SAN DIEGO — Multiple topical and systemic medications are safe for treating pregnant women with bacterial, viral, and fungal infections, a dermatologist told colleagues at the annual meeting of the American Academy of Dermatology. However, several drugs should be avoided or used with caution because of potential risks during pregnancy. 

When treating bacterial infections in pregnant women, there are many options, “especially for the sort of short-term antibiotic use that we tend to use for treating infections,” said Jenny Murase, MD, of the Palo Alto Foundation Medical Group and the University of California San Francisco.

During a presentation on treating infections in pregnant patients, she made the following recommendations for treating pyogenic infections: 

• Impetigo: First-line treatments are topical mupirocin, oral first-generation cephalosporins, and oral dicloxacillin.
• Cellulitis: Recommended treatments are oral or intravenous penicillin, oral first-generation cephalosporins, and oral dicloxacillin.
• Methicillin-resistant Staphylococcus aureus (MRSA): “Clindamycin is first-line, dependent on bacteria culture and sensitivities,” and because of its safety, “it’s a really good choice for a pregnant woman.” Dr. Murase said. However, be aware of potential inducible resistance and test for the erm gene, she said.
• Abscesses: Incision and drainage are recommended. “Whenever we’re managing a patient with a condition during pregnancy, we want to try to use nonmedications when possible,” Dr. Murase said. “No antibiotic is necessary unless the abscess is greater than 5 cm or if it’s greater than 2 cm with erythema around the abscess.”
• Tuberculosis: The best strategy is rifampin, but peripartum vitamin K prophylaxis for mother and fetus should be used, she said. 

General Infections

With regard to antibiotics to treat general infections — for instance, if a patient with atopic dermatitis has a secondary skin infection — Dr. Murase recommended first-line oral antibiotic therapy with penicillin, first-generation cephalosporins, or dicloxacillin. For second-line therapy, erythromycin is the preferred macrolide over azithromycin and clarithromycin, she said. 

She noted that there is an increased risk for atrial/ventricular septal defects and pyloric stenosis associated with the use of erythromycin when used during the first trimester of pregnancy. In addition, erythromycin estolate increases the risk of liver toxicity, while erythromycin base and erythromycin ethylsuccinate do not. 

Sulfonamides are a second-line line choice up until the third trimester. If given to a patient in the first trimester, she said, “make sure that they are supplementing with folic acid efficiently, at least 0.5 mg a day.” During the peripartum period they are contraindicated, as they pose a risk for hemolytic anemia, hyperbilirubinemia, and kernicterus.

The combination drug trimethoprim/sulfamethoxazole is a second-line choice for complicated infections because of the associated risk for low birth weight and prematurity, Dr. Murase said.

Quinolones are also a second-line option during pregnancy she said, and ciprofloxacin and norfloxacin have been studied the most. “If you have to choose a quinolone for a complicated infection in pregnancy, those would be the quinolones of choice,” Dr. Murase said.

Considering the bad reputation of tetracyclines in pregnancy, dermatologists may be surprised to learn that they are considered a second-line therapy up to 14 weeks’ gestation, she said. After that time, however, they’re contraindicated because of bone growth inhibition, teeth discoloration, and maternal hepatitis.


 

Fungal Infections

As for fungal infections, clotrimazole is the first choice for topical treatment of tinea corporis, followed by miconazole and then ketoconazole, according to Dr. Murase. There are limited data for topical terbinafine, naftifine, and ciclopirox during pregnancy she noted, but they are likely safe.

There is also limited data about these drugs when used for topical treatment of candidiasis during pregnancy. Nystatin is safe, but less effective than other options, Dr. Murase said. Other options include clotrimazole, miconazole, and ketoconazole, which, in animals exposed to high doses, have not been associated with defects, and topical gentian violet (0.5%-1% solution), she noted.

For topical treatment of tinea versicolor during pregnancy, limited application of clotrimazole or miconazole is considered safe, and zinc pyrithione soap or topical benzoyl peroxide soap can be used for more widespread areas. 

Dr. Murase recommended caution when using selenium sulfide since poisoning has been linked to miscarriages, she said. Limited application appears to be safe, “so make sure that the patient is using it on smaller body surface areas.”

As for systemic antifungal treatments, fluconazole, ketoconazole, and itraconazole should be avoided in pregnancy because of the risks of craniosynostosis, congenital heart defects, and skeletal anomalies, Dr. Murase said. However, she referred to a study that found no increased risk of congenital malformations with fluconazole during the first trimester, and a patient could be reassured if, for example, she was treated for a yeast infection before she knew she was pregnant, she said.

Griseofulvin is not recommended during pregnancy, but a 2020 study suggests that terbinafine is safe, she said. In that study, oral or topical terbinafine did not appear to be associated with an increased risk for spontaneous abortion or major malformations. “Certainly, we can wait until after the pregnancy to treat onychomycosis. But I have had situations that even in spite of regular topical therapy, pregnant patients needed to take some kind of oral agent” because of severe itching. 

Viral Infections

For herpes simplex, acyclovir is the top choice, and famciclovir and valacyclovir (Valtrex) are likely safe, but daily prophylaxis is not recommended during pregnancy, Dr. Murase said. 

Because of a lack of data, podofilox, cantharidin, and imiquimod for treating human papillomavirus (HPV) should be avoided, she said. Podophyllin is extremely dangerous in pregnancy and has been linked to maternal and fetal deaths, and malformations, and is contraindicated in pregnancy, she added.

Instead, liquid nitrogen is the treatment of choice for HPV in pregnant patients, she said. 

Trichloracetic acid is the treatment of choice for condylomata acuminata, and squaric acid or intralesional Candida antigen injection for periungual verrucas can be used, she said, and limited applications of salicylic acid are considered safe. 

Dr. Murase highlighted a 2014 paper that she coauthored on the safety of dermatologic medications during pregnancy, noting that an updated report will be published later this year.

Dr. Murase disclosed relationships with Regeneron and UCB (speaker), Sanofi/Regeneron and Bristol-Myers Squibb (advisory board), and UCB, AbbVie, and UpToDate (consulting). 
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Multiple topical and systemic medications are safe for treating pregnant women with bacterial, viral, and fungal infections, a dermatologist told colleagues at the annual meeting of the American Academy of Dermatology. However, several drugs should be avoided or used with caution because of potential risks during pregnancy. 

When treating bacterial infections in pregnant women, there are many options, “especially for the sort of short-term antibiotic use that we tend to use for treating infections,” said Jenny Murase, MD, of the Palo Alto Foundation Medical Group and the University of California San Francisco.

During a presentation on treating infections in pregnant patients, she made the following recommendations for treating pyogenic infections: 

• Impetigo: First-line treatments are topical mupirocin, oral first-generation cephalosporins, and oral dicloxacillin.
• Cellulitis: Recommended treatments are oral or intravenous penicillin, oral first-generation cephalosporins, and oral dicloxacillin.
• Methicillin-resistant Staphylococcus aureus (MRSA): “Clindamycin is first-line, dependent on bacteria culture and sensitivities,” and because of its safety, “it’s a really good choice for a pregnant woman.” Dr. Murase said. However, be aware of potential inducible resistance and test for the erm gene, she said.
• Abscesses: Incision and drainage are recommended. “Whenever we’re managing a patient with a condition during pregnancy, we want to try to use nonmedications when possible,” Dr. Murase said. “No antibiotic is necessary unless the abscess is greater than 5 cm or if it’s greater than 2 cm with erythema around the abscess.”
• Tuberculosis: The best strategy is rifampin, but peripartum vitamin K prophylaxis for mother and fetus should be used, she said. 

General Infections

With regard to antibiotics to treat general infections — for instance, if a patient with atopic dermatitis has a secondary skin infection — Dr. Murase recommended first-line oral antibiotic therapy with penicillin, first-generation cephalosporins, or dicloxacillin. For second-line therapy, erythromycin is the preferred macrolide over azithromycin and clarithromycin, she said. 

She noted that there is an increased risk for atrial/ventricular septal defects and pyloric stenosis associated with the use of erythromycin when used during the first trimester of pregnancy. In addition, erythromycin estolate increases the risk of liver toxicity, while erythromycin base and erythromycin ethylsuccinate do not. 

Sulfonamides are a second-line line choice up until the third trimester. If given to a patient in the first trimester, she said, “make sure that they are supplementing with folic acid efficiently, at least 0.5 mg a day.” During the peripartum period they are contraindicated, as they pose a risk for hemolytic anemia, hyperbilirubinemia, and kernicterus.

The combination drug trimethoprim/sulfamethoxazole is a second-line choice for complicated infections because of the associated risk for low birth weight and prematurity, Dr. Murase said.

Quinolones are also a second-line option during pregnancy she said, and ciprofloxacin and norfloxacin have been studied the most. “If you have to choose a quinolone for a complicated infection in pregnancy, those would be the quinolones of choice,” Dr. Murase said.

Considering the bad reputation of tetracyclines in pregnancy, dermatologists may be surprised to learn that they are considered a second-line therapy up to 14 weeks’ gestation, she said. After that time, however, they’re contraindicated because of bone growth inhibition, teeth discoloration, and maternal hepatitis.


 

Fungal Infections

As for fungal infections, clotrimazole is the first choice for topical treatment of tinea corporis, followed by miconazole and then ketoconazole, according to Dr. Murase. There are limited data for topical terbinafine, naftifine, and ciclopirox during pregnancy she noted, but they are likely safe.

There is also limited data about these drugs when used for topical treatment of candidiasis during pregnancy. Nystatin is safe, but less effective than other options, Dr. Murase said. Other options include clotrimazole, miconazole, and ketoconazole, which, in animals exposed to high doses, have not been associated with defects, and topical gentian violet (0.5%-1% solution), she noted.

For topical treatment of tinea versicolor during pregnancy, limited application of clotrimazole or miconazole is considered safe, and zinc pyrithione soap or topical benzoyl peroxide soap can be used for more widespread areas. 

Dr. Murase recommended caution when using selenium sulfide since poisoning has been linked to miscarriages, she said. Limited application appears to be safe, “so make sure that the patient is using it on smaller body surface areas.”

As for systemic antifungal treatments, fluconazole, ketoconazole, and itraconazole should be avoided in pregnancy because of the risks of craniosynostosis, congenital heart defects, and skeletal anomalies, Dr. Murase said. However, she referred to a study that found no increased risk of congenital malformations with fluconazole during the first trimester, and a patient could be reassured if, for example, she was treated for a yeast infection before she knew she was pregnant, she said.

Griseofulvin is not recommended during pregnancy, but a 2020 study suggests that terbinafine is safe, she said. In that study, oral or topical terbinafine did not appear to be associated with an increased risk for spontaneous abortion or major malformations. “Certainly, we can wait until after the pregnancy to treat onychomycosis. But I have had situations that even in spite of regular topical therapy, pregnant patients needed to take some kind of oral agent” because of severe itching. 

Viral Infections

For herpes simplex, acyclovir is the top choice, and famciclovir and valacyclovir (Valtrex) are likely safe, but daily prophylaxis is not recommended during pregnancy, Dr. Murase said. 

Because of a lack of data, podofilox, cantharidin, and imiquimod for treating human papillomavirus (HPV) should be avoided, she said. Podophyllin is extremely dangerous in pregnancy and has been linked to maternal and fetal deaths, and malformations, and is contraindicated in pregnancy, she added.

Instead, liquid nitrogen is the treatment of choice for HPV in pregnant patients, she said. 

Trichloracetic acid is the treatment of choice for condylomata acuminata, and squaric acid or intralesional Candida antigen injection for periungual verrucas can be used, she said, and limited applications of salicylic acid are considered safe. 

Dr. Murase highlighted a 2014 paper that she coauthored on the safety of dermatologic medications during pregnancy, noting that an updated report will be published later this year.

Dr. Murase disclosed relationships with Regeneron and UCB (speaker), Sanofi/Regeneron and Bristol-Myers Squibb (advisory board), and UCB, AbbVie, and UpToDate (consulting). 
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Multiple topical and systemic medications are safe for treating pregnant women with bacterial, viral, and fungal infections, a dermatologist told colleagues at the annual meeting of the American Academy of Dermatology. However, several drugs should be avoided or used with caution because of potential risks during pregnancy. 

When treating bacterial infections in pregnant women, there are many options, “especially for the sort of short-term antibiotic use that we tend to use for treating infections,” said Jenny Murase, MD, of the Palo Alto Foundation Medical Group and the University of California San Francisco.

During a presentation on treating infections in pregnant patients, she made the following recommendations for treating pyogenic infections: 

• Impetigo: First-line treatments are topical mupirocin, oral first-generation cephalosporins, and oral dicloxacillin.
• Cellulitis: Recommended treatments are oral or intravenous penicillin, oral first-generation cephalosporins, and oral dicloxacillin.
• Methicillin-resistant Staphylococcus aureus (MRSA): “Clindamycin is first-line, dependent on bacteria culture and sensitivities,” and because of its safety, “it’s a really good choice for a pregnant woman.” Dr. Murase said. However, be aware of potential inducible resistance and test for the erm gene, she said.
• Abscesses: Incision and drainage are recommended. “Whenever we’re managing a patient with a condition during pregnancy, we want to try to use nonmedications when possible,” Dr. Murase said. “No antibiotic is necessary unless the abscess is greater than 5 cm or if it’s greater than 2 cm with erythema around the abscess.”
• Tuberculosis: The best strategy is rifampin, but peripartum vitamin K prophylaxis for mother and fetus should be used, she said. 

General Infections

With regard to antibiotics to treat general infections — for instance, if a patient with atopic dermatitis has a secondary skin infection — Dr. Murase recommended first-line oral antibiotic therapy with penicillin, first-generation cephalosporins, or dicloxacillin. For second-line therapy, erythromycin is the preferred macrolide over azithromycin and clarithromycin, she said. 

She noted that there is an increased risk for atrial/ventricular septal defects and pyloric stenosis associated with the use of erythromycin when used during the first trimester of pregnancy. In addition, erythromycin estolate increases the risk of liver toxicity, while erythromycin base and erythromycin ethylsuccinate do not. 

Sulfonamides are a second-line line choice up until the third trimester. If given to a patient in the first trimester, she said, “make sure that they are supplementing with folic acid efficiently, at least 0.5 mg a day.” During the peripartum period they are contraindicated, as they pose a risk for hemolytic anemia, hyperbilirubinemia, and kernicterus.

The combination drug trimethoprim/sulfamethoxazole is a second-line choice for complicated infections because of the associated risk for low birth weight and prematurity, Dr. Murase said.

Quinolones are also a second-line option during pregnancy she said, and ciprofloxacin and norfloxacin have been studied the most. “If you have to choose a quinolone for a complicated infection in pregnancy, those would be the quinolones of choice,” Dr. Murase said.

Considering the bad reputation of tetracyclines in pregnancy, dermatologists may be surprised to learn that they are considered a second-line therapy up to 14 weeks’ gestation, she said. After that time, however, they’re contraindicated because of bone growth inhibition, teeth discoloration, and maternal hepatitis.


 

Fungal Infections

As for fungal infections, clotrimazole is the first choice for topical treatment of tinea corporis, followed by miconazole and then ketoconazole, according to Dr. Murase. There are limited data for topical terbinafine, naftifine, and ciclopirox during pregnancy she noted, but they are likely safe.

There is also limited data about these drugs when used for topical treatment of candidiasis during pregnancy. Nystatin is safe, but less effective than other options, Dr. Murase said. Other options include clotrimazole, miconazole, and ketoconazole, which, in animals exposed to high doses, have not been associated with defects, and topical gentian violet (0.5%-1% solution), she noted.

For topical treatment of tinea versicolor during pregnancy, limited application of clotrimazole or miconazole is considered safe, and zinc pyrithione soap or topical benzoyl peroxide soap can be used for more widespread areas. 

Dr. Murase recommended caution when using selenium sulfide since poisoning has been linked to miscarriages, she said. Limited application appears to be safe, “so make sure that the patient is using it on smaller body surface areas.”

As for systemic antifungal treatments, fluconazole, ketoconazole, and itraconazole should be avoided in pregnancy because of the risks of craniosynostosis, congenital heart defects, and skeletal anomalies, Dr. Murase said. However, she referred to a study that found no increased risk of congenital malformations with fluconazole during the first trimester, and a patient could be reassured if, for example, she was treated for a yeast infection before she knew she was pregnant, she said.

Griseofulvin is not recommended during pregnancy, but a 2020 study suggests that terbinafine is safe, she said. In that study, oral or topical terbinafine did not appear to be associated with an increased risk for spontaneous abortion or major malformations. “Certainly, we can wait until after the pregnancy to treat onychomycosis. But I have had situations that even in spite of regular topical therapy, pregnant patients needed to take some kind of oral agent” because of severe itching. 

Viral Infections

For herpes simplex, acyclovir is the top choice, and famciclovir and valacyclovir (Valtrex) are likely safe, but daily prophylaxis is not recommended during pregnancy, Dr. Murase said. 

Because of a lack of data, podofilox, cantharidin, and imiquimod for treating human papillomavirus (HPV) should be avoided, she said. Podophyllin is extremely dangerous in pregnancy and has been linked to maternal and fetal deaths, and malformations, and is contraindicated in pregnancy, she added.

Instead, liquid nitrogen is the treatment of choice for HPV in pregnant patients, she said. 

Trichloracetic acid is the treatment of choice for condylomata acuminata, and squaric acid or intralesional Candida antigen injection for periungual verrucas can be used, she said, and limited applications of salicylic acid are considered safe. 

Dr. Murase highlighted a 2014 paper that she coauthored on the safety of dermatologic medications during pregnancy, noting that an updated report will be published later this year.

Dr. Murase disclosed relationships with Regeneron and UCB (speaker), Sanofi/Regeneron and Bristol-Myers Squibb (advisory board), and UCB, AbbVie, and UpToDate (consulting). 
 

A version of this article appeared on Medscape.com.

Treatment with the investigational monoclonal antibody drug batoclimab significantly improved symptoms in patients with antibody-positive generalized myasthenia gravis, data from a new phase 3 study showed.

After 6 weeks of treatment, patients reported nearly 60% sustained improvement in daily activities and a rapid onset of action from batoclimab, a neonatal crystallizable fragment receptor (FcRn) antagonist.

The clinical effects and the extent of immunoglobulin G (IgG) reduction in this study were similar to those previously reported for efgartigimod and rozanolixizumab, two other FcRn antagonists, the investigators noted, adding that larger studies are needed to better understand the safety profile of batoclimab.

“While most generalized myasthenia gravis patients can achieve good disease control through conventional immunotherapy, there are still unmet needs with this disease,” said study investigator Chongbo Zhao, MD, National Center for Neurological Disorders, Huashan Rare Disease Centre, Department of Neurology, Huashan Hospital of Fudan University, Shanghai, China.

The findings were published online in JAMA Neurology.
 

Unmet Need

A rare chronic disease, myasthenia gravis is caused by autoantibodies that disrupt the neuromuscular junction, most commonly against the nicotinic acetylcholine receptor (AChR). This can cause a variety of symptoms, including difficulty swallowing, chewing, and talking, as well as severe, sometimes life-threatening, muscle weakness.

The estimated global prevalence of myasthenia gravis is 15-25 per 100,000, with cases doubling in the past 20 years.

Treatment for myasthenia gravis typically includes immune-suppressing drugs. But research suggests almost half of patients with generalized myasthenia gravis don’t achieve an adequate response or are intolerant to these treatments, and some therapies are costly or not readily accessible.

“Our treatment goal has evolved from saving patients to improving their quality of life, so we still need to explore safer and more effective novel treatment methods,” Dr. Zhao said.

Batoclimab is a fully humanized monoclonal IgG antibody that binds to FcRn and accelerates clearance of harmful IgG. A phase 2 trial provided preliminary evidence to support the efficacy of this agent in Chinese patients with generalized myasthenia gravis.

The current double-blind phase 3 trial included 132 adult patients (mean age, 44 years; 67% female) of Chinese Han ethnicity with generalized myasthenia gravis at 27 centers in China. Participants had a mean Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 8.4 at baseline, and all but one was positive for AChR or muscle-specific kinase (MuSK) antibodies.

The treatment group received weekly subcutaneous injections of batoclimab at 680 mg for 6 weeks, followed by 4 weeks of observation. The control group received a placebo with the same treatment and follow-up schedule.

All patients received standard of care in addition to the assigned treatment, but changes in dosage and/or dosing frequency were not permitted. Patients received a second cycle if they still required treatment.
 

Bests Placebo

Overall, 90% of participants completed all six doses in cycle 1. The second treatment cycle was conducted in 115 patients, with 88% completing all six doses.

Patients were evaluated at baseline and then weekly for MG-ADL, Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite, and the 15-item revised version of the Myasthenia Gravis Quality of Life.

Sustained MG-ADL improvement — the primary outcome — was significantly higher in the batoclimab group compared with placebo (58% vs 31%, respectively; odds ratio, 3.45; P = .001).

While the rate of sustained MG-ADL improvement with batoclimab was lower than that reported for efgartigimod (68%) in a previous trial, that was primarily because of the more stringent definition of sustained MG-ADL improvement (three-point reduction vs two-point reduction from baseline), investigators said.

In the current trial, batoclimab had a rapid onset of action, with scores diverging between the treatment and placebo groups as early as the second week of therapy.

In the second treatment cycle, batoclimab once again outperformed placebo in sustained MG-ADL improvement (63% vs 36%, respectively; P = .002).

Batoclimab also bested placebo on secondary outcomes, including sustained QMG improvement (64% vs 41%; P = .008) and percent of patients achieving minimal symptom expression (25% vs 5%; P = .004).

Results of all subgroup analyses, including by age groups, sex, body weight, body mass index, and MG Foundation of America clinical classification, were consistent with those of the main analysis. The efficacy of batoclimab was also supported by all sensitivity analyses, underscoring the robustness of results.

Batoclimab led to a rapid and sustained reduction in serum AChR antibody levels, with a median reduction of 81% at week 6.
 

Well Tolerated

On discontinuation of batoclimab, serum total IgG returned to a level comparable with the baseline after 4 weeks. Reversibility of the drug’s effect is important considering the risk for infection from prolonged immune suppression, the authors noted.

The rate of peripheral edema was significantly higher in the treatment than in the placebo groups (39% vs 5%), but all cases were mild or moderate and deemed not clinically significant. The treatment group also had higher rates of upper respiratory tract infections (36% vs 22%) and of urinary tract infections (19% vs 15%).

“Although the incidence of upper respiratory tract and urinary tract infections was higher in the batoclimab group numerically, these were mild infections that did not require special treatment, so this is not a concern,” said Dr. Zhao.

Plasma albumin levels in the batoclimab group decreased significantly throughout the treatment cycle, starting at week 1 and reaching a decline of up to 31% at week 6. These levels increased rapidly toward baseline after treatment discontinuation.

High cholesterol levels were noted in the batoclimab group, plateauing by week 6. But levels returned to near baseline levels within 4 weeks after the final dose, and there were no serious related adverse reactions.

The rate of headache was slightly higher in the treatment group (6% vs 5% for placebo). “This finding may seem minor but could potentially translate into improved adherence in daily practice settings,” the authors wrote.

In previous studies, the efficacy of FcRn inhibitors in the Asian population was only examined in subgroup analyses with limited subjects. Finding an effective FcRn antagonist for China and surrounding regions is particularly important “considering the high mortality rate in hospitalized generalized myasthenia gravis patients in China,” the researchers noted.

The trial included only two treatment cycles, although results of an open-label extension trial examining longer-term efficacy of batoclimab should be available by the end of this year, said Dr. Zhao.

The trial was also not designed to investigate long-term safety, particularly infections and cardiovascular events. Only one study subject was negative for AChR or MuSK antibodies, which prevented researchers from assessing the drug’s efficacy in this subpopulation.
 

Questions Remain

Commenting on the study, Fredrik Piehl, MD, PhD, professor of neurology, Karolinska Institute, Stockholm, Sweden , said that recent studies of the two other FcRn antagonists were short-term and had limited long-term data. “We don’t know how valuable they may be for continued treatment,” Dr. Piehl said.

It’s also unclear how this new treatment modality compares with existing and emerging drug strategies in terms of the long-term benefit-risk balance, he added.

The rate of adverse events with batoclimab was high compared with placebo in this study and higher than in earlier studies of efgartigimod, Dr. Piehl noted.

“In this study, almost twice as many reported adverse events in the active arm compared with controls, while these differences tended to be smaller in previously reported trials,” he said.

The trial was funded by Nona Biosciences (Suzhou). Dr. Zhao reported being a full-time employee of Nona Biosciences (Suzhou), a subsidiary of Harbour BioMed Inc. He also reported receiving advisory board/consultant fees from Nona Biosciences, Roche, Sanofi, and Zailab outside the submitted work. Dr. Piehl has received research grants from Janssen, Merck KGaA, and UCB; and fees for serving on DMC in clinical trials with Chugai, Lundbeck, and Roche; and preparation of expert witness statement for Novartis.

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

Treatment with the investigational monoclonal antibody drug batoclimab significantly improved symptoms in patients with antibody-positive generalized myasthenia gravis, data from a new phase 3 study showed.

After 6 weeks of treatment, patients reported nearly 60% sustained improvement in daily activities and a rapid onset of action from batoclimab, a neonatal crystallizable fragment receptor (FcRn) antagonist.

The clinical effects and the extent of immunoglobulin G (IgG) reduction in this study were similar to those previously reported for efgartigimod and rozanolixizumab, two other FcRn antagonists, the investigators noted, adding that larger studies are needed to better understand the safety profile of batoclimab.

“While most generalized myasthenia gravis patients can achieve good disease control through conventional immunotherapy, there are still unmet needs with this disease,” said study investigator Chongbo Zhao, MD, National Center for Neurological Disorders, Huashan Rare Disease Centre, Department of Neurology, Huashan Hospital of Fudan University, Shanghai, China.

The findings were published online in JAMA Neurology.
 

Unmet Need

A rare chronic disease, myasthenia gravis is caused by autoantibodies that disrupt the neuromuscular junction, most commonly against the nicotinic acetylcholine receptor (AChR). This can cause a variety of symptoms, including difficulty swallowing, chewing, and talking, as well as severe, sometimes life-threatening, muscle weakness.

The estimated global prevalence of myasthenia gravis is 15-25 per 100,000, with cases doubling in the past 20 years.

Treatment for myasthenia gravis typically includes immune-suppressing drugs. But research suggests almost half of patients with generalized myasthenia gravis don’t achieve an adequate response or are intolerant to these treatments, and some therapies are costly or not readily accessible.

“Our treatment goal has evolved from saving patients to improving their quality of life, so we still need to explore safer and more effective novel treatment methods,” Dr. Zhao said.

Batoclimab is a fully humanized monoclonal IgG antibody that binds to FcRn and accelerates clearance of harmful IgG. A phase 2 trial provided preliminary evidence to support the efficacy of this agent in Chinese patients with generalized myasthenia gravis.

The current double-blind phase 3 trial included 132 adult patients (mean age, 44 years; 67% female) of Chinese Han ethnicity with generalized myasthenia gravis at 27 centers in China. Participants had a mean Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 8.4 at baseline, and all but one was positive for AChR or muscle-specific kinase (MuSK) antibodies.

The treatment group received weekly subcutaneous injections of batoclimab at 680 mg for 6 weeks, followed by 4 weeks of observation. The control group received a placebo with the same treatment and follow-up schedule.

All patients received standard of care in addition to the assigned treatment, but changes in dosage and/or dosing frequency were not permitted. Patients received a second cycle if they still required treatment.
 

Bests Placebo

Overall, 90% of participants completed all six doses in cycle 1. The second treatment cycle was conducted in 115 patients, with 88% completing all six doses.

Patients were evaluated at baseline and then weekly for MG-ADL, Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite, and the 15-item revised version of the Myasthenia Gravis Quality of Life.

Sustained MG-ADL improvement — the primary outcome — was significantly higher in the batoclimab group compared with placebo (58% vs 31%, respectively; odds ratio, 3.45; P = .001).

While the rate of sustained MG-ADL improvement with batoclimab was lower than that reported for efgartigimod (68%) in a previous trial, that was primarily because of the more stringent definition of sustained MG-ADL improvement (three-point reduction vs two-point reduction from baseline), investigators said.

In the current trial, batoclimab had a rapid onset of action, with scores diverging between the treatment and placebo groups as early as the second week of therapy.

In the second treatment cycle, batoclimab once again outperformed placebo in sustained MG-ADL improvement (63% vs 36%, respectively; P = .002).

Batoclimab also bested placebo on secondary outcomes, including sustained QMG improvement (64% vs 41%; P = .008) and percent of patients achieving minimal symptom expression (25% vs 5%; P = .004).

Results of all subgroup analyses, including by age groups, sex, body weight, body mass index, and MG Foundation of America clinical classification, were consistent with those of the main analysis. The efficacy of batoclimab was also supported by all sensitivity analyses, underscoring the robustness of results.

Batoclimab led to a rapid and sustained reduction in serum AChR antibody levels, with a median reduction of 81% at week 6.
 

Well Tolerated

On discontinuation of batoclimab, serum total IgG returned to a level comparable with the baseline after 4 weeks. Reversibility of the drug’s effect is important considering the risk for infection from prolonged immune suppression, the authors noted.

The rate of peripheral edema was significantly higher in the treatment than in the placebo groups (39% vs 5%), but all cases were mild or moderate and deemed not clinically significant. The treatment group also had higher rates of upper respiratory tract infections (36% vs 22%) and of urinary tract infections (19% vs 15%).

“Although the incidence of upper respiratory tract and urinary tract infections was higher in the batoclimab group numerically, these were mild infections that did not require special treatment, so this is not a concern,” said Dr. Zhao.

Plasma albumin levels in the batoclimab group decreased significantly throughout the treatment cycle, starting at week 1 and reaching a decline of up to 31% at week 6. These levels increased rapidly toward baseline after treatment discontinuation.

High cholesterol levels were noted in the batoclimab group, plateauing by week 6. But levels returned to near baseline levels within 4 weeks after the final dose, and there were no serious related adverse reactions.

The rate of headache was slightly higher in the treatment group (6% vs 5% for placebo). “This finding may seem minor but could potentially translate into improved adherence in daily practice settings,” the authors wrote.

In previous studies, the efficacy of FcRn inhibitors in the Asian population was only examined in subgroup analyses with limited subjects. Finding an effective FcRn antagonist for China and surrounding regions is particularly important “considering the high mortality rate in hospitalized generalized myasthenia gravis patients in China,” the researchers noted.

The trial included only two treatment cycles, although results of an open-label extension trial examining longer-term efficacy of batoclimab should be available by the end of this year, said Dr. Zhao.

The trial was also not designed to investigate long-term safety, particularly infections and cardiovascular events. Only one study subject was negative for AChR or MuSK antibodies, which prevented researchers from assessing the drug’s efficacy in this subpopulation.
 

Questions Remain

Commenting on the study, Fredrik Piehl, MD, PhD, professor of neurology, Karolinska Institute, Stockholm, Sweden , said that recent studies of the two other FcRn antagonists were short-term and had limited long-term data. “We don’t know how valuable they may be for continued treatment,” Dr. Piehl said.

It’s also unclear how this new treatment modality compares with existing and emerging drug strategies in terms of the long-term benefit-risk balance, he added.

The rate of adverse events with batoclimab was high compared with placebo in this study and higher than in earlier studies of efgartigimod, Dr. Piehl noted.

“In this study, almost twice as many reported adverse events in the active arm compared with controls, while these differences tended to be smaller in previously reported trials,” he said.

The trial was funded by Nona Biosciences (Suzhou). Dr. Zhao reported being a full-time employee of Nona Biosciences (Suzhou), a subsidiary of Harbour BioMed Inc. He also reported receiving advisory board/consultant fees from Nona Biosciences, Roche, Sanofi, and Zailab outside the submitted work. Dr. Piehl has received research grants from Janssen, Merck KGaA, and UCB; and fees for serving on DMC in clinical trials with Chugai, Lundbeck, and Roche; and preparation of expert witness statement for Novartis.

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

Treatment with the investigational monoclonal antibody drug batoclimab significantly improved symptoms in patients with antibody-positive generalized myasthenia gravis, data from a new phase 3 study showed.

After 6 weeks of treatment, patients reported nearly 60% sustained improvement in daily activities and a rapid onset of action from batoclimab, a neonatal crystallizable fragment receptor (FcRn) antagonist.

The clinical effects and the extent of immunoglobulin G (IgG) reduction in this study were similar to those previously reported for efgartigimod and rozanolixizumab, two other FcRn antagonists, the investigators noted, adding that larger studies are needed to better understand the safety profile of batoclimab.

“While most generalized myasthenia gravis patients can achieve good disease control through conventional immunotherapy, there are still unmet needs with this disease,” said study investigator Chongbo Zhao, MD, National Center for Neurological Disorders, Huashan Rare Disease Centre, Department of Neurology, Huashan Hospital of Fudan University, Shanghai, China.

The findings were published online in JAMA Neurology.
 

Unmet Need

A rare chronic disease, myasthenia gravis is caused by autoantibodies that disrupt the neuromuscular junction, most commonly against the nicotinic acetylcholine receptor (AChR). This can cause a variety of symptoms, including difficulty swallowing, chewing, and talking, as well as severe, sometimes life-threatening, muscle weakness.

The estimated global prevalence of myasthenia gravis is 15-25 per 100,000, with cases doubling in the past 20 years.

Treatment for myasthenia gravis typically includes immune-suppressing drugs. But research suggests almost half of patients with generalized myasthenia gravis don’t achieve an adequate response or are intolerant to these treatments, and some therapies are costly or not readily accessible.

“Our treatment goal has evolved from saving patients to improving their quality of life, so we still need to explore safer and more effective novel treatment methods,” Dr. Zhao said.

Batoclimab is a fully humanized monoclonal IgG antibody that binds to FcRn and accelerates clearance of harmful IgG. A phase 2 trial provided preliminary evidence to support the efficacy of this agent in Chinese patients with generalized myasthenia gravis.

The current double-blind phase 3 trial included 132 adult patients (mean age, 44 years; 67% female) of Chinese Han ethnicity with generalized myasthenia gravis at 27 centers in China. Participants had a mean Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 8.4 at baseline, and all but one was positive for AChR or muscle-specific kinase (MuSK) antibodies.

The treatment group received weekly subcutaneous injections of batoclimab at 680 mg for 6 weeks, followed by 4 weeks of observation. The control group received a placebo with the same treatment and follow-up schedule.

All patients received standard of care in addition to the assigned treatment, but changes in dosage and/or dosing frequency were not permitted. Patients received a second cycle if they still required treatment.
 

Bests Placebo

Overall, 90% of participants completed all six doses in cycle 1. The second treatment cycle was conducted in 115 patients, with 88% completing all six doses.

Patients were evaluated at baseline and then weekly for MG-ADL, Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite, and the 15-item revised version of the Myasthenia Gravis Quality of Life.

Sustained MG-ADL improvement — the primary outcome — was significantly higher in the batoclimab group compared with placebo (58% vs 31%, respectively; odds ratio, 3.45; P = .001).

While the rate of sustained MG-ADL improvement with batoclimab was lower than that reported for efgartigimod (68%) in a previous trial, that was primarily because of the more stringent definition of sustained MG-ADL improvement (three-point reduction vs two-point reduction from baseline), investigators said.

In the current trial, batoclimab had a rapid onset of action, with scores diverging between the treatment and placebo groups as early as the second week of therapy.

In the second treatment cycle, batoclimab once again outperformed placebo in sustained MG-ADL improvement (63% vs 36%, respectively; P = .002).

Batoclimab also bested placebo on secondary outcomes, including sustained QMG improvement (64% vs 41%; P = .008) and percent of patients achieving minimal symptom expression (25% vs 5%; P = .004).

Results of all subgroup analyses, including by age groups, sex, body weight, body mass index, and MG Foundation of America clinical classification, were consistent with those of the main analysis. The efficacy of batoclimab was also supported by all sensitivity analyses, underscoring the robustness of results.

Batoclimab led to a rapid and sustained reduction in serum AChR antibody levels, with a median reduction of 81% at week 6.
 

Well Tolerated

On discontinuation of batoclimab, serum total IgG returned to a level comparable with the baseline after 4 weeks. Reversibility of the drug’s effect is important considering the risk for infection from prolonged immune suppression, the authors noted.

The rate of peripheral edema was significantly higher in the treatment than in the placebo groups (39% vs 5%), but all cases were mild or moderate and deemed not clinically significant. The treatment group also had higher rates of upper respiratory tract infections (36% vs 22%) and of urinary tract infections (19% vs 15%).

“Although the incidence of upper respiratory tract and urinary tract infections was higher in the batoclimab group numerically, these were mild infections that did not require special treatment, so this is not a concern,” said Dr. Zhao.

Plasma albumin levels in the batoclimab group decreased significantly throughout the treatment cycle, starting at week 1 and reaching a decline of up to 31% at week 6. These levels increased rapidly toward baseline after treatment discontinuation.

High cholesterol levels were noted in the batoclimab group, plateauing by week 6. But levels returned to near baseline levels within 4 weeks after the final dose, and there were no serious related adverse reactions.

The rate of headache was slightly higher in the treatment group (6% vs 5% for placebo). “This finding may seem minor but could potentially translate into improved adherence in daily practice settings,” the authors wrote.

In previous studies, the efficacy of FcRn inhibitors in the Asian population was only examined in subgroup analyses with limited subjects. Finding an effective FcRn antagonist for China and surrounding regions is particularly important “considering the high mortality rate in hospitalized generalized myasthenia gravis patients in China,” the researchers noted.

The trial included only two treatment cycles, although results of an open-label extension trial examining longer-term efficacy of batoclimab should be available by the end of this year, said Dr. Zhao.

The trial was also not designed to investigate long-term safety, particularly infections and cardiovascular events. Only one study subject was negative for AChR or MuSK antibodies, which prevented researchers from assessing the drug’s efficacy in this subpopulation.
 

Questions Remain

Commenting on the study, Fredrik Piehl, MD, PhD, professor of neurology, Karolinska Institute, Stockholm, Sweden , said that recent studies of the two other FcRn antagonists were short-term and had limited long-term data. “We don’t know how valuable they may be for continued treatment,” Dr. Piehl said.

It’s also unclear how this new treatment modality compares with existing and emerging drug strategies in terms of the long-term benefit-risk balance, he added.

The rate of adverse events with batoclimab was high compared with placebo in this study and higher than in earlier studies of efgartigimod, Dr. Piehl noted.

“In this study, almost twice as many reported adverse events in the active arm compared with controls, while these differences tended to be smaller in previously reported trials,” he said.

The trial was funded by Nona Biosciences (Suzhou). Dr. Zhao reported being a full-time employee of Nona Biosciences (Suzhou), a subsidiary of Harbour BioMed Inc. He also reported receiving advisory board/consultant fees from Nona Biosciences, Roche, Sanofi, and Zailab outside the submitted work. Dr. Piehl has received research grants from Janssen, Merck KGaA, and UCB; and fees for serving on DMC in clinical trials with Chugai, Lundbeck, and Roche; and preparation of expert witness statement for Novartis.

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

TOPLINE:

Tapering glucocorticoids (GCs) does not increase the risk for flare in modified serologically active clinically quiescent (mSACQ) patients with systemic lupus erythematosus (SLE) with a low daily exposure to GC.

METHODOLOGY:

• Previous research has indicated that SACQ SLE is associated with an increased risk for flare after low-dose GC withdrawal.
• Researchers assessed the risk for flare and damage accrual after tapering GCs in mSACQ patients with SLE.
• They used data from the Asia Pacific Lupus Collaboration (APLC) to study 1850 patients (mean age, 40 years; 91.6% women) who met the criteria for SLE, including the definition of mSACQ at least once during observation and being followed up for 2 years after the first mSACQ visit.
• mSACQ was defined as a condition with serological activity but without clinical activity managed with ≤ 7.5 mg/d of -equivalent GCs, regardless of duration.
• The primary outcome was disease flare (both severe and overall) on the basis of the SELENA-SLEDAI flare index definitions.

TAKEAWAY:

• A total of 742 patients experienced an overall flare, 271 experienced a severe flare, and 180 experienced damage accrual.
• Reducing the prednisolone-equivalent GC dosage by 1 mg/d did not increase the risk for an overall (P = .27) or severe (P = .11) flare in patients initially on prednisolone-equivalent GC dosages of 0-7.5 mg/d.
• Antimalarial use decreased the risk for overall (hazard ratio [HR], 0.78; P = .002) and severe (HR, 0.59; P < .001) flares, and immunosuppressant use decreased the risk for severe flares (HR, 0.77; P = .043) but not overall flares.
• Reducing the GC dosage by 1 mg/d reduced the risk for damage accrual by 4% in patients who started taking prednisolone at a dose > 5 but ≤ 7.5 mg/d (P = .007).

IN PRACTICE:

“Cautious tapering of GCs is a feasible option for mSACQ-SLE with low daily exposure to GCs (≤ 7.5 mg/d of prednisolone-equivalent) and can reduce GC burden,” wrote the authors.

SOURCE:

The study, led by Yasuhiro Katsumata, Division of Rheumatology, Tokyo Women’s Medical University School of Medicine, Tokyo, Japan, was published online in Annals of the Rheumatic Diseases.

LIMITATIONS:

The data were collected retrospectively. A short follow-up duration might have prevented the demonstration of clear benefits in terms of damage accrual among patients receiving < 5 mg of GCs. Moreover, the findings may have limited generalizability as the majority of patients had Asian ancestry.

DISCLOSURES:

This work was supported by grants and funding from AstraZeneca, Bristol-Myers Squibb, Eli Lily, Janssen, Merck Serono, UCB, GlaxoSmithKline, Australia, and others to APLC. Some of the authors declared receiving honoraria, consulting fees, research grants, and research support from various sources.

A version of this article appeared on Medscape.com.

TOPLINE:

Tapering glucocorticoids (GCs) does not increase the risk for flare in modified serologically active clinically quiescent (mSACQ) patients with systemic lupus erythematosus (SLE) with a low daily exposure to GC.

METHODOLOGY:

• Previous research has indicated that SACQ SLE is associated with an increased risk for flare after low-dose GC withdrawal.
• Researchers assessed the risk for flare and damage accrual after tapering GCs in mSACQ patients with SLE.
• They used data from the Asia Pacific Lupus Collaboration (APLC) to study 1850 patients (mean age, 40 years; 91.6% women) who met the criteria for SLE, including the definition of mSACQ at least once during observation and being followed up for 2 years after the first mSACQ visit.
• mSACQ was defined as a condition with serological activity but without clinical activity managed with ≤ 7.5 mg/d of -equivalent GCs, regardless of duration.
• The primary outcome was disease flare (both severe and overall) on the basis of the SELENA-SLEDAI flare index definitions.

TAKEAWAY:

• A total of 742 patients experienced an overall flare, 271 experienced a severe flare, and 180 experienced damage accrual.
• Reducing the prednisolone-equivalent GC dosage by 1 mg/d did not increase the risk for an overall (P = .27) or severe (P = .11) flare in patients initially on prednisolone-equivalent GC dosages of 0-7.5 mg/d.
• Antimalarial use decreased the risk for overall (hazard ratio [HR], 0.78; P = .002) and severe (HR, 0.59; P < .001) flares, and immunosuppressant use decreased the risk for severe flares (HR, 0.77; P = .043) but not overall flares.
• Reducing the GC dosage by 1 mg/d reduced the risk for damage accrual by 4% in patients who started taking prednisolone at a dose > 5 but ≤ 7.5 mg/d (P = .007).

IN PRACTICE:

“Cautious tapering of GCs is a feasible option for mSACQ-SLE with low daily exposure to GCs (≤ 7.5 mg/d of prednisolone-equivalent) and can reduce GC burden,” wrote the authors.

SOURCE:

The study, led by Yasuhiro Katsumata, Division of Rheumatology, Tokyo Women’s Medical University School of Medicine, Tokyo, Japan, was published online in Annals of the Rheumatic Diseases.

LIMITATIONS:

The data were collected retrospectively. A short follow-up duration might have prevented the demonstration of clear benefits in terms of damage accrual among patients receiving < 5 mg of GCs. Moreover, the findings may have limited generalizability as the majority of patients had Asian ancestry.

DISCLOSURES:

This work was supported by grants and funding from AstraZeneca, Bristol-Myers Squibb, Eli Lily, Janssen, Merck Serono, UCB, GlaxoSmithKline, Australia, and others to APLC. Some of the authors declared receiving honoraria, consulting fees, research grants, and research support from various sources.

A version of this article appeared on Medscape.com.

TOPLINE:

Tapering glucocorticoids (GCs) does not increase the risk for flare in modified serologically active clinically quiescent (mSACQ) patients with systemic lupus erythematosus (SLE) with a low daily exposure to GC.

METHODOLOGY:

• Previous research has indicated that SACQ SLE is associated with an increased risk for flare after low-dose GC withdrawal.
• Researchers assessed the risk for flare and damage accrual after tapering GCs in mSACQ patients with SLE.
• They used data from the Asia Pacific Lupus Collaboration (APLC) to study 1850 patients (mean age, 40 years; 91.6% women) who met the criteria for SLE, including the definition of mSACQ at least once during observation and being followed up for 2 years after the first mSACQ visit.
• mSACQ was defined as a condition with serological activity but without clinical activity managed with ≤ 7.5 mg/d of -equivalent GCs, regardless of duration.
• The primary outcome was disease flare (both severe and overall) on the basis of the SELENA-SLEDAI flare index definitions.

TAKEAWAY:

• A total of 742 patients experienced an overall flare, 271 experienced a severe flare, and 180 experienced damage accrual.
• Reducing the prednisolone-equivalent GC dosage by 1 mg/d did not increase the risk for an overall (P = .27) or severe (P = .11) flare in patients initially on prednisolone-equivalent GC dosages of 0-7.5 mg/d.
• Antimalarial use decreased the risk for overall (hazard ratio [HR], 0.78; P = .002) and severe (HR, 0.59; P < .001) flares, and immunosuppressant use decreased the risk for severe flares (HR, 0.77; P = .043) but not overall flares.
• Reducing the GC dosage by 1 mg/d reduced the risk for damage accrual by 4% in patients who started taking prednisolone at a dose > 5 but ≤ 7.5 mg/d (P = .007).

IN PRACTICE:

“Cautious tapering of GCs is a feasible option for mSACQ-SLE with low daily exposure to GCs (≤ 7.5 mg/d of prednisolone-equivalent) and can reduce GC burden,” wrote the authors.

SOURCE:

The study, led by Yasuhiro Katsumata, Division of Rheumatology, Tokyo Women’s Medical University School of Medicine, Tokyo, Japan, was published online in Annals of the Rheumatic Diseases.

LIMITATIONS:

The data were collected retrospectively. A short follow-up duration might have prevented the demonstration of clear benefits in terms of damage accrual among patients receiving < 5 mg of GCs. Moreover, the findings may have limited generalizability as the majority of patients had Asian ancestry.

DISCLOSURES:

This work was supported by grants and funding from AstraZeneca, Bristol-Myers Squibb, Eli Lily, Janssen, Merck Serono, UCB, GlaxoSmithKline, Australia, and others to APLC. Some of the authors declared receiving honoraria, consulting fees, research grants, and research support from various sources.

A version of this article appeared on Medscape.com.

TOPLINE:

Changes in plasma growth hormone mediators such as growth hormone receptor (GHR) and insulin-like growth factor-binding protein 1 (IGFBP-1) were associated with glycemic failure in youth-onset type 2 diabetes (T2D), an analysis of the TODAY trial showed.

METHODOLOGY:

• In youth, T2D often occurs during or after puberty, hinting at hormonal influences in the development and/or progression of the disease.
• This secondary analysis assessed the role of growth hormone mediators including insulin-like growth factor-1 (IGF-1), GHR, and IGFBP-1 in glycemic failure in a subset of 398 youths, aged 10-17 years, with a T2D duration of less than 2 years (62% girls; 21% White).
• The participants were followed up for a mean of 3.9 years.
• The primary outcomes included glycemic failure, defined as an A1c level of 8% or more for 6 months, or acute metabolic decompensation requiring insulin.
• Other assessments included baseline and 36-month measures of glycemia, insulin sensitivity, high molecular weight adiponectin, and beta cell function.

TAKEAWAY:

• Of 398 participants, 182 (46%) experienced glycemic failure, while 216 (54%) retained glycemic control.
• At 36 months, youths with glycemic failure had lower IGF-1 levels (P < .001) and higher log₂ GHR (P = .03) and log₂ IGFBP-1 (P = .009) levels than those who maintained glycemic control.
• A greater increase in IGF-1 level at 36 months was associated with lower odds of glycemic failure (odds ratio [OR], 0.995; P < .001).
• Increased levels of log₂ GHR and log₂ IGFBP-1 were associated with higher odds of glycemic failure (OR, 1.75; P = .04 and OR, 1.37; P = .007, respectively). Results were adjusted for body mass index (BMI), suggesting that associations between GHR level and glycemic outcomes exist independent of BMI.
• Interhormonal correlations suggested an association between glucose metabolism and growth hormone signaling or a shared process leading to changes in both processes.

IN PRACTICE:

“Our study has identified GHR level as a novel biomarker of decrease in glycemic control in youths with T2D,” the study authors wrote. Future research is needed, with an emphasis on assessing alterations in growth hormone mediators which may contribute to diabetes complications in youth.

SOURCE:

The study, published online in JAMA Network Open, was led by Chang Lu, MD, Division of Endocrinology, Boston Children’s Hospital, and Joslin Diabetes Center at Harvard Medical School, Boston, Massachusetts.

LIMITATIONS:

The study did not include a control group (individuals without diabetes). The cohort largely included youth in late puberty or after puberty, affecting subgroup analysis. Moreover, only circulating growth hormone mediators were measured, limiting the identity of the source tissue of the hormone and the target organs.

DISCLOSURES:

Some authors reported receiving grants from the National Institutes of Health and National Institute of Diabetes and Digestive and Kidney Diseases while conducting the study. Also, certain authors reported receiving grants and personal fees from various trusts as well as pharmaceutical, healthcare, and medical technology companies outside the submitted work.

TOPLINE:

Changes in plasma growth hormone mediators such as growth hormone receptor (GHR) and insulin-like growth factor-binding protein 1 (IGFBP-1) were associated with glycemic failure in youth-onset type 2 diabetes (T2D), an analysis of the TODAY trial showed.

METHODOLOGY:

• In youth, T2D often occurs during or after puberty, hinting at hormonal influences in the development and/or progression of the disease.
• This secondary analysis assessed the role of growth hormone mediators including insulin-like growth factor-1 (IGF-1), GHR, and IGFBP-1 in glycemic failure in a subset of 398 youths, aged 10-17 years, with a T2D duration of less than 2 years (62% girls; 21% White).
• The participants were followed up for a mean of 3.9 years.
• The primary outcomes included glycemic failure, defined as an A1c level of 8% or more for 6 months, or acute metabolic decompensation requiring insulin.
• Other assessments included baseline and 36-month measures of glycemia, insulin sensitivity, high molecular weight adiponectin, and beta cell function.

TAKEAWAY:

• Of 398 participants, 182 (46%) experienced glycemic failure, while 216 (54%) retained glycemic control.
• At 36 months, youths with glycemic failure had lower IGF-1 levels (P < .001) and higher log₂ GHR (P = .03) and log₂ IGFBP-1 (P = .009) levels than those who maintained glycemic control.
• A greater increase in IGF-1 level at 36 months was associated with lower odds of glycemic failure (odds ratio [OR], 0.995; P < .001).
• Increased levels of log₂ GHR and log₂ IGFBP-1 were associated with higher odds of glycemic failure (OR, 1.75; P = .04 and OR, 1.37; P = .007, respectively). Results were adjusted for body mass index (BMI), suggesting that associations between GHR level and glycemic outcomes exist independent of BMI.
• Interhormonal correlations suggested an association between glucose metabolism and growth hormone signaling or a shared process leading to changes in both processes.

IN PRACTICE:

“Our study has identified GHR level as a novel biomarker of decrease in glycemic control in youths with T2D,” the study authors wrote. Future research is needed, with an emphasis on assessing alterations in growth hormone mediators which may contribute to diabetes complications in youth.

SOURCE:

The study, published online in JAMA Network Open, was led by Chang Lu, MD, Division of Endocrinology, Boston Children’s Hospital, and Joslin Diabetes Center at Harvard Medical School, Boston, Massachusetts.

LIMITATIONS:

The study did not include a control group (individuals without diabetes). The cohort largely included youth in late puberty or after puberty, affecting subgroup analysis. Moreover, only circulating growth hormone mediators were measured, limiting the identity of the source tissue of the hormone and the target organs.

DISCLOSURES:

Some authors reported receiving grants from the National Institutes of Health and National Institute of Diabetes and Digestive and Kidney Diseases while conducting the study. Also, certain authors reported receiving grants and personal fees from various trusts as well as pharmaceutical, healthcare, and medical technology companies outside the submitted work.

TOPLINE:

Changes in plasma growth hormone mediators such as growth hormone receptor (GHR) and insulin-like growth factor-binding protein 1 (IGFBP-1) were associated with glycemic failure in youth-onset type 2 diabetes (T2D), an analysis of the TODAY trial showed.

METHODOLOGY:

• In youth, T2D often occurs during or after puberty, hinting at hormonal influences in the development and/or progression of the disease.
• This secondary analysis assessed the role of growth hormone mediators including insulin-like growth factor-1 (IGF-1), GHR, and IGFBP-1 in glycemic failure in a subset of 398 youths, aged 10-17 years, with a T2D duration of less than 2 years (62% girls; 21% White).
• The participants were followed up for a mean of 3.9 years.
• The primary outcomes included glycemic failure, defined as an A1c level of 8% or more for 6 months, or acute metabolic decompensation requiring insulin.
• Other assessments included baseline and 36-month measures of glycemia, insulin sensitivity, high molecular weight adiponectin, and beta cell function.

TAKEAWAY:

• Of 398 participants, 182 (46%) experienced glycemic failure, while 216 (54%) retained glycemic control.
• At 36 months, youths with glycemic failure had lower IGF-1 levels (P < .001) and higher log₂ GHR (P = .03) and log₂ IGFBP-1 (P = .009) levels than those who maintained glycemic control.
• A greater increase in IGF-1 level at 36 months was associated with lower odds of glycemic failure (odds ratio [OR], 0.995; P < .001).
• Increased levels of log₂ GHR and log₂ IGFBP-1 were associated with higher odds of glycemic failure (OR, 1.75; P = .04 and OR, 1.37; P = .007, respectively). Results were adjusted for body mass index (BMI), suggesting that associations between GHR level and glycemic outcomes exist independent of BMI.
• Interhormonal correlations suggested an association between glucose metabolism and growth hormone signaling or a shared process leading to changes in both processes.

IN PRACTICE:

“Our study has identified GHR level as a novel biomarker of decrease in glycemic control in youths with T2D,” the study authors wrote. Future research is needed, with an emphasis on assessing alterations in growth hormone mediators which may contribute to diabetes complications in youth.

SOURCE:

The study, published online in JAMA Network Open, was led by Chang Lu, MD, Division of Endocrinology, Boston Children’s Hospital, and Joslin Diabetes Center at Harvard Medical School, Boston, Massachusetts.

LIMITATIONS:

The study did not include a control group (individuals without diabetes). The cohort largely included youth in late puberty or after puberty, affecting subgroup analysis. Moreover, only circulating growth hormone mediators were measured, limiting the identity of the source tissue of the hormone and the target organs.

DISCLOSURES:

Some authors reported receiving grants from the National Institutes of Health and National Institute of Diabetes and Digestive and Kidney Diseases while conducting the study. Also, certain authors reported receiving grants and personal fees from various trusts as well as pharmaceutical, healthcare, and medical technology companies outside the submitted work.

TOPLINE:

Obstructive sleep apnea (OSA) is associated with a significantly higher risk for stroke — regardless of continuous positive airway pressure (CPAP) device use — but only in White individuals, new data suggested. The study also found that stroke risk among Black individuals with OSA was lower in those who used CPAP machines vs those who didn›t.

METHODOLOGY:

• Researchers used data on 22,192 people from the Reasons for Geographic and Racial Differences in Stroke study, a US population-based cohort of Black and White individuals with no history of stroke at baseline (mean age, 64 years; 38% Black individuals).
• 11% of overall participants had provider diagnosed OSA at baseline.
• Participants were followed for a mean of 12 years.
• Researchers adjusted for demographic, socioeconomic, and stroke risk factors.

TAKEAWAY: 

• During the follow-up period, 969 participants (4.4%) experienced a stroke.
• After adjusting for confounders, having high OSA risk and diagnosed OSA were associated with higher risks for incident stroke in White individuals (adjusted hazard ratio [aHR], 1.22; 95% CI, 1.01-1.47 and aHR, 1.33; 95% CI, 1.04-1.70, respectively) but not in Black individuals.
• Among those with diagnosed OSA, CPAP use was associated with a higher risk for incident stroke in White individuals (aHR, 1.38; 95% CI, 1.05-1.80) but a lower stroke risk in Black individuals (aHR, 0.36; 95% CI, 0.14-0.90) compared with no CPAP use.Snoring was not associated with incident stroke in either Black or White individuals.
• Snoring was not associated with incident stroke in either Black or White individuals.

IN PRACTICE:

“These results were not what we were expecting to find since Black people have been shown to have a higher risk of stroke and are more likely to have sleep apnea than White people,” lead author Rebecca Robbins, MMSc, PhD, of Brigham and Women’s Hospital in Boston, Massachusetts, said in a news release. “Since it has been shown that Black people have more severe sleep apnea than White people and take longer to be screened and treated than White people, it’s possible that using a CPAP machine provides a greater benefit on reducing stroke risk for Black people.”

SOURCE:

Robbins was the lead and corresponding author of the study. It was published online in Neurology. 

LIMITATIONS:

The current study assessed only self-reported OSA symptoms, risk, diagnosis, and treatment and did not include data on the hours of CPAP usage at night, number of days of treatment, adherence during the follow-up period, and OSA severity. 

DISCLOSURES:

The study was funded by the National Institute of Neurological Disorders and Stroke and the National Institute on Aging. Robbins received consulting income from Sonesta Hotels International, Oura Ring Ltd., Savoir Beds Ltd., Castle Hot Springs, and ByNacht GmbH. The other authors’ disclosures are listed in the original paper.

A version of this article appeared on Medscape.com.

TOPLINE:

Obstructive sleep apnea (OSA) is associated with a significantly higher risk for stroke — regardless of continuous positive airway pressure (CPAP) device use — but only in White individuals, new data suggested. The study also found that stroke risk among Black individuals with OSA was lower in those who used CPAP machines vs those who didn›t.

METHODOLOGY:

• Researchers used data on 22,192 people from the Reasons for Geographic and Racial Differences in Stroke study, a US population-based cohort of Black and White individuals with no history of stroke at baseline (mean age, 64 years; 38% Black individuals).
• 11% of overall participants had provider diagnosed OSA at baseline.
• Participants were followed for a mean of 12 years.
• Researchers adjusted for demographic, socioeconomic, and stroke risk factors.

TAKEAWAY: 

• During the follow-up period, 969 participants (4.4%) experienced a stroke.
• After adjusting for confounders, having high OSA risk and diagnosed OSA were associated with higher risks for incident stroke in White individuals (adjusted hazard ratio [aHR], 1.22; 95% CI, 1.01-1.47 and aHR, 1.33; 95% CI, 1.04-1.70, respectively) but not in Black individuals.
• Among those with diagnosed OSA, CPAP use was associated with a higher risk for incident stroke in White individuals (aHR, 1.38; 95% CI, 1.05-1.80) but a lower stroke risk in Black individuals (aHR, 0.36; 95% CI, 0.14-0.90) compared with no CPAP use.Snoring was not associated with incident stroke in either Black or White individuals.
• Snoring was not associated with incident stroke in either Black or White individuals.

IN PRACTICE:

“These results were not what we were expecting to find since Black people have been shown to have a higher risk of stroke and are more likely to have sleep apnea than White people,” lead author Rebecca Robbins, MMSc, PhD, of Brigham and Women’s Hospital in Boston, Massachusetts, said in a news release. “Since it has been shown that Black people have more severe sleep apnea than White people and take longer to be screened and treated than White people, it’s possible that using a CPAP machine provides a greater benefit on reducing stroke risk for Black people.”

SOURCE:

Robbins was the lead and corresponding author of the study. It was published online in Neurology. 

LIMITATIONS:

The current study assessed only self-reported OSA symptoms, risk, diagnosis, and treatment and did not include data on the hours of CPAP usage at night, number of days of treatment, adherence during the follow-up period, and OSA severity. 

DISCLOSURES:

The study was funded by the National Institute of Neurological Disorders and Stroke and the National Institute on Aging. Robbins received consulting income from Sonesta Hotels International, Oura Ring Ltd., Savoir Beds Ltd., Castle Hot Springs, and ByNacht GmbH. The other authors’ disclosures are listed in the original paper.

A version of this article appeared on Medscape.com.

TOPLINE:

Obstructive sleep apnea (OSA) is associated with a significantly higher risk for stroke — regardless of continuous positive airway pressure (CPAP) device use — but only in White individuals, new data suggested. The study also found that stroke risk among Black individuals with OSA was lower in those who used CPAP machines vs those who didn›t.

METHODOLOGY:

• Researchers used data on 22,192 people from the Reasons for Geographic and Racial Differences in Stroke study, a US population-based cohort of Black and White individuals with no history of stroke at baseline (mean age, 64 years; 38% Black individuals).
• 11% of overall participants had provider diagnosed OSA at baseline.
• Participants were followed for a mean of 12 years.
• Researchers adjusted for demographic, socioeconomic, and stroke risk factors.

TAKEAWAY: 

• During the follow-up period, 969 participants (4.4%) experienced a stroke.
• After adjusting for confounders, having high OSA risk and diagnosed OSA were associated with higher risks for incident stroke in White individuals (adjusted hazard ratio [aHR], 1.22; 95% CI, 1.01-1.47 and aHR, 1.33; 95% CI, 1.04-1.70, respectively) but not in Black individuals.
• Among those with diagnosed OSA, CPAP use was associated with a higher risk for incident stroke in White individuals (aHR, 1.38; 95% CI, 1.05-1.80) but a lower stroke risk in Black individuals (aHR, 0.36; 95% CI, 0.14-0.90) compared with no CPAP use.Snoring was not associated with incident stroke in either Black or White individuals.
• Snoring was not associated with incident stroke in either Black or White individuals.

IN PRACTICE:

“These results were not what we were expecting to find since Black people have been shown to have a higher risk of stroke and are more likely to have sleep apnea than White people,” lead author Rebecca Robbins, MMSc, PhD, of Brigham and Women’s Hospital in Boston, Massachusetts, said in a news release. “Since it has been shown that Black people have more severe sleep apnea than White people and take longer to be screened and treated than White people, it’s possible that using a CPAP machine provides a greater benefit on reducing stroke risk for Black people.”

SOURCE:

Robbins was the lead and corresponding author of the study. It was published online in Neurology. 

LIMITATIONS:

The current study assessed only self-reported OSA symptoms, risk, diagnosis, and treatment and did not include data on the hours of CPAP usage at night, number of days of treatment, adherence during the follow-up period, and OSA severity. 

DISCLOSURES:

The study was funded by the National Institute of Neurological Disorders and Stroke and the National Institute on Aging. Robbins received consulting income from Sonesta Hotels International, Oura Ring Ltd., Savoir Beds Ltd., Castle Hot Springs, and ByNacht GmbH. The other authors’ disclosures are listed in the original paper.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Rachel S. Rubin, MD: I’m Dr. Rachel Rubin, urologist and sexual medicine specialist in the Washington, DC, area. We are coming to you live from the Mayo Clinic Urology Conference in Maui, Hawaii, with the world’s leading experts in men’s health, sexual health, and quality of life. I’m bringing in Dr. Allen Morey from the North Dallas area, one of the world’s leading experts in reconstructive urology. He deals with all things urinary incontinence, penile curvature, and sexual health.

Dr. Morey said something at this conference that really put my chin on the floor. He said, “The urethra is a sex organ. It is androgen dependent.” This is so important because it’s true for all genders. So, Dr. Morey, tell us more about why you made that comment and about the incontinence in men that you deal with all the time.

Allen F. Morey, MD: For many years, I’ve worked at cancer centers where, through the various treatments for prostate cancer, the men suffered from urinary incontinence and we put a lot of artificial urinary sphincters in those patients. I had one patient who asked, “Why do I keep having this erosion?” Of course, the erosion is where the cuff compresses the tissue surrounding the urethra, and the tissue gives way, leaving a hole in the urethra. I looked at him and noticed that he was pale. And I thought, Let me check his testosterone level. We started checking it on everybody who had this problem, and sure enough, the ones who had the cup erosion — who had the atrophic tissue around the urethra — most of them had low testosterone levels. Some of this was due to the cancer treatment, but in other men, it was just due to old age.

We started thinking that this is a causal relationship. And we tested it. I had a fellow who was a board-certified pathologist before becoming a urologist. He obtained some specimens from the urethra and did very sophisticated, elegant stains on that tissue. We found that it’s just erectile tissue surrounding the urethra. That’s why I call it a sex organ. I tell my patients, “When you are a teenager, this tissue is thin, like on your pinky finger. As you get older, it becomes thicker. And then as you get even older, and you may be having cancer treatment, that tissue is gone.” You can show them your little finger; it’s about that size. All the meat is off the bone. There’s nothing left protecting the urinary mucosa from the device.

That’s why it’s important to maintain the optimal health of those tissues and for them to remain dry. Because let’s face it: Urinary incontinence is a horrible quality of life. These are my happiest patients when we fix it. Before that, when they go on vacation, they have a separate suitcase filled with diapers. They can’t go anywhere. They can’t do anything. When they become incontinent after the prostatectomy, they gain weight. And when you put in the device to treat it, they lose weight and you can track it. The urinary incontinence patients really suffer. And we need to consider the medical optimization of those patients.

Dr. Rubin: It’s so important, and I love how analogous this is to our female patients. We know that incontinence is devastating to our female patients as well, and there’s a lot of hope. As we get older we start to pee every time we cough, laugh, or sneeze. Men are a little more bothered by it when it happens; they don’t expect it. Among women, it’s thought of as normal, but it’s not normal. There is so much we can do to help these patients, ranging from conservative treatment to surgical therapies.

The connection between hormones and urethral health is true on the female side as well. As you go through menopause, the urethral tissue thins out, gets dry, gets irritated, and can cause worsening incontinence, pain with sex, and genital urinary syndrome of menopause. It’s really important.

For our primary care doctors, how should we talk about stress incontinence in men? How do we diagnose it?

Dr. Morey: It’s easy to diagnose. Just do a quick history. Find out how many pads a day they are using. You have to ask the question, and then you have them stand up and look inside their underwear. You’ll see what kind of pad they are wearing. Is it just a shield or are they actually wearing full diapers? Then I have them do a standing cough test. I stand off to the side, holding a couple of towels, and have the patient cough four times. I can tell if it’s a full stream or just a couple of drops. Is it nothing but they are wearing a pad? You match up what you see with their experience, and in an instant it tells you how severe their problem is and it helps you direct them on to further treatment, because many patients have treatment fatigue. They’ve already been through the system. They have really suffered and they don’t know which way to go. They don’t know what’s available.

Dr. Rubin: On the female side, we have pelvic floor physical therapy. We have pads and devices that you can wear, and pessaries. We have surgical options, like bulking agents into the urethra as well as urethral slings, which can be quite helpful for women. So there’s a lot of hope out there for women, and from what I learned from you at this conference, there’s a lot of hope for men as well. So talk us through treatment, from conservative to surgical options.

Dr. Morey: There hasn’t been much innovation in male incontinence treatment over the past few decades, but we’re starting to see signs of new products appearing on the horizon, so I’m very optimistic that in the next 5 or 10 years, we’ll have more. But right now it comes down to slings and artificial sphincters, which are devices with little pumps and hydraulics, and they’re very good. But they’ve been around for 50 years, and they have this other potential risk factor of the erosion of the tissue.

We don’t have a pill that we can give the patient to tighten up those muscles. We can help them with overactive bladder. But maybe the hormonal influence is a way to optimize the health of the tissue so that these surgical treatments can really deliver the best outcomes. And as I always say, and having treated so many of these patients, it’s really a game of millimeters — how much coaptation you get. If you’re off by the slightest amount, that’s an unhappy patient. So it doesn’t take much to make it a lot better.

Dr. Rubin: There’s so much hope for our patients, and this can really have an effect on sexual health. You know the benefits you see in their quality of life and sexual health when you can stop leakage.

Dr. Morey: I always take care of the waterworks first. Many of the men have both urinary problems and erectile problems. Nobody feels sexy when they’re leaking urine all over their partner. So first we take care of that. And then, in the motivated younger patients, we bring them back and talk to them about potentially having a second operation.

Dr. Rubin: And so similarly, in women with urinary incontinence, it can have a major impact on sexual health — how they show up and how they talk to their partner. So, it is really important for our primary care docs to talk to patients about urinary incontinence and not just say, “Oh, well, you’re getting older. There’s nothing that you can do.” There’s actually no age at which there is nothing that we can do. And it’s really important to refer patients to those urologists who have extra training in incontinence and sexual health, because we do care about these quality-of-life measures and there is a lot we can do, ranging from conservative to more invasive treatments. But patients really should have options.

Dr. Morey: I heard during this meeting that urinary incontinence was the number-one source of treatment regret among patients who had their prostate treated for cancer. So, this is a really big deal for our patients. And it impacts wellness, quality of life, and overall well-being.

Dr. Rubin: When we are counseling patients for cancer surgeries or cancer treatments such as radiation therapy, it’s really hard for the patients who have never had urinary incontinence to imagine what that might be like. When you’re telling them they could have a stroke or a heart attack, or they could have erectile dysfunction or urinary incontinence, it all sounds similar to them. It could happen to someone else. It’s very hard to truly counsel patients on these quality-of-life issues that they’ve never encountered before.

Dr. Morey: We have found that it takes a long time for patients to get into our office for treatment, and it’s unbelievable — often 5 years in diapers before they find us.

Dr. Rubin: Hopefully videos like this will teach our docs and our patients that there is hope out there, that you don’t need to wait through years of suffering from incontinence. So, how does somebody find a reconstructive urologist or a sexual medicine urologist?

Dr. Morey: There are a couple of good websites out there, such as fixincontinence.com and edcure.org. The device manufacturers have pretty good information for patients.

Dr. Rubin: The Sexual Medicine Society of North America (SMSNA) has a great find-a-provider website, which provides a list of urologists who are trained in both sexual health and urinary incontinence, because they both matter. Our patients deeply care about these issues.

Rachel S. Rubin, MD, has disclosed the following relevant financial relationships: Serve(d) as a speaker for Sprout; received research grant from Maternal Medical; received income in an amount equal to or greater than $250 from Absorption Pharmaceuticals, GSK, Endo.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Rachel S. Rubin, MD: I’m Dr. Rachel Rubin, urologist and sexual medicine specialist in the Washington, DC, area. We are coming to you live from the Mayo Clinic Urology Conference in Maui, Hawaii, with the world’s leading experts in men’s health, sexual health, and quality of life. I’m bringing in Dr. Allen Morey from the North Dallas area, one of the world’s leading experts in reconstructive urology. He deals with all things urinary incontinence, penile curvature, and sexual health.

Dr. Morey said something at this conference that really put my chin on the floor. He said, “The urethra is a sex organ. It is androgen dependent.” This is so important because it’s true for all genders. So, Dr. Morey, tell us more about why you made that comment and about the incontinence in men that you deal with all the time.

Allen F. Morey, MD: For many years, I’ve worked at cancer centers where, through the various treatments for prostate cancer, the men suffered from urinary incontinence and we put a lot of artificial urinary sphincters in those patients. I had one patient who asked, “Why do I keep having this erosion?” Of course, the erosion is where the cuff compresses the tissue surrounding the urethra, and the tissue gives way, leaving a hole in the urethra. I looked at him and noticed that he was pale. And I thought, Let me check his testosterone level. We started checking it on everybody who had this problem, and sure enough, the ones who had the cup erosion — who had the atrophic tissue around the urethra — most of them had low testosterone levels. Some of this was due to the cancer treatment, but in other men, it was just due to old age.

We started thinking that this is a causal relationship. And we tested it. I had a fellow who was a board-certified pathologist before becoming a urologist. He obtained some specimens from the urethra and did very sophisticated, elegant stains on that tissue. We found that it’s just erectile tissue surrounding the urethra. That’s why I call it a sex organ. I tell my patients, “When you are a teenager, this tissue is thin, like on your pinky finger. As you get older, it becomes thicker. And then as you get even older, and you may be having cancer treatment, that tissue is gone.” You can show them your little finger; it’s about that size. All the meat is off the bone. There’s nothing left protecting the urinary mucosa from the device.

That’s why it’s important to maintain the optimal health of those tissues and for them to remain dry. Because let’s face it: Urinary incontinence is a horrible quality of life. These are my happiest patients when we fix it. Before that, when they go on vacation, they have a separate suitcase filled with diapers. They can’t go anywhere. They can’t do anything. When they become incontinent after the prostatectomy, they gain weight. And when you put in the device to treat it, they lose weight and you can track it. The urinary incontinence patients really suffer. And we need to consider the medical optimization of those patients.

Dr. Rubin: It’s so important, and I love how analogous this is to our female patients. We know that incontinence is devastating to our female patients as well, and there’s a lot of hope. As we get older we start to pee every time we cough, laugh, or sneeze. Men are a little more bothered by it when it happens; they don’t expect it. Among women, it’s thought of as normal, but it’s not normal. There is so much we can do to help these patients, ranging from conservative treatment to surgical therapies.

The connection between hormones and urethral health is true on the female side as well. As you go through menopause, the urethral tissue thins out, gets dry, gets irritated, and can cause worsening incontinence, pain with sex, and genital urinary syndrome of menopause. It’s really important.

For our primary care doctors, how should we talk about stress incontinence in men? How do we diagnose it?

Dr. Morey: It’s easy to diagnose. Just do a quick history. Find out how many pads a day they are using. You have to ask the question, and then you have them stand up and look inside their underwear. You’ll see what kind of pad they are wearing. Is it just a shield or are they actually wearing full diapers? Then I have them do a standing cough test. I stand off to the side, holding a couple of towels, and have the patient cough four times. I can tell if it’s a full stream or just a couple of drops. Is it nothing but they are wearing a pad? You match up what you see with their experience, and in an instant it tells you how severe their problem is and it helps you direct them on to further treatment, because many patients have treatment fatigue. They’ve already been through the system. They have really suffered and they don’t know which way to go. They don’t know what’s available.

Dr. Rubin: On the female side, we have pelvic floor physical therapy. We have pads and devices that you can wear, and pessaries. We have surgical options, like bulking agents into the urethra as well as urethral slings, which can be quite helpful for women. So there’s a lot of hope out there for women, and from what I learned from you at this conference, there’s a lot of hope for men as well. So talk us through treatment, from conservative to surgical options.

Dr. Morey: There hasn’t been much innovation in male incontinence treatment over the past few decades, but we’re starting to see signs of new products appearing on the horizon, so I’m very optimistic that in the next 5 or 10 years, we’ll have more. But right now it comes down to slings and artificial sphincters, which are devices with little pumps and hydraulics, and they’re very good. But they’ve been around for 50 years, and they have this other potential risk factor of the erosion of the tissue.

We don’t have a pill that we can give the patient to tighten up those muscles. We can help them with overactive bladder. But maybe the hormonal influence is a way to optimize the health of the tissue so that these surgical treatments can really deliver the best outcomes. And as I always say, and having treated so many of these patients, it’s really a game of millimeters — how much coaptation you get. If you’re off by the slightest amount, that’s an unhappy patient. So it doesn’t take much to make it a lot better.

Dr. Rubin: There’s so much hope for our patients, and this can really have an effect on sexual health. You know the benefits you see in their quality of life and sexual health when you can stop leakage.

Dr. Morey: I always take care of the waterworks first. Many of the men have both urinary problems and erectile problems. Nobody feels sexy when they’re leaking urine all over their partner. So first we take care of that. And then, in the motivated younger patients, we bring them back and talk to them about potentially having a second operation.

Dr. Rubin: And so similarly, in women with urinary incontinence, it can have a major impact on sexual health — how they show up and how they talk to their partner. So, it is really important for our primary care docs to talk to patients about urinary incontinence and not just say, “Oh, well, you’re getting older. There’s nothing that you can do.” There’s actually no age at which there is nothing that we can do. And it’s really important to refer patients to those urologists who have extra training in incontinence and sexual health, because we do care about these quality-of-life measures and there is a lot we can do, ranging from conservative to more invasive treatments. But patients really should have options.

Dr. Morey: I heard during this meeting that urinary incontinence was the number-one source of treatment regret among patients who had their prostate treated for cancer. So, this is a really big deal for our patients. And it impacts wellness, quality of life, and overall well-being.

Dr. Rubin: When we are counseling patients for cancer surgeries or cancer treatments such as radiation therapy, it’s really hard for the patients who have never had urinary incontinence to imagine what that might be like. When you’re telling them they could have a stroke or a heart attack, or they could have erectile dysfunction or urinary incontinence, it all sounds similar to them. It could happen to someone else. It’s very hard to truly counsel patients on these quality-of-life issues that they’ve never encountered before.

Dr. Morey: We have found that it takes a long time for patients to get into our office for treatment, and it’s unbelievable — often 5 years in diapers before they find us.

Dr. Rubin: Hopefully videos like this will teach our docs and our patients that there is hope out there, that you don’t need to wait through years of suffering from incontinence. So, how does somebody find a reconstructive urologist or a sexual medicine urologist?

Dr. Morey: There are a couple of good websites out there, such as fixincontinence.com and edcure.org. The device manufacturers have pretty good information for patients.

Dr. Rubin: The Sexual Medicine Society of North America (SMSNA) has a great find-a-provider website, which provides a list of urologists who are trained in both sexual health and urinary incontinence, because they both matter. Our patients deeply care about these issues.

Rachel S. Rubin, MD, has disclosed the following relevant financial relationships: Serve(d) as a speaker for Sprout; received research grant from Maternal Medical; received income in an amount equal to or greater than $250 from Absorption Pharmaceuticals, GSK, Endo.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Rachel S. Rubin, MD: I’m Dr. Rachel Rubin, urologist and sexual medicine specialist in the Washington, DC, area. We are coming to you live from the Mayo Clinic Urology Conference in Maui, Hawaii, with the world’s leading experts in men’s health, sexual health, and quality of life. I’m bringing in Dr. Allen Morey from the North Dallas area, one of the world’s leading experts in reconstructive urology. He deals with all things urinary incontinence, penile curvature, and sexual health.

Dr. Morey said something at this conference that really put my chin on the floor. He said, “The urethra is a sex organ. It is androgen dependent.” This is so important because it’s true for all genders. So, Dr. Morey, tell us more about why you made that comment and about the incontinence in men that you deal with all the time.

Allen F. Morey, MD: For many years, I’ve worked at cancer centers where, through the various treatments for prostate cancer, the men suffered from urinary incontinence and we put a lot of artificial urinary sphincters in those patients. I had one patient who asked, “Why do I keep having this erosion?” Of course, the erosion is where the cuff compresses the tissue surrounding the urethra, and the tissue gives way, leaving a hole in the urethra. I looked at him and noticed that he was pale. And I thought, Let me check his testosterone level. We started checking it on everybody who had this problem, and sure enough, the ones who had the cup erosion — who had the atrophic tissue around the urethra — most of them had low testosterone levels. Some of this was due to the cancer treatment, but in other men, it was just due to old age.

We started thinking that this is a causal relationship. And we tested it. I had a fellow who was a board-certified pathologist before becoming a urologist. He obtained some specimens from the urethra and did very sophisticated, elegant stains on that tissue. We found that it’s just erectile tissue surrounding the urethra. That’s why I call it a sex organ. I tell my patients, “When you are a teenager, this tissue is thin, like on your pinky finger. As you get older, it becomes thicker. And then as you get even older, and you may be having cancer treatment, that tissue is gone.” You can show them your little finger; it’s about that size. All the meat is off the bone. There’s nothing left protecting the urinary mucosa from the device.

That’s why it’s important to maintain the optimal health of those tissues and for them to remain dry. Because let’s face it: Urinary incontinence is a horrible quality of life. These are my happiest patients when we fix it. Before that, when they go on vacation, they have a separate suitcase filled with diapers. They can’t go anywhere. They can’t do anything. When they become incontinent after the prostatectomy, they gain weight. And when you put in the device to treat it, they lose weight and you can track it. The urinary incontinence patients really suffer. And we need to consider the medical optimization of those patients.

Dr. Rubin: It’s so important, and I love how analogous this is to our female patients. We know that incontinence is devastating to our female patients as well, and there’s a lot of hope. As we get older we start to pee every time we cough, laugh, or sneeze. Men are a little more bothered by it when it happens; they don’t expect it. Among women, it’s thought of as normal, but it’s not normal. There is so much we can do to help these patients, ranging from conservative treatment to surgical therapies.

The connection between hormones and urethral health is true on the female side as well. As you go through menopause, the urethral tissue thins out, gets dry, gets irritated, and can cause worsening incontinence, pain with sex, and genital urinary syndrome of menopause. It’s really important.

For our primary care doctors, how should we talk about stress incontinence in men? How do we diagnose it?

Dr. Morey: It’s easy to diagnose. Just do a quick history. Find out how many pads a day they are using. You have to ask the question, and then you have them stand up and look inside their underwear. You’ll see what kind of pad they are wearing. Is it just a shield or are they actually wearing full diapers? Then I have them do a standing cough test. I stand off to the side, holding a couple of towels, and have the patient cough four times. I can tell if it’s a full stream or just a couple of drops. Is it nothing but they are wearing a pad? You match up what you see with their experience, and in an instant it tells you how severe their problem is and it helps you direct them on to further treatment, because many patients have treatment fatigue. They’ve already been through the system. They have really suffered and they don’t know which way to go. They don’t know what’s available.

Dr. Rubin: On the female side, we have pelvic floor physical therapy. We have pads and devices that you can wear, and pessaries. We have surgical options, like bulking agents into the urethra as well as urethral slings, which can be quite helpful for women. So there’s a lot of hope out there for women, and from what I learned from you at this conference, there’s a lot of hope for men as well. So talk us through treatment, from conservative to surgical options.

Dr. Morey: There hasn’t been much innovation in male incontinence treatment over the past few decades, but we’re starting to see signs of new products appearing on the horizon, so I’m very optimistic that in the next 5 or 10 years, we’ll have more. But right now it comes down to slings and artificial sphincters, which are devices with little pumps and hydraulics, and they’re very good. But they’ve been around for 50 years, and they have this other potential risk factor of the erosion of the tissue.

We don’t have a pill that we can give the patient to tighten up those muscles. We can help them with overactive bladder. But maybe the hormonal influence is a way to optimize the health of the tissue so that these surgical treatments can really deliver the best outcomes. And as I always say, and having treated so many of these patients, it’s really a game of millimeters — how much coaptation you get. If you’re off by the slightest amount, that’s an unhappy patient. So it doesn’t take much to make it a lot better.

Dr. Rubin: There’s so much hope for our patients, and this can really have an effect on sexual health. You know the benefits you see in their quality of life and sexual health when you can stop leakage.

Dr. Morey: I always take care of the waterworks first. Many of the men have both urinary problems and erectile problems. Nobody feels sexy when they’re leaking urine all over their partner. So first we take care of that. And then, in the motivated younger patients, we bring them back and talk to them about potentially having a second operation.

Dr. Rubin: And so similarly, in women with urinary incontinence, it can have a major impact on sexual health — how they show up and how they talk to their partner. So, it is really important for our primary care docs to talk to patients about urinary incontinence and not just say, “Oh, well, you’re getting older. There’s nothing that you can do.” There’s actually no age at which there is nothing that we can do. And it’s really important to refer patients to those urologists who have extra training in incontinence and sexual health, because we do care about these quality-of-life measures and there is a lot we can do, ranging from conservative to more invasive treatments. But patients really should have options.

Dr. Morey: I heard during this meeting that urinary incontinence was the number-one source of treatment regret among patients who had their prostate treated for cancer. So, this is a really big deal for our patients. And it impacts wellness, quality of life, and overall well-being.

Dr. Rubin: When we are counseling patients for cancer surgeries or cancer treatments such as radiation therapy, it’s really hard for the patients who have never had urinary incontinence to imagine what that might be like. When you’re telling them they could have a stroke or a heart attack, or they could have erectile dysfunction or urinary incontinence, it all sounds similar to them. It could happen to someone else. It’s very hard to truly counsel patients on these quality-of-life issues that they’ve never encountered before.

Dr. Morey: We have found that it takes a long time for patients to get into our office for treatment, and it’s unbelievable — often 5 years in diapers before they find us.

Dr. Rubin: Hopefully videos like this will teach our docs and our patients that there is hope out there, that you don’t need to wait through years of suffering from incontinence. So, how does somebody find a reconstructive urologist or a sexual medicine urologist?

Dr. Morey: There are a couple of good websites out there, such as fixincontinence.com and edcure.org. The device manufacturers have pretty good information for patients.

Dr. Rubin: The Sexual Medicine Society of North America (SMSNA) has a great find-a-provider website, which provides a list of urologists who are trained in both sexual health and urinary incontinence, because they both matter. Our patients deeply care about these issues.

Rachel S. Rubin, MD, has disclosed the following relevant financial relationships: Serve(d) as a speaker for Sprout; received research grant from Maternal Medical; received income in an amount equal to or greater than $250 from Absorption Pharmaceuticals, GSK, Endo.

A version of this article appeared on Medscape.com.

Nearly 18 months after the US Food and Drug Administration (FDA) first acknowledged a national shortage of Adderall, the most common drug used to treat attention-deficit/hyperactivity disorder (ADHD), there is now a widespread scarcity of other stimulant medications — with no end in sight. How did this crisis develop and what measures are underway to address it?

The first shortage of immediate release formulations of amphetamine mixed salts (Adderall, Adderall IR) was reported by the FDA in October 2022. Now, the list includes Focalin, Ritalin, and Vyvanse, among others.

Adding to the ongoing crisis, the FDA announced in early February that Azurity Pharmaceuticals was voluntarily withdrawing one lot of its Zenzedi (dextroamphetamine sulfate) 30 mg tablets because of contamination with the antihistamine, carbinoxamine.

For the roughly 10 million adults and 6 million children in the United States grappling with ADHD, getting a prescription filled with the exact medication ordered by a physician is dictated by geographic location, insurance formularies, and pharmacy supply chains. It’s particularly challenging for those who live in rural or underserved areas with limited access to nearby pharmacies.

“Not a day goes by when I don’t hear from a number of unfortunately struggling patients about this shortage,” said Aditya Pawar, MD, a child and adolescent psychiatrist with the Kennedy Krieger Institute and an assistant professor of psychiatry and behavioral sciences at Johns Hopkins School of Medicine, Baltimore, Maryland.

The ADHD drug shortage is now well into its second year, and clinicians and advocates alike say there is no apparent end in sight.

How Did We Get Here?

Manufacturers and federal agencies blame the shortage on rising demand and each other, while clinicians say that insurers, drug distributors, and middlemen are also playing a role in keeping medications out of patients’ hands.

In August 2023, the Drug Enforcement Administration (DEA), which sets quotas for the production of controlled substances, and the FDA publicly blamed manufacturers for the shortages, claiming they were not using up their allocations.

At the time, the DEA said manufacturers made and sold only 70% of their quota, nearly 1 billion doses short of what they were allowed to produce and ship that year.

The agencies also noted a record-high number of prescriptions for stimulants from 2012 to 2021. Driven in part by telehealth, the demand intensified during the pandemic. One recent study reported a 14% increase in ADHD stimulant prescriptions between 2020 and 2022.

Insurers also play a role in the shortage, David Goodman, MD, an assistant professor of psychiatry and behavioral sciences also at Johns Hopkins University, told this news organization.

Stepped therapy — in which patients must try one, two, or three medications before they are authorized to receive a more expensive or newer drug — contributes to the problem, Dr. Goodman said. Demand for such medications is high and supply low. In addition, some insurers only provide coverage for in-network pharmacies, regardless of the ability of other providers outside such networks to fill prescriptions.

“If the insurance dictates where you get your pills, and that pharmacy doesn’t have the pills or that pharmacy chain in your area doesn’t have those pills, you’re out of luck,” Dr. Goodman said.

Patients as Detectives

To get prescriptions filled, patients must “turn into detectives,” Laurie Kulikosky, CEO of Children and Adults with Attention-Deficit/Hyperactivity Disorder, told this news organization. “It’s a huge stressor.”

Tracking which ADHD medications are available, on back order, or discontinued requires frequent checking of the FDA’s drug shortages website.

Some manufacturers of generic versions of mixed amphetamine salts are only fulfilling orders for existing contracts, while others say new product won’t be available until at least April or as late as September. All blame the delay on the shortage of active ingredients.

Teva, which makes both the brand and generic of Adderall, reported on the FDA’s site that its manufacturing and distribution is at record-high levels, but demand continues to rise.

The branded Concerta is available, but some makers of generic methylphenidate reported supplies won’t be available until July.

Lisdexamfetamine dimesylate in almost all dosages is either unavailable, available in restricted quantities, or on extended back order. However, the branded product Vyvanse is available.

Industry, Government Respond

In a November 2023 statement, the DEA reported that 17 of 18 drug manufacturers the agency contacted planned to use their full DEA quota and increase production for that year. The agency said it had made it easier for manufacturers to request changes in allocations and that periodically updating quotas was a possibility.

This news organization asked the DEA whether any manufacturers had not met their 2023 quotas, but an agency spokesperson said it would not comment.

An FDA spokesperson said it could help manufacturers ask for bigger quotas and to increase production, noting that in 2023, the DEA increased the quota for methylphenidate following an FDA request.

“The FDA is in frequent communication with the manufacturers of ADHD stimulant medications and the DEA, and we will continue to monitor supply,” the spokesperson said.

For 2024, the FDA told the DEA that it predicted a 3.1% increase in use of amphetamine, methylphenidate (including dexmethylphenidate), and lisdexamfetamine. The DEA took that into account when it issued its final quotas for 2024. Whether those amounts will be enough remains to be seen.

With many drugs — not just those for ADHD — in short supply, in February, the US Department of Health and Human Services (HHS) and the Federal Trade Commission opened an inquiry of sorts, seeking comments on how middlemen and others were influencing pricing and supply of generic drugs.

“When you’re prescribed an important medication by your doctor and you learn the drug is out of stock, your heart sinks,” HHS Secretary Xavier Becerra said in a statement. “This devastating reality is the case for too many Americans who need generic drugs for ADHD, cancer, and other conditions.”

On the comments site, which is open until April 15, many of the 4000-plus complaints filed to-date are from individuals with ADHD.

Dr. Pawar said clinicians can’t know what’s going on between the FDA, the DEA, and manufacturers, adding that, “they need to sit together and figure something out.”

Even Members of Congress have had trouble getting answers. In October, Rep. Abigail Spanberger (D-Virginia) and a dozen colleagues wrote to the FDA and DEA seeking information on how the agencies were responding to stimulant shortages. The DEA has still not replied.

Workarounds the Only Option?

In the past, physicians would prescribe the optimal medication for individual patients based on clinical factors. Now, one of the major factors in determining drug choice is the agent that has “the highest likelihood of benefit and the lowest likelihood of administrative demand or burden,” Dr. Goodman said.

With so many medications in short supply, clinicians have figured out workarounds to get prescriptions filled, but they don’t often pan out.

If a patient needs a 60-mg daily dose of a medication and the pharmacy doesn’t have any 60-mg pills, Dr. Goodman said he might write a prescription for a 30-mg pill to be taken twice a day. However, insurers often will cover only 30 pills for a month, which can thwart this strategy.

Dr. Pawar said he sometimes prescribes Journay PM in lieu of Concerta because it is often available. But insurers may deny coverage of Journay PM because it is a newer medication, he said. When prescribing ADHD medications, he also provides his patients with a list of potential substitutes so they can ask the pharmacist if any are in stock.

With no end to the shortage in sight, clinicians must often prescribe multiple medications until their patients are able to find one that’s available. In addition, patients are burdened with making calls and visits to multiple pharmacies until they find one that can fill their prescription.

Meanwhile, the ripple effects to the ADHD drug shortage continue to spread. Extended periods without treatment can lead to declining job performance or job loss, fractured relationships, and even financial distress, Dr. Goodman said.

“If you go without your pills for a month and you’re not performing, your work declines and you lose your job as a result, that’s not on you — that’s on the fact that you can’t get your treatment,” he noted. “The shortage is no longer an inconvenience.”

Dr. Goodman, Dr. Pawar, and Ms. Kulikosky reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Nearly 18 months after the US Food and Drug Administration (FDA) first acknowledged a national shortage of Adderall, the most common drug used to treat attention-deficit/hyperactivity disorder (ADHD), there is now a widespread scarcity of other stimulant medications — with no end in sight. How did this crisis develop and what measures are underway to address it?

The first shortage of immediate release formulations of amphetamine mixed salts (Adderall, Adderall IR) was reported by the FDA in October 2022. Now, the list includes Focalin, Ritalin, and Vyvanse, among others.

Adding to the ongoing crisis, the FDA announced in early February that Azurity Pharmaceuticals was voluntarily withdrawing one lot of its Zenzedi (dextroamphetamine sulfate) 30 mg tablets because of contamination with the antihistamine, carbinoxamine.

For the roughly 10 million adults and 6 million children in the United States grappling with ADHD, getting a prescription filled with the exact medication ordered by a physician is dictated by geographic location, insurance formularies, and pharmacy supply chains. It’s particularly challenging for those who live in rural or underserved areas with limited access to nearby pharmacies.

“Not a day goes by when I don’t hear from a number of unfortunately struggling patients about this shortage,” said Aditya Pawar, MD, a child and adolescent psychiatrist with the Kennedy Krieger Institute and an assistant professor of psychiatry and behavioral sciences at Johns Hopkins School of Medicine, Baltimore, Maryland.

The ADHD drug shortage is now well into its second year, and clinicians and advocates alike say there is no apparent end in sight.

How Did We Get Here?

Manufacturers and federal agencies blame the shortage on rising demand and each other, while clinicians say that insurers, drug distributors, and middlemen are also playing a role in keeping medications out of patients’ hands.

In August 2023, the Drug Enforcement Administration (DEA), which sets quotas for the production of controlled substances, and the FDA publicly blamed manufacturers for the shortages, claiming they were not using up their allocations.

At the time, the DEA said manufacturers made and sold only 70% of their quota, nearly 1 billion doses short of what they were allowed to produce and ship that year.

The agencies also noted a record-high number of prescriptions for stimulants from 2012 to 2021. Driven in part by telehealth, the demand intensified during the pandemic. One recent study reported a 14% increase in ADHD stimulant prescriptions between 2020 and 2022.

Insurers also play a role in the shortage, David Goodman, MD, an assistant professor of psychiatry and behavioral sciences also at Johns Hopkins University, told this news organization.

Stepped therapy — in which patients must try one, two, or three medications before they are authorized to receive a more expensive or newer drug — contributes to the problem, Dr. Goodman said. Demand for such medications is high and supply low. In addition, some insurers only provide coverage for in-network pharmacies, regardless of the ability of other providers outside such networks to fill prescriptions.

“If the insurance dictates where you get your pills, and that pharmacy doesn’t have the pills or that pharmacy chain in your area doesn’t have those pills, you’re out of luck,” Dr. Goodman said.

Patients as Detectives

To get prescriptions filled, patients must “turn into detectives,” Laurie Kulikosky, CEO of Children and Adults with Attention-Deficit/Hyperactivity Disorder, told this news organization. “It’s a huge stressor.”

Tracking which ADHD medications are available, on back order, or discontinued requires frequent checking of the FDA’s drug shortages website.

Some manufacturers of generic versions of mixed amphetamine salts are only fulfilling orders for existing contracts, while others say new product won’t be available until at least April or as late as September. All blame the delay on the shortage of active ingredients.

Teva, which makes both the brand and generic of Adderall, reported on the FDA’s site that its manufacturing and distribution is at record-high levels, but demand continues to rise.

The branded Concerta is available, but some makers of generic methylphenidate reported supplies won’t be available until July.

Lisdexamfetamine dimesylate in almost all dosages is either unavailable, available in restricted quantities, or on extended back order. However, the branded product Vyvanse is available.

Industry, Government Respond

In a November 2023 statement, the DEA reported that 17 of 18 drug manufacturers the agency contacted planned to use their full DEA quota and increase production for that year. The agency said it had made it easier for manufacturers to request changes in allocations and that periodically updating quotas was a possibility.

This news organization asked the DEA whether any manufacturers had not met their 2023 quotas, but an agency spokesperson said it would not comment.

An FDA spokesperson said it could help manufacturers ask for bigger quotas and to increase production, noting that in 2023, the DEA increased the quota for methylphenidate following an FDA request.

“The FDA is in frequent communication with the manufacturers of ADHD stimulant medications and the DEA, and we will continue to monitor supply,” the spokesperson said.

For 2024, the FDA told the DEA that it predicted a 3.1% increase in use of amphetamine, methylphenidate (including dexmethylphenidate), and lisdexamfetamine. The DEA took that into account when it issued its final quotas for 2024. Whether those amounts will be enough remains to be seen.

With many drugs — not just those for ADHD — in short supply, in February, the US Department of Health and Human Services (HHS) and the Federal Trade Commission opened an inquiry of sorts, seeking comments on how middlemen and others were influencing pricing and supply of generic drugs.

“When you’re prescribed an important medication by your doctor and you learn the drug is out of stock, your heart sinks,” HHS Secretary Xavier Becerra said in a statement. “This devastating reality is the case for too many Americans who need generic drugs for ADHD, cancer, and other conditions.”

On the comments site, which is open until April 15, many of the 4000-plus complaints filed to-date are from individuals with ADHD.

Dr. Pawar said clinicians can’t know what’s going on between the FDA, the DEA, and manufacturers, adding that, “they need to sit together and figure something out.”

Even Members of Congress have had trouble getting answers. In October, Rep. Abigail Spanberger (D-Virginia) and a dozen colleagues wrote to the FDA and DEA seeking information on how the agencies were responding to stimulant shortages. The DEA has still not replied.

Workarounds the Only Option?

In the past, physicians would prescribe the optimal medication for individual patients based on clinical factors. Now, one of the major factors in determining drug choice is the agent that has “the highest likelihood of benefit and the lowest likelihood of administrative demand or burden,” Dr. Goodman said.

With so many medications in short supply, clinicians have figured out workarounds to get prescriptions filled, but they don’t often pan out.

If a patient needs a 60-mg daily dose of a medication and the pharmacy doesn’t have any 60-mg pills, Dr. Goodman said he might write a prescription for a 30-mg pill to be taken twice a day. However, insurers often will cover only 30 pills for a month, which can thwart this strategy.

Dr. Pawar said he sometimes prescribes Journay PM in lieu of Concerta because it is often available. But insurers may deny coverage of Journay PM because it is a newer medication, he said. When prescribing ADHD medications, he also provides his patients with a list of potential substitutes so they can ask the pharmacist if any are in stock.

With no end to the shortage in sight, clinicians must often prescribe multiple medications until their patients are able to find one that’s available. In addition, patients are burdened with making calls and visits to multiple pharmacies until they find one that can fill their prescription.

Meanwhile, the ripple effects to the ADHD drug shortage continue to spread. Extended periods without treatment can lead to declining job performance or job loss, fractured relationships, and even financial distress, Dr. Goodman said.

“If you go without your pills for a month and you’re not performing, your work declines and you lose your job as a result, that’s not on you — that’s on the fact that you can’t get your treatment,” he noted. “The shortage is no longer an inconvenience.”

Dr. Goodman, Dr. Pawar, and Ms. Kulikosky reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Nearly 18 months after the US Food and Drug Administration (FDA) first acknowledged a national shortage of Adderall, the most common drug used to treat attention-deficit/hyperactivity disorder (ADHD), there is now a widespread scarcity of other stimulant medications — with no end in sight. How did this crisis develop and what measures are underway to address it?

The first shortage of immediate release formulations of amphetamine mixed salts (Adderall, Adderall IR) was reported by the FDA in October 2022. Now, the list includes Focalin, Ritalin, and Vyvanse, among others.

Adding to the ongoing crisis, the FDA announced in early February that Azurity Pharmaceuticals was voluntarily withdrawing one lot of its Zenzedi (dextroamphetamine sulfate) 30 mg tablets because of contamination with the antihistamine, carbinoxamine.

For the roughly 10 million adults and 6 million children in the United States grappling with ADHD, getting a prescription filled with the exact medication ordered by a physician is dictated by geographic location, insurance formularies, and pharmacy supply chains. It’s particularly challenging for those who live in rural or underserved areas with limited access to nearby pharmacies.

“Not a day goes by when I don’t hear from a number of unfortunately struggling patients about this shortage,” said Aditya Pawar, MD, a child and adolescent psychiatrist with the Kennedy Krieger Institute and an assistant professor of psychiatry and behavioral sciences at Johns Hopkins School of Medicine, Baltimore, Maryland.

The ADHD drug shortage is now well into its second year, and clinicians and advocates alike say there is no apparent end in sight.

How Did We Get Here?

Manufacturers and federal agencies blame the shortage on rising demand and each other, while clinicians say that insurers, drug distributors, and middlemen are also playing a role in keeping medications out of patients’ hands.

In August 2023, the Drug Enforcement Administration (DEA), which sets quotas for the production of controlled substances, and the FDA publicly blamed manufacturers for the shortages, claiming they were not using up their allocations.

At the time, the DEA said manufacturers made and sold only 70% of their quota, nearly 1 billion doses short of what they were allowed to produce and ship that year.

The agencies also noted a record-high number of prescriptions for stimulants from 2012 to 2021. Driven in part by telehealth, the demand intensified during the pandemic. One recent study reported a 14% increase in ADHD stimulant prescriptions between 2020 and 2022.

Insurers also play a role in the shortage, David Goodman, MD, an assistant professor of psychiatry and behavioral sciences also at Johns Hopkins University, told this news organization.

Stepped therapy — in which patients must try one, two, or three medications before they are authorized to receive a more expensive or newer drug — contributes to the problem, Dr. Goodman said. Demand for such medications is high and supply low. In addition, some insurers only provide coverage for in-network pharmacies, regardless of the ability of other providers outside such networks to fill prescriptions.

“If the insurance dictates where you get your pills, and that pharmacy doesn’t have the pills or that pharmacy chain in your area doesn’t have those pills, you’re out of luck,” Dr. Goodman said.

Patients as Detectives

To get prescriptions filled, patients must “turn into detectives,” Laurie Kulikosky, CEO of Children and Adults with Attention-Deficit/Hyperactivity Disorder, told this news organization. “It’s a huge stressor.”

Tracking which ADHD medications are available, on back order, or discontinued requires frequent checking of the FDA’s drug shortages website.

Some manufacturers of generic versions of mixed amphetamine salts are only fulfilling orders for existing contracts, while others say new product won’t be available until at least April or as late as September. All blame the delay on the shortage of active ingredients.

Teva, which makes both the brand and generic of Adderall, reported on the FDA’s site that its manufacturing and distribution is at record-high levels, but demand continues to rise.

The branded Concerta is available, but some makers of generic methylphenidate reported supplies won’t be available until July.

Lisdexamfetamine dimesylate in almost all dosages is either unavailable, available in restricted quantities, or on extended back order. However, the branded product Vyvanse is available.

Industry, Government Respond

In a November 2023 statement, the DEA reported that 17 of 18 drug manufacturers the agency contacted planned to use their full DEA quota and increase production for that year. The agency said it had made it easier for manufacturers to request changes in allocations and that periodically updating quotas was a possibility.

This news organization asked the DEA whether any manufacturers had not met their 2023 quotas, but an agency spokesperson said it would not comment.

An FDA spokesperson said it could help manufacturers ask for bigger quotas and to increase production, noting that in 2023, the DEA increased the quota for methylphenidate following an FDA request.

“The FDA is in frequent communication with the manufacturers of ADHD stimulant medications and the DEA, and we will continue to monitor supply,” the spokesperson said.

For 2024, the FDA told the DEA that it predicted a 3.1% increase in use of amphetamine, methylphenidate (including dexmethylphenidate), and lisdexamfetamine. The DEA took that into account when it issued its final quotas for 2024. Whether those amounts will be enough remains to be seen.

With many drugs — not just those for ADHD — in short supply, in February, the US Department of Health and Human Services (HHS) and the Federal Trade Commission opened an inquiry of sorts, seeking comments on how middlemen and others were influencing pricing and supply of generic drugs.

“When you’re prescribed an important medication by your doctor and you learn the drug is out of stock, your heart sinks,” HHS Secretary Xavier Becerra said in a statement. “This devastating reality is the case for too many Americans who need generic drugs for ADHD, cancer, and other conditions.”

On the comments site, which is open until April 15, many of the 4000-plus complaints filed to-date are from individuals with ADHD.

Dr. Pawar said clinicians can’t know what’s going on between the FDA, the DEA, and manufacturers, adding that, “they need to sit together and figure something out.”

Even Members of Congress have had trouble getting answers. In October, Rep. Abigail Spanberger (D-Virginia) and a dozen colleagues wrote to the FDA and DEA seeking information on how the agencies were responding to stimulant shortages. The DEA has still not replied.

Workarounds the Only Option?

In the past, physicians would prescribe the optimal medication for individual patients based on clinical factors. Now, one of the major factors in determining drug choice is the agent that has “the highest likelihood of benefit and the lowest likelihood of administrative demand or burden,” Dr. Goodman said.

With so many medications in short supply, clinicians have figured out workarounds to get prescriptions filled, but they don’t often pan out.

If a patient needs a 60-mg daily dose of a medication and the pharmacy doesn’t have any 60-mg pills, Dr. Goodman said he might write a prescription for a 30-mg pill to be taken twice a day. However, insurers often will cover only 30 pills for a month, which can thwart this strategy.

Dr. Pawar said he sometimes prescribes Journay PM in lieu of Concerta because it is often available. But insurers may deny coverage of Journay PM because it is a newer medication, he said. When prescribing ADHD medications, he also provides his patients with a list of potential substitutes so they can ask the pharmacist if any are in stock.

With no end to the shortage in sight, clinicians must often prescribe multiple medications until their patients are able to find one that’s available. In addition, patients are burdened with making calls and visits to multiple pharmacies until they find one that can fill their prescription.

Meanwhile, the ripple effects to the ADHD drug shortage continue to spread. Extended periods without treatment can lead to declining job performance or job loss, fractured relationships, and even financial distress, Dr. Goodman said.

“If you go without your pills for a month and you’re not performing, your work declines and you lose your job as a result, that’s not on you — that’s on the fact that you can’t get your treatment,” he noted. “The shortage is no longer an inconvenience.”

Dr. Goodman, Dr. Pawar, and Ms. Kulikosky reported no relevant financial relationships.

A version of this article appeared on Medscape.com.