less educational attainment, or may have fewer people in their communities that are already receiving vaccines – those I think are going to be the populations where we’re going to be more likely to see the effects of an intervention like this,” she said in an interview.

Neither Dr. Appel nor Dr. Bedell reported any relevant financial interests. The study was funded by Pfizer.

SAN DIEGO – Video and text messaging may not increase the proportion of people with inflammatory bowel disease (IBD) who get influenza vaccinations.

Although patients who received the messages expressed greater intention to get the vaccinations in a trial of the two methods, they didn’t follow through and get the shots, said Keren Appel, MD, a pediatric gastroenterologist at Children’s Hospital of Orange County in Orange, Calif.

“We found there was no difference in the uptake of the influenza vaccine between the two groups,” she said in an interview. Dr. Appel, who participated in the research while at Cedars-Sinai Medical Center in Los Angeles, presented the finding at the annual Digestive Diseases Week^® (DDW) 2022.

People with IBD run an increased risk of complications such as infection, bone fractures, and cancer, said Dr. Appel. Previous research has suggested many people with IBD lack understanding or awareness or are skeptical of immunizations.

A previous trial with text-based email reminders did not result in more immunizations, according to Dr. Appel, so she and her colleagues decided to try promoting health prevention with videos. With feedback from patients, they created a series of animations encouraging patients to get influenza, pneumococcal, and zoster vaccinations and screening for bone health and skin cancer.

They randomly assigned 511 to receive videos and 545 patients to receive texts as a control group. After 6 months, 345 patients remained in the text group and 322 remained in the video group. The two groups had similar demographics, health status, and preventive health behaviors. They were mostly educated White women whose IBD was in remission.

The percentage of those who got flu vaccines increased from 59% (for the 2018-2019 season) to 63% (for the 2019-2020 flu season) in the group that watched the videos. However this change did not quite reach statistical significance (P = .07). The change in the text group, from 55% to 57%, was also not significant (P = .23).

The subjects did express more intention to get flu vaccines. The percentage with this intention increased from 59 to 75 in the video group, and from 55 to 72 in the text group. Both changes were statistically significant (P < .001).

Intentions to receive pneumonia and shingles vaccines, and bone and skin cancer screening, were not statistically different between the groups.

The researchers looked at age, immunosuppression, gender, and education to see if these factors could predict who was most likely to get the flu vaccine, but the only significant predictor was having received a previous flu shot.

Dr. Appel speculated that the videos might have been more effective in a more racially diverse, less educated population, or one where fewer people had previously received vaccinations.

“While we didn’t see a difference in this study, I think it opens up a lot of other questions that we can explore and answer,” she said. “It’s possible that patients may not have a one size fits all on their response. Some may respond better to video. Some may respond to text. Some may need more frequent reminders. Some might need to hear it from their doctor directly.”

Session comoderator Alyse Bedell, PhD, an assistant professor of psychiatry and behavioral neuroscience at the University of Chicago, agreed that a different patient population might have responded differently. “A population that may have lower access to educational resources, or has less educational attainment, or may have fewer people in their communities that are already receiving vaccines – those I think are going to be the populations where we’re going to be more likely to see the effects of an intervention like this,” she said in an interview.

Neither Dr. Appel nor Dr. Bedell reported any relevant financial interests. The study was funded by Pfizer.

Male breast cancer is linked to infertility, according to a new case-control study from the Institute of Cancer Research in London. The report follows other studies that generally failed to identify a statistically significant association, but the resources of Great Britain’s National Health Service made it possible to achieve greater power than previous efforts.

“It’s a very difficult disease to study because it’s about 100 times rarer than female breast cancer. To do the equivalent study, you either have to make your study 100 times bigger, or think laterally and approach it a different way. (That’s) why we did a case control study where you identify the cases and find controls, rather than wait for men to develop breast cancer,” said Michael Edwin Jones, PhD, the lead author of the study, which was published online in Breast Cancer Research.

The new study found that men who self-reported infertility had a doubled risk of breast cancer, while there was no difference if the fertility was linked to their female partner. Sex hormones are known to play a key role in female breast cancer, and they have a suspected role in male breast cancer as well, though it’s hard to pin down because there is no concentrated source of exposure like hormone therapy or activity from the ovary to cause spiked levels. “It’s more subtle in men, but there’s a reason to think it’s important,” Dr. Jones said.

Although the results hint at a possible role of sex hormones, the research can’t confirm that. Blood draws were taken from participants, but many were conducted after treatment had begun, leading to inconsistent results. Dr. Jones called for more research into biological mechanisms that might explain the increased risk, and suggested that such efforts could lead to a better understanding of breast cancer overall, since the disease in men is not effected by factors like pregnancy and menopause.

Historically, few clinical trials for breast cancer drugs included men, and this has resulted in few approved treatments. However, the impact of breast cancer on men is increasingly being recognized, and most such trials now accept male patients. The Food and Drug Administration has even produced a guidance document for inclusion of men in development of breast cancer drugs, which states that men should be excluded only if there is a clear scientific rationale. When there are too few male participants to draw direct conclusions, it may be possible to extrapolate findings in women to men for FDA approval, provided the mechanism of action suggests that there should be no difference in efficacy.

The Breast Cancer Now study included 1,998 cases and 1,597 controls, who were asked about infertility and whether they had children. Men with male-origin infertility had a higher risk of breast cancer (odds ratio, 2.03; 95% confidence interval [CI], 1.18-3.49), but not men who reported female-origin infertility (OR, 0.86; 95% CI, 0.51-1.45). There was also a heightened risk among men who had not fathered children versus those who had (OR, 1.50; 95% CI, 1.21-1.86).

The association was statistically significant for invasive tumors (OR, 1.96; P = .02), but only a trend was observed for in situ breast cancer (OR, 1.72; P = .39). A possible explanation is that diagnosis of in situ breast cancer is less common than invasive cancer in men, which could have led to the study being underpowered. “Unfortunately, there were too few in-situ breast cancers to allow us to say anything definitive,” said Dr. Jones.

Dr. Jones has no relevant financial disclosures. The study was funded by Breast Cancer Now.

Male breast cancer is linked to infertility, according to a new case-control study from the Institute of Cancer Research in London. The report follows other studies that generally failed to identify a statistically significant association, but the resources of Great Britain’s National Health Service made it possible to achieve greater power than previous efforts.

“It’s a very difficult disease to study because it’s about 100 times rarer than female breast cancer. To do the equivalent study, you either have to make your study 100 times bigger, or think laterally and approach it a different way. (That’s) why we did a case control study where you identify the cases and find controls, rather than wait for men to develop breast cancer,” said Michael Edwin Jones, PhD, the lead author of the study, which was published online in Breast Cancer Research.

The new study found that men who self-reported infertility had a doubled risk of breast cancer, while there was no difference if the fertility was linked to their female partner. Sex hormones are known to play a key role in female breast cancer, and they have a suspected role in male breast cancer as well, though it’s hard to pin down because there is no concentrated source of exposure like hormone therapy or activity from the ovary to cause spiked levels. “It’s more subtle in men, but there’s a reason to think it’s important,” Dr. Jones said.

Although the results hint at a possible role of sex hormones, the research can’t confirm that. Blood draws were taken from participants, but many were conducted after treatment had begun, leading to inconsistent results. Dr. Jones called for more research into biological mechanisms that might explain the increased risk, and suggested that such efforts could lead to a better understanding of breast cancer overall, since the disease in men is not effected by factors like pregnancy and menopause.

Historically, few clinical trials for breast cancer drugs included men, and this has resulted in few approved treatments. However, the impact of breast cancer on men is increasingly being recognized, and most such trials now accept male patients. The Food and Drug Administration has even produced a guidance document for inclusion of men in development of breast cancer drugs, which states that men should be excluded only if there is a clear scientific rationale. When there are too few male participants to draw direct conclusions, it may be possible to extrapolate findings in women to men for FDA approval, provided the mechanism of action suggests that there should be no difference in efficacy.

The Breast Cancer Now study included 1,998 cases and 1,597 controls, who were asked about infertility and whether they had children. Men with male-origin infertility had a higher risk of breast cancer (odds ratio, 2.03; 95% confidence interval [CI], 1.18-3.49), but not men who reported female-origin infertility (OR, 0.86; 95% CI, 0.51-1.45). There was also a heightened risk among men who had not fathered children versus those who had (OR, 1.50; 95% CI, 1.21-1.86).

The association was statistically significant for invasive tumors (OR, 1.96; P = .02), but only a trend was observed for in situ breast cancer (OR, 1.72; P = .39). A possible explanation is that diagnosis of in situ breast cancer is less common than invasive cancer in men, which could have led to the study being underpowered. “Unfortunately, there were too few in-situ breast cancers to allow us to say anything definitive,” said Dr. Jones.

Dr. Jones has no relevant financial disclosures. The study was funded by Breast Cancer Now.

Male breast cancer is linked to infertility, according to a new case-control study from the Institute of Cancer Research in London. The report follows other studies that generally failed to identify a statistically significant association, but the resources of Great Britain’s National Health Service made it possible to achieve greater power than previous efforts.

“It’s a very difficult disease to study because it’s about 100 times rarer than female breast cancer. To do the equivalent study, you either have to make your study 100 times bigger, or think laterally and approach it a different way. (That’s) why we did a case control study where you identify the cases and find controls, rather than wait for men to develop breast cancer,” said Michael Edwin Jones, PhD, the lead author of the study, which was published online in Breast Cancer Research.

The new study found that men who self-reported infertility had a doubled risk of breast cancer, while there was no difference if the fertility was linked to their female partner. Sex hormones are known to play a key role in female breast cancer, and they have a suspected role in male breast cancer as well, though it’s hard to pin down because there is no concentrated source of exposure like hormone therapy or activity from the ovary to cause spiked levels. “It’s more subtle in men, but there’s a reason to think it’s important,” Dr. Jones said.

Although the results hint at a possible role of sex hormones, the research can’t confirm that. Blood draws were taken from participants, but many were conducted after treatment had begun, leading to inconsistent results. Dr. Jones called for more research into biological mechanisms that might explain the increased risk, and suggested that such efforts could lead to a better understanding of breast cancer overall, since the disease in men is not effected by factors like pregnancy and menopause.

Historically, few clinical trials for breast cancer drugs included men, and this has resulted in few approved treatments. However, the impact of breast cancer on men is increasingly being recognized, and most such trials now accept male patients. The Food and Drug Administration has even produced a guidance document for inclusion of men in development of breast cancer drugs, which states that men should be excluded only if there is a clear scientific rationale. When there are too few male participants to draw direct conclusions, it may be possible to extrapolate findings in women to men for FDA approval, provided the mechanism of action suggests that there should be no difference in efficacy.

The Breast Cancer Now study included 1,998 cases and 1,597 controls, who were asked about infertility and whether they had children. Men with male-origin infertility had a higher risk of breast cancer (odds ratio, 2.03; 95% confidence interval [CI], 1.18-3.49), but not men who reported female-origin infertility (OR, 0.86; 95% CI, 0.51-1.45). There was also a heightened risk among men who had not fathered children versus those who had (OR, 1.50; 95% CI, 1.21-1.86).

The association was statistically significant for invasive tumors (OR, 1.96; P = .02), but only a trend was observed for in situ breast cancer (OR, 1.72; P = .39). A possible explanation is that diagnosis of in situ breast cancer is less common than invasive cancer in men, which could have led to the study being underpowered. “Unfortunately, there were too few in-situ breast cancers to allow us to say anything definitive,” said Dr. Jones.

Dr. Jones has no relevant financial disclosures. The study was funded by Breast Cancer Now.