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Radioactive iodine can be first-line for hyperthyroidism, says UK
New UK guidelines for the treatment of hyperthyroidism, including Graves’ disease, place heavier emphasis on the use of radioactive iodine as the frontline treatment for patients unlikely to remain remission-free on the medications, as opposed to the alternative of antithyroid medications as a first choice.
senior author Kristien Boelaert, MD, PhD, who led the guideline committee, said in an interview.
“Recommending the use of radioactive iodine as first-line treatment for adults with Graves’ disease is a change to current practice and should reduce the variation between centers as to when radioactive iodine is considered appropriate,” the guidelines further state.
The new recommendations on hyperthyroidism are part of broader guidelines on thyroid disease by the UK National Institute for Health and Care Excellence (NICE), which concludes that radioactive iodine results in cure in as many as 90% of hyperthyroidism cases.
The recommendations were published in a guideline summary in BMJ by research fellow Melina Vasileiou of the National Guideline Centre, Royal College of Physicians, London, and colleagues.
Current guidelines in the United Kingdom and Europe typically call for radioactive iodine to be reserved for use as a definitive treatment only after relapse following antithyroid medication treatment. The latest European Thyroid Association guidelines were published in 2018.
Elsewhere guidelines vary, with many, including those by the American Thyroid Association (ATA) – the most recent published in 2016 – generally calling for treatment with either antithyroid medications, radioactive iodine, or total thyroidectomy, in the absence of any contraindications to each treatment option.
“The U.S. tends to use more radioactive iodine, while Europe, Latin America, and Japan lean more toward (perhaps longer) use of antithyroid medications,” Angela Leung, MD, associate clinical professor of medicine in the division of endocrinology, diabetes, and metabolism, department of medicine, University of California, Los Angeles, said in an interview.
“Preferences of deciding which treatment option, which may involve more than one option if antithyroid medications are used initially, depend on a variety of factors related to patient desire, comorbidities, and availability of the therapy,” she explained.
Concerns including worsening thyroid eye disease, cardiovascular disease, and development of secondary cancers have caused some hesitation in the use of frontline radioiodine therapy.
And one notably controversial article, published last year, suggested a link between radioactive iodine therapy and an increased risk of cancer mortality. However, as reported by Medscape Medical News, the article spurred debate, with the Society for Endocrinology and British Thyroid Association issuing a joint statement urging caution in interpretation of the findings.
Evidence supporting first-line radioactive iodine
Patients treated with radioactive iodine take a single tablet that contains iodine and a low dose of radiation, which is absorbed by the thyroid. After taking the treatment patients are advised to avoid prolonged close contact with children and pregnant women for a few days or weeks and to avoid getting pregnant or fathering a child for several months. The treatment is likely to lead to an underactive thyroid gland that will require ongoing treatment with thyroid hormone replacement.
In providing evidence in favor of the benefits of radioactive iodine over the risks, the new NICE guidelines cite five randomized controlled trials of people with hyperthyroid disease, which, though defined as “low quality” evidence, collectively indicate that long-term outcomes were improved with radioactive iodine treatment compared with antithyroid drugs – despite the former having a higher risk of thyroid eye disease (also known as Graves’ ophthalmopathy).
In addition, eight nonrandomized studies show no evidence of a clinically important increase in cancer diagnoses or deaths between people treated with radioactive iodine or surgery, or between people treated with radioactive iodine and healthy controls, the guideline committee notes.
“The strongest arguments (in favor of radioactive iodine as a first-line therapy) were the likelihood of inducing remission of Graves’ disease with radioactive iodine, the finding that radioiodine is a safe treatment (confirmed in the safety review undertaken by NICE), and the reduction in the need for patients to remain on antithyroid drugs, which may have significant side effects and treatment which usually requires repeated hospital visits or follow-up under a hospital service,” said Dr. Boelaert.
The new guideline does recommend that antithyroid medication is acceptable as the first-line treatment among patients considered likely to achieve remission.
Dr. Leung explains that the percentage of patients with Graves’ disease who can achieve remission with antithyroid drugs ranges from 30% to 50%. She noted some evidence does suggest the long-term use of the drugs may be acceptable.
“There are some data that ... report the relative safety of long-term use of antithyroid drugs (beyond 24 months) for both Graves’ disease and autonomous thyroid nodules,” Dr. Leung elaborated.
Pregnancy concerns and cost-effectiveness of radioactive iodine
Radioactive iodine therapy is meanwhile not suitable if malignancy is suspected, if the patient is pregnant or trying to become pregnant, or if the patient has active thyroid eye disease, the experts agree.
Dr. Leung noted that although “it is generally advised to not treat Graves’ disease with radioiodine if there is concurrent thyroid eye disease, steroids are a proven effective therapy to decrease this risk in select patients.”
And among pregnant patients, “antithyroid medications should be minimally used in the lowest possible doses,” Dr. Leung said, although she added that, despite their potential risks, the drugs “represent a viable option” for this patient population.
“Also, many would actually advocate for total thyroidectomy in women who are thinking of pregnancy in the near future,” she noted.
Another factor of relevance in the guideline recommendations – cost – also favors radioactive iodine, the committee noted.
“Economic evidence showed that radioactive iodine was the most cost-effective intervention,” the committee pointed out.
Trabs advised for determination of hyperthyroidism cause
The new U.K. guidelines further underscore the importance of establishing the underlying cause of hyperthyroidism to ensure appropriate treatment, and the preferred method for doing so is the measurement of thyroid-stimulating hormone receptor antibodies (TRAbs).
“It is important to identify the underlying cause of thyrotoxicosis through measurement of TRAbs, or radioisotope scanning, in order to distinguish hyperthyroidism from transient causes of thyrotoxicosis such as transient thyroiditis, which only requires supportive treatment,” explained Dr. Boelaert, consultant endocrinologist and director of the National Institute for Health Research Integrated Academic Training Program at the Institute of Applied Health Research, University of Birmingham (England).
“In addition, this will help distinguish Graves’ disease from toxic nodular hyperthyroidism, which is important as antithyroid drugs are not effective in inducing a cure in the latter,” she explained.
Meanwhile, the new guidelines further note that although use of diagnostic ultrasound is informative when palpation suggests thyroid nodules, it is of limited diagnostic value for Graves’ disease.
“The recommendation (suggests that) thyroid ultrasonography should only be offered if there is a palpable thyroid nodule,” Dr. Boelaert noted.
She concluded: “There has been uncertainty in the U.K. about the best treatment for hyperthyroidism despite radioactive iodine being the most common first-line treatment for this condition in the United States. We are very pleased to have been able to work with NICE to provide clear new guidance which we hope will improve outcomes for patients with this condition.”
The National Guideline Centre was commissioned and funded by NICE to develop the guideline. No authors received specific funding to write the summary. Dr. Boelaert has reported no relevant financial relationships. Disclosures for the other authors are listed in the article.
This article first appeared on Medscape.com.
New UK guidelines for the treatment of hyperthyroidism, including Graves’ disease, place heavier emphasis on the use of radioactive iodine as the frontline treatment for patients unlikely to remain remission-free on the medications, as opposed to the alternative of antithyroid medications as a first choice.
senior author Kristien Boelaert, MD, PhD, who led the guideline committee, said in an interview.
“Recommending the use of radioactive iodine as first-line treatment for adults with Graves’ disease is a change to current practice and should reduce the variation between centers as to when radioactive iodine is considered appropriate,” the guidelines further state.
The new recommendations on hyperthyroidism are part of broader guidelines on thyroid disease by the UK National Institute for Health and Care Excellence (NICE), which concludes that radioactive iodine results in cure in as many as 90% of hyperthyroidism cases.
The recommendations were published in a guideline summary in BMJ by research fellow Melina Vasileiou of the National Guideline Centre, Royal College of Physicians, London, and colleagues.
Current guidelines in the United Kingdom and Europe typically call for radioactive iodine to be reserved for use as a definitive treatment only after relapse following antithyroid medication treatment. The latest European Thyroid Association guidelines were published in 2018.
Elsewhere guidelines vary, with many, including those by the American Thyroid Association (ATA) – the most recent published in 2016 – generally calling for treatment with either antithyroid medications, radioactive iodine, or total thyroidectomy, in the absence of any contraindications to each treatment option.
“The U.S. tends to use more radioactive iodine, while Europe, Latin America, and Japan lean more toward (perhaps longer) use of antithyroid medications,” Angela Leung, MD, associate clinical professor of medicine in the division of endocrinology, diabetes, and metabolism, department of medicine, University of California, Los Angeles, said in an interview.
“Preferences of deciding which treatment option, which may involve more than one option if antithyroid medications are used initially, depend on a variety of factors related to patient desire, comorbidities, and availability of the therapy,” she explained.
Concerns including worsening thyroid eye disease, cardiovascular disease, and development of secondary cancers have caused some hesitation in the use of frontline radioiodine therapy.
And one notably controversial article, published last year, suggested a link between radioactive iodine therapy and an increased risk of cancer mortality. However, as reported by Medscape Medical News, the article spurred debate, with the Society for Endocrinology and British Thyroid Association issuing a joint statement urging caution in interpretation of the findings.
Evidence supporting first-line radioactive iodine
Patients treated with radioactive iodine take a single tablet that contains iodine and a low dose of radiation, which is absorbed by the thyroid. After taking the treatment patients are advised to avoid prolonged close contact with children and pregnant women for a few days or weeks and to avoid getting pregnant or fathering a child for several months. The treatment is likely to lead to an underactive thyroid gland that will require ongoing treatment with thyroid hormone replacement.
In providing evidence in favor of the benefits of radioactive iodine over the risks, the new NICE guidelines cite five randomized controlled trials of people with hyperthyroid disease, which, though defined as “low quality” evidence, collectively indicate that long-term outcomes were improved with radioactive iodine treatment compared with antithyroid drugs – despite the former having a higher risk of thyroid eye disease (also known as Graves’ ophthalmopathy).
In addition, eight nonrandomized studies show no evidence of a clinically important increase in cancer diagnoses or deaths between people treated with radioactive iodine or surgery, or between people treated with radioactive iodine and healthy controls, the guideline committee notes.
“The strongest arguments (in favor of radioactive iodine as a first-line therapy) were the likelihood of inducing remission of Graves’ disease with radioactive iodine, the finding that radioiodine is a safe treatment (confirmed in the safety review undertaken by NICE), and the reduction in the need for patients to remain on antithyroid drugs, which may have significant side effects and treatment which usually requires repeated hospital visits or follow-up under a hospital service,” said Dr. Boelaert.
The new guideline does recommend that antithyroid medication is acceptable as the first-line treatment among patients considered likely to achieve remission.
Dr. Leung explains that the percentage of patients with Graves’ disease who can achieve remission with antithyroid drugs ranges from 30% to 50%. She noted some evidence does suggest the long-term use of the drugs may be acceptable.
“There are some data that ... report the relative safety of long-term use of antithyroid drugs (beyond 24 months) for both Graves’ disease and autonomous thyroid nodules,” Dr. Leung elaborated.
Pregnancy concerns and cost-effectiveness of radioactive iodine
Radioactive iodine therapy is meanwhile not suitable if malignancy is suspected, if the patient is pregnant or trying to become pregnant, or if the patient has active thyroid eye disease, the experts agree.
Dr. Leung noted that although “it is generally advised to not treat Graves’ disease with radioiodine if there is concurrent thyroid eye disease, steroids are a proven effective therapy to decrease this risk in select patients.”
And among pregnant patients, “antithyroid medications should be minimally used in the lowest possible doses,” Dr. Leung said, although she added that, despite their potential risks, the drugs “represent a viable option” for this patient population.
“Also, many would actually advocate for total thyroidectomy in women who are thinking of pregnancy in the near future,” she noted.
Another factor of relevance in the guideline recommendations – cost – also favors radioactive iodine, the committee noted.
“Economic evidence showed that radioactive iodine was the most cost-effective intervention,” the committee pointed out.
Trabs advised for determination of hyperthyroidism cause
The new U.K. guidelines further underscore the importance of establishing the underlying cause of hyperthyroidism to ensure appropriate treatment, and the preferred method for doing so is the measurement of thyroid-stimulating hormone receptor antibodies (TRAbs).
“It is important to identify the underlying cause of thyrotoxicosis through measurement of TRAbs, or radioisotope scanning, in order to distinguish hyperthyroidism from transient causes of thyrotoxicosis such as transient thyroiditis, which only requires supportive treatment,” explained Dr. Boelaert, consultant endocrinologist and director of the National Institute for Health Research Integrated Academic Training Program at the Institute of Applied Health Research, University of Birmingham (England).
“In addition, this will help distinguish Graves’ disease from toxic nodular hyperthyroidism, which is important as antithyroid drugs are not effective in inducing a cure in the latter,” she explained.
Meanwhile, the new guidelines further note that although use of diagnostic ultrasound is informative when palpation suggests thyroid nodules, it is of limited diagnostic value for Graves’ disease.
“The recommendation (suggests that) thyroid ultrasonography should only be offered if there is a palpable thyroid nodule,” Dr. Boelaert noted.
She concluded: “There has been uncertainty in the U.K. about the best treatment for hyperthyroidism despite radioactive iodine being the most common first-line treatment for this condition in the United States. We are very pleased to have been able to work with NICE to provide clear new guidance which we hope will improve outcomes for patients with this condition.”
The National Guideline Centre was commissioned and funded by NICE to develop the guideline. No authors received specific funding to write the summary. Dr. Boelaert has reported no relevant financial relationships. Disclosures for the other authors are listed in the article.
This article first appeared on Medscape.com.
New UK guidelines for the treatment of hyperthyroidism, including Graves’ disease, place heavier emphasis on the use of radioactive iodine as the frontline treatment for patients unlikely to remain remission-free on the medications, as opposed to the alternative of antithyroid medications as a first choice.
senior author Kristien Boelaert, MD, PhD, who led the guideline committee, said in an interview.
“Recommending the use of radioactive iodine as first-line treatment for adults with Graves’ disease is a change to current practice and should reduce the variation between centers as to when radioactive iodine is considered appropriate,” the guidelines further state.
The new recommendations on hyperthyroidism are part of broader guidelines on thyroid disease by the UK National Institute for Health and Care Excellence (NICE), which concludes that radioactive iodine results in cure in as many as 90% of hyperthyroidism cases.
The recommendations were published in a guideline summary in BMJ by research fellow Melina Vasileiou of the National Guideline Centre, Royal College of Physicians, London, and colleagues.
Current guidelines in the United Kingdom and Europe typically call for radioactive iodine to be reserved for use as a definitive treatment only after relapse following antithyroid medication treatment. The latest European Thyroid Association guidelines were published in 2018.
Elsewhere guidelines vary, with many, including those by the American Thyroid Association (ATA) – the most recent published in 2016 – generally calling for treatment with either antithyroid medications, radioactive iodine, or total thyroidectomy, in the absence of any contraindications to each treatment option.
“The U.S. tends to use more radioactive iodine, while Europe, Latin America, and Japan lean more toward (perhaps longer) use of antithyroid medications,” Angela Leung, MD, associate clinical professor of medicine in the division of endocrinology, diabetes, and metabolism, department of medicine, University of California, Los Angeles, said in an interview.
“Preferences of deciding which treatment option, which may involve more than one option if antithyroid medications are used initially, depend on a variety of factors related to patient desire, comorbidities, and availability of the therapy,” she explained.
Concerns including worsening thyroid eye disease, cardiovascular disease, and development of secondary cancers have caused some hesitation in the use of frontline radioiodine therapy.
And one notably controversial article, published last year, suggested a link between radioactive iodine therapy and an increased risk of cancer mortality. However, as reported by Medscape Medical News, the article spurred debate, with the Society for Endocrinology and British Thyroid Association issuing a joint statement urging caution in interpretation of the findings.
Evidence supporting first-line radioactive iodine
Patients treated with radioactive iodine take a single tablet that contains iodine and a low dose of radiation, which is absorbed by the thyroid. After taking the treatment patients are advised to avoid prolonged close contact with children and pregnant women for a few days or weeks and to avoid getting pregnant or fathering a child for several months. The treatment is likely to lead to an underactive thyroid gland that will require ongoing treatment with thyroid hormone replacement.
In providing evidence in favor of the benefits of radioactive iodine over the risks, the new NICE guidelines cite five randomized controlled trials of people with hyperthyroid disease, which, though defined as “low quality” evidence, collectively indicate that long-term outcomes were improved with radioactive iodine treatment compared with antithyroid drugs – despite the former having a higher risk of thyroid eye disease (also known as Graves’ ophthalmopathy).
In addition, eight nonrandomized studies show no evidence of a clinically important increase in cancer diagnoses or deaths between people treated with radioactive iodine or surgery, or between people treated with radioactive iodine and healthy controls, the guideline committee notes.
“The strongest arguments (in favor of radioactive iodine as a first-line therapy) were the likelihood of inducing remission of Graves’ disease with radioactive iodine, the finding that radioiodine is a safe treatment (confirmed in the safety review undertaken by NICE), and the reduction in the need for patients to remain on antithyroid drugs, which may have significant side effects and treatment which usually requires repeated hospital visits or follow-up under a hospital service,” said Dr. Boelaert.
The new guideline does recommend that antithyroid medication is acceptable as the first-line treatment among patients considered likely to achieve remission.
Dr. Leung explains that the percentage of patients with Graves’ disease who can achieve remission with antithyroid drugs ranges from 30% to 50%. She noted some evidence does suggest the long-term use of the drugs may be acceptable.
“There are some data that ... report the relative safety of long-term use of antithyroid drugs (beyond 24 months) for both Graves’ disease and autonomous thyroid nodules,” Dr. Leung elaborated.
Pregnancy concerns and cost-effectiveness of radioactive iodine
Radioactive iodine therapy is meanwhile not suitable if malignancy is suspected, if the patient is pregnant or trying to become pregnant, or if the patient has active thyroid eye disease, the experts agree.
Dr. Leung noted that although “it is generally advised to not treat Graves’ disease with radioiodine if there is concurrent thyroid eye disease, steroids are a proven effective therapy to decrease this risk in select patients.”
And among pregnant patients, “antithyroid medications should be minimally used in the lowest possible doses,” Dr. Leung said, although she added that, despite their potential risks, the drugs “represent a viable option” for this patient population.
“Also, many would actually advocate for total thyroidectomy in women who are thinking of pregnancy in the near future,” she noted.
Another factor of relevance in the guideline recommendations – cost – also favors radioactive iodine, the committee noted.
“Economic evidence showed that radioactive iodine was the most cost-effective intervention,” the committee pointed out.
Trabs advised for determination of hyperthyroidism cause
The new U.K. guidelines further underscore the importance of establishing the underlying cause of hyperthyroidism to ensure appropriate treatment, and the preferred method for doing so is the measurement of thyroid-stimulating hormone receptor antibodies (TRAbs).
“It is important to identify the underlying cause of thyrotoxicosis through measurement of TRAbs, or radioisotope scanning, in order to distinguish hyperthyroidism from transient causes of thyrotoxicosis such as transient thyroiditis, which only requires supportive treatment,” explained Dr. Boelaert, consultant endocrinologist and director of the National Institute for Health Research Integrated Academic Training Program at the Institute of Applied Health Research, University of Birmingham (England).
“In addition, this will help distinguish Graves’ disease from toxic nodular hyperthyroidism, which is important as antithyroid drugs are not effective in inducing a cure in the latter,” she explained.
Meanwhile, the new guidelines further note that although use of diagnostic ultrasound is informative when palpation suggests thyroid nodules, it is of limited diagnostic value for Graves’ disease.
“The recommendation (suggests that) thyroid ultrasonography should only be offered if there is a palpable thyroid nodule,” Dr. Boelaert noted.
She concluded: “There has been uncertainty in the U.K. about the best treatment for hyperthyroidism despite radioactive iodine being the most common first-line treatment for this condition in the United States. We are very pleased to have been able to work with NICE to provide clear new guidance which we hope will improve outcomes for patients with this condition.”
The National Guideline Centre was commissioned and funded by NICE to develop the guideline. No authors received specific funding to write the summary. Dr. Boelaert has reported no relevant financial relationships. Disclosures for the other authors are listed in the article.
This article first appeared on Medscape.com.
Teprotumumab gets FDA go-ahead for thyroid eye disease
according to a press release.
Thyroid eye disease is a rare, progressive, autoimmune condition that causes the eyes to bulge (proptosis) and can lead to blindness. Until now, treatment has focused on managing its symptoms – which can include eye pain, double vision, or sensitivity to light – with steroids, and in some cases, multiple invasive surgeries.
The human monoclonal antibody and a targeted inhibitor of the insulinlike growth factor-1 receptor is administered to patients once every 3 weeks, for a total of eight infusions, according to a statement from Horizon Therapeutics, which manufactures the drug.
The approval was based on the findings from two similarly designed, parallel-group studies (Studies 1 and 2) involving 170 patients with thyroid eye disease who were randomized to receive either teprotumumab or placebo. Of those receiving the study drug, 71% in Study 1 and 83% in Study 2 had a reduction of more than 2 mm in eye protrusion, compared with 20% and 10%, respectively, among the placebo participants.
The most common adverse reactions in patients receiving teprotumumab were muscle spasm, nausea, alopecia, diarrhea, fatigue, and hyperglycemia. The treatment is contraindicated for pregnancy.
according to a press release.
Thyroid eye disease is a rare, progressive, autoimmune condition that causes the eyes to bulge (proptosis) and can lead to blindness. Until now, treatment has focused on managing its symptoms – which can include eye pain, double vision, or sensitivity to light – with steroids, and in some cases, multiple invasive surgeries.
The human monoclonal antibody and a targeted inhibitor of the insulinlike growth factor-1 receptor is administered to patients once every 3 weeks, for a total of eight infusions, according to a statement from Horizon Therapeutics, which manufactures the drug.
The approval was based on the findings from two similarly designed, parallel-group studies (Studies 1 and 2) involving 170 patients with thyroid eye disease who were randomized to receive either teprotumumab or placebo. Of those receiving the study drug, 71% in Study 1 and 83% in Study 2 had a reduction of more than 2 mm in eye protrusion, compared with 20% and 10%, respectively, among the placebo participants.
The most common adverse reactions in patients receiving teprotumumab were muscle spasm, nausea, alopecia, diarrhea, fatigue, and hyperglycemia. The treatment is contraindicated for pregnancy.
according to a press release.
Thyroid eye disease is a rare, progressive, autoimmune condition that causes the eyes to bulge (proptosis) and can lead to blindness. Until now, treatment has focused on managing its symptoms – which can include eye pain, double vision, or sensitivity to light – with steroids, and in some cases, multiple invasive surgeries.
The human monoclonal antibody and a targeted inhibitor of the insulinlike growth factor-1 receptor is administered to patients once every 3 weeks, for a total of eight infusions, according to a statement from Horizon Therapeutics, which manufactures the drug.
The approval was based on the findings from two similarly designed, parallel-group studies (Studies 1 and 2) involving 170 patients with thyroid eye disease who were randomized to receive either teprotumumab or placebo. Of those receiving the study drug, 71% in Study 1 and 83% in Study 2 had a reduction of more than 2 mm in eye protrusion, compared with 20% and 10%, respectively, among the placebo participants.
The most common adverse reactions in patients receiving teprotumumab were muscle spasm, nausea, alopecia, diarrhea, fatigue, and hyperglycemia. The treatment is contraindicated for pregnancy.
FROM THE FDA
FDA panel okays teprotumumab for thyroid eye disease
TED is a rare autoimmune disease that causes the eyes to bulge (proptosis) and can lead to blindness. It is also known as thyroid-associated ophthalmopathy, Graves ophthalmopathy, and Graves orbitopathy. Current treatment is aimed at relief of symptoms and includes corticosteroids and orbital decompression.
“TED can affect patients both physically and emotionally, limiting their ability to perform everyday activities like driving, working, reading, sleeping, and participating in social activities,” Jeff Todd, president and chief executive officer, Prevent Blindness, said in a news release.
“As an organization dedicated to helping patients with vision impairment and those who are at significant risk, we are extremely encouraged by today’s vote and hopeful this will change the future of TED treatment by giving patients an option that has been shown to improve the painful and vision-threatening aspects of the disease,” Mr. Todd said.
Teprotumumab was granted fast-track status in April 2015 and breakthrough therapy designation in July 2016. It received orphan drug designation on June 19, 2019. If approved, it would be the first approved treatment for this indication.
All 12 members of the Dermatologic and Ophthalmic Drugs Advisory Committee of the FDA voted to recommend approval of teprotumumab.
“It’s clearly a pleasure to participate in seeing a drug being designed and moving forward in a clinical trial for a disease that really has not been treatable for us in the past,” said voting committee member Timothy Murray, MD, MBA, of the Bascom Palmer Eye Institute, Miami.
Efficacy demonstrated
The FDA advisory committee considered data from two randomized, double-masked, placebo-controlled, parallel-group studies that were similar in design and that demonstrated efficacy.
The studies included a total of 171 patients, fewer than 90 of whom were treated with teprotumumab, the agency explained in a briefing document. “This is a considerably smaller database than the common safety database of greater than 300 patients treated with a course of therapy,” it observed.
The study required that patients have proptosis but did not require that they have “progressive forward motion of the globe,” it noted.
The primary objective – a reduction in proptosis of 2 or more mm – was met in 82% of patients who received teprotumumab, compared with 16% of those who received placebo.
Review study No. 1 (TED01RV) was a phase 2 study, and review study No. 2 (OPTIC) was a phase 3 study. Both trials included a 24-week treatment period during which participants received teprotumumab or placebo intravenously every 3 weeks for a total of eight doses. Patients in both studies underwent a follow-up period during which they received no further treatment.
Some patients experienced a reduction in proptosis as early as 6 weeks after they received the first infusion. In an extension of TED01RV, that reduction extended for at least 4 weeks after the last infusion. For about 60% of responders, no relapse had occurred by week 72. The extension of OPTIC and an open-label treatment period for those with no response to placebo or teprotumumab are ongoing.
“I welcome the addition of this drug to our armamentarium to treat this horrible, horrible disease,” said temporary voting committee member John F. Stamler, MD, PhD, clinical instructor, ophthalmology and visual sciences, University of Iowa, Iowa City.
Adverse events
Teprotumumab inhibits the insulinlike growth factor–1 receptor, which can interfere with the body’s ability to regulate glucose, particularly in patients with diabetes. In the study, some patients with diabetes required additional insulin for glycemic control.
In three study participants whose baseline fasting blood glucose levels were normal, blood glucose levels were found to be elevated at one or more visits during the treatment period. None had a history of diabetes mellitus, but for two, baseline hemoglobin A1c levels were elevated.
Five or more patients reported loss of hearing (hypoacusis), and others reported tinnitus. One of them experienced a spontaneous return of hearing the day after the hypoacusis developed, whereas for others, hearing did not return until after teprotumumab treatment was completed. The mechanism of action for hearing loss is unclear.
Panel members felt the potential for hearing loss is important and that patients should receive some type of monitoring, but they did not all agree on when that testing should occur or who should be responsible for getting it done.
“It strikes me that, if this drug were approved, there would be centers that would be interested in undertaking independent studies of hearing loss in treated patients, and that that could be done outside the sponsor’s responsibility and probably would be of interest to independent investigators,” noted committee chairperson James Chodosh, MD, MPH, of Massachusetts Eye and Ear and Harvard Medical School, Boston.
Benefits outweigh risks
More than one-third of patients (36%) experienced gastrointestinal complaints such as nausea and diarrhea (12% each) and abdominal pain (5%). None of the cases caused any patient to discontinue the study drug.
The overall incidence of muscle spasms was more than three times higher in the teprotumumab group (32%) than in the placebo group (9.5%).
One patient stopped taking teprotumumab after being hospitalized for Escherichia coli sepsis and dehydration, and another participant stopped after experiencing an episode of inflammatory bowel disease. It is not clear whether there is a causal association between teprotumumab and inflammatory bowel disease.
No study participants died.
Panel members expressed concern about safety in the longer term or in patients who receive multiple courses of teprotumumab, but they felt the potential benefits from teprotumumab outweigh the risks. The committee also wanted more information about the effects of teprotumumab with respect to glucose control, hearing loss, and other outcomes that are very important to patients, such as alopecia.
The panel favored including diarrhea in the list of adverse events in the label and felt that there should be a warning about inflammatory bowel disease.
“We’re finally going to be able to get a lot of people some help,” concluded voting committee member Sidney Gicheru, MD, LaserCare Eye Center, Irving, Texas.
A version of this story originally appeared on Medscape.com.
TED is a rare autoimmune disease that causes the eyes to bulge (proptosis) and can lead to blindness. It is also known as thyroid-associated ophthalmopathy, Graves ophthalmopathy, and Graves orbitopathy. Current treatment is aimed at relief of symptoms and includes corticosteroids and orbital decompression.
“TED can affect patients both physically and emotionally, limiting their ability to perform everyday activities like driving, working, reading, sleeping, and participating in social activities,” Jeff Todd, president and chief executive officer, Prevent Blindness, said in a news release.
“As an organization dedicated to helping patients with vision impairment and those who are at significant risk, we are extremely encouraged by today’s vote and hopeful this will change the future of TED treatment by giving patients an option that has been shown to improve the painful and vision-threatening aspects of the disease,” Mr. Todd said.
Teprotumumab was granted fast-track status in April 2015 and breakthrough therapy designation in July 2016. It received orphan drug designation on June 19, 2019. If approved, it would be the first approved treatment for this indication.
All 12 members of the Dermatologic and Ophthalmic Drugs Advisory Committee of the FDA voted to recommend approval of teprotumumab.
“It’s clearly a pleasure to participate in seeing a drug being designed and moving forward in a clinical trial for a disease that really has not been treatable for us in the past,” said voting committee member Timothy Murray, MD, MBA, of the Bascom Palmer Eye Institute, Miami.
Efficacy demonstrated
The FDA advisory committee considered data from two randomized, double-masked, placebo-controlled, parallel-group studies that were similar in design and that demonstrated efficacy.
The studies included a total of 171 patients, fewer than 90 of whom were treated with teprotumumab, the agency explained in a briefing document. “This is a considerably smaller database than the common safety database of greater than 300 patients treated with a course of therapy,” it observed.
The study required that patients have proptosis but did not require that they have “progressive forward motion of the globe,” it noted.
The primary objective – a reduction in proptosis of 2 or more mm – was met in 82% of patients who received teprotumumab, compared with 16% of those who received placebo.
Review study No. 1 (TED01RV) was a phase 2 study, and review study No. 2 (OPTIC) was a phase 3 study. Both trials included a 24-week treatment period during which participants received teprotumumab or placebo intravenously every 3 weeks for a total of eight doses. Patients in both studies underwent a follow-up period during which they received no further treatment.
Some patients experienced a reduction in proptosis as early as 6 weeks after they received the first infusion. In an extension of TED01RV, that reduction extended for at least 4 weeks after the last infusion. For about 60% of responders, no relapse had occurred by week 72. The extension of OPTIC and an open-label treatment period for those with no response to placebo or teprotumumab are ongoing.
“I welcome the addition of this drug to our armamentarium to treat this horrible, horrible disease,” said temporary voting committee member John F. Stamler, MD, PhD, clinical instructor, ophthalmology and visual sciences, University of Iowa, Iowa City.
Adverse events
Teprotumumab inhibits the insulinlike growth factor–1 receptor, which can interfere with the body’s ability to regulate glucose, particularly in patients with diabetes. In the study, some patients with diabetes required additional insulin for glycemic control.
In three study participants whose baseline fasting blood glucose levels were normal, blood glucose levels were found to be elevated at one or more visits during the treatment period. None had a history of diabetes mellitus, but for two, baseline hemoglobin A1c levels were elevated.
Five or more patients reported loss of hearing (hypoacusis), and others reported tinnitus. One of them experienced a spontaneous return of hearing the day after the hypoacusis developed, whereas for others, hearing did not return until after teprotumumab treatment was completed. The mechanism of action for hearing loss is unclear.
Panel members felt the potential for hearing loss is important and that patients should receive some type of monitoring, but they did not all agree on when that testing should occur or who should be responsible for getting it done.
“It strikes me that, if this drug were approved, there would be centers that would be interested in undertaking independent studies of hearing loss in treated patients, and that that could be done outside the sponsor’s responsibility and probably would be of interest to independent investigators,” noted committee chairperson James Chodosh, MD, MPH, of Massachusetts Eye and Ear and Harvard Medical School, Boston.
Benefits outweigh risks
More than one-third of patients (36%) experienced gastrointestinal complaints such as nausea and diarrhea (12% each) and abdominal pain (5%). None of the cases caused any patient to discontinue the study drug.
The overall incidence of muscle spasms was more than three times higher in the teprotumumab group (32%) than in the placebo group (9.5%).
One patient stopped taking teprotumumab after being hospitalized for Escherichia coli sepsis and dehydration, and another participant stopped after experiencing an episode of inflammatory bowel disease. It is not clear whether there is a causal association between teprotumumab and inflammatory bowel disease.
No study participants died.
Panel members expressed concern about safety in the longer term or in patients who receive multiple courses of teprotumumab, but they felt the potential benefits from teprotumumab outweigh the risks. The committee also wanted more information about the effects of teprotumumab with respect to glucose control, hearing loss, and other outcomes that are very important to patients, such as alopecia.
The panel favored including diarrhea in the list of adverse events in the label and felt that there should be a warning about inflammatory bowel disease.
“We’re finally going to be able to get a lot of people some help,” concluded voting committee member Sidney Gicheru, MD, LaserCare Eye Center, Irving, Texas.
A version of this story originally appeared on Medscape.com.
TED is a rare autoimmune disease that causes the eyes to bulge (proptosis) and can lead to blindness. It is also known as thyroid-associated ophthalmopathy, Graves ophthalmopathy, and Graves orbitopathy. Current treatment is aimed at relief of symptoms and includes corticosteroids and orbital decompression.
“TED can affect patients both physically and emotionally, limiting their ability to perform everyday activities like driving, working, reading, sleeping, and participating in social activities,” Jeff Todd, president and chief executive officer, Prevent Blindness, said in a news release.
“As an organization dedicated to helping patients with vision impairment and those who are at significant risk, we are extremely encouraged by today’s vote and hopeful this will change the future of TED treatment by giving patients an option that has been shown to improve the painful and vision-threatening aspects of the disease,” Mr. Todd said.
Teprotumumab was granted fast-track status in April 2015 and breakthrough therapy designation in July 2016. It received orphan drug designation on June 19, 2019. If approved, it would be the first approved treatment for this indication.
All 12 members of the Dermatologic and Ophthalmic Drugs Advisory Committee of the FDA voted to recommend approval of teprotumumab.
“It’s clearly a pleasure to participate in seeing a drug being designed and moving forward in a clinical trial for a disease that really has not been treatable for us in the past,” said voting committee member Timothy Murray, MD, MBA, of the Bascom Palmer Eye Institute, Miami.
Efficacy demonstrated
The FDA advisory committee considered data from two randomized, double-masked, placebo-controlled, parallel-group studies that were similar in design and that demonstrated efficacy.
The studies included a total of 171 patients, fewer than 90 of whom were treated with teprotumumab, the agency explained in a briefing document. “This is a considerably smaller database than the common safety database of greater than 300 patients treated with a course of therapy,” it observed.
The study required that patients have proptosis but did not require that they have “progressive forward motion of the globe,” it noted.
The primary objective – a reduction in proptosis of 2 or more mm – was met in 82% of patients who received teprotumumab, compared with 16% of those who received placebo.
Review study No. 1 (TED01RV) was a phase 2 study, and review study No. 2 (OPTIC) was a phase 3 study. Both trials included a 24-week treatment period during which participants received teprotumumab or placebo intravenously every 3 weeks for a total of eight doses. Patients in both studies underwent a follow-up period during which they received no further treatment.
Some patients experienced a reduction in proptosis as early as 6 weeks after they received the first infusion. In an extension of TED01RV, that reduction extended for at least 4 weeks after the last infusion. For about 60% of responders, no relapse had occurred by week 72. The extension of OPTIC and an open-label treatment period for those with no response to placebo or teprotumumab are ongoing.
“I welcome the addition of this drug to our armamentarium to treat this horrible, horrible disease,” said temporary voting committee member John F. Stamler, MD, PhD, clinical instructor, ophthalmology and visual sciences, University of Iowa, Iowa City.
Adverse events
Teprotumumab inhibits the insulinlike growth factor–1 receptor, which can interfere with the body’s ability to regulate glucose, particularly in patients with diabetes. In the study, some patients with diabetes required additional insulin for glycemic control.
In three study participants whose baseline fasting blood glucose levels were normal, blood glucose levels were found to be elevated at one or more visits during the treatment period. None had a history of diabetes mellitus, but for two, baseline hemoglobin A1c levels were elevated.
Five or more patients reported loss of hearing (hypoacusis), and others reported tinnitus. One of them experienced a spontaneous return of hearing the day after the hypoacusis developed, whereas for others, hearing did not return until after teprotumumab treatment was completed. The mechanism of action for hearing loss is unclear.
Panel members felt the potential for hearing loss is important and that patients should receive some type of monitoring, but they did not all agree on when that testing should occur or who should be responsible for getting it done.
“It strikes me that, if this drug were approved, there would be centers that would be interested in undertaking independent studies of hearing loss in treated patients, and that that could be done outside the sponsor’s responsibility and probably would be of interest to independent investigators,” noted committee chairperson James Chodosh, MD, MPH, of Massachusetts Eye and Ear and Harvard Medical School, Boston.
Benefits outweigh risks
More than one-third of patients (36%) experienced gastrointestinal complaints such as nausea and diarrhea (12% each) and abdominal pain (5%). None of the cases caused any patient to discontinue the study drug.
The overall incidence of muscle spasms was more than three times higher in the teprotumumab group (32%) than in the placebo group (9.5%).
One patient stopped taking teprotumumab after being hospitalized for Escherichia coli sepsis and dehydration, and another participant stopped after experiencing an episode of inflammatory bowel disease. It is not clear whether there is a causal association between teprotumumab and inflammatory bowel disease.
No study participants died.
Panel members expressed concern about safety in the longer term or in patients who receive multiple courses of teprotumumab, but they felt the potential benefits from teprotumumab outweigh the risks. The committee also wanted more information about the effects of teprotumumab with respect to glucose control, hearing loss, and other outcomes that are very important to patients, such as alopecia.
The panel favored including diarrhea in the list of adverse events in the label and felt that there should be a warning about inflammatory bowel disease.
“We’re finally going to be able to get a lot of people some help,” concluded voting committee member Sidney Gicheru, MD, LaserCare Eye Center, Irving, Texas.
A version of this story originally appeared on Medscape.com.
Iscalimab normalizes thyroid hormone levels in some patients with Graves disease
CHICAGO – The investigational monoclonal antibody iscalimab reduced levels of thyroid hormone and thyroid-stimulating hormone–receptor antibodies (TSHR-Ab) in some patients with Graves disease in a small study.
Of 15 patients with Graves disease, 7 patients, or 47%, saw their thyroid hormone levels normalize, and levels of TSHR-Ab normalized in 4 patients, or 27% of the cohort. In addition, mean levels of a chemokine associated with Graves disease activity dropped.
“These results suggest that iscalimab may be an effective and attractive immunomodulation strategy for Graves disease,” said George Kahaly, MD, PhD, in his presentation of the phase 2 results at the annual meeting of the American Thyroid Association (J Clin Endocrinol Metab. 2019 Sep 12. doi: 10.1210/clinem/dgz013).
Overall, patients who responded had lower levels of free triiodothyronine (FT3), free thyroxine (FT4), and TSHR-Ab and lower thyroid volume at baseline.
Iscalimab is a fully human monoclonal antibody that is active against the costimulatory protein CD40 that is present on the surface of antigen-presenting cells. Dr. Kahaly, professor of endocrinology at Johannes Gutenberg University Medical Center, Mainz, Germany, explained that in primate studies, iscalimab inhibits the T cell–dependent antibody response to an antigen, without depletion of B cells. However, iscalimab would be expected to block B-cell activation and differentiation, “leading to reduced de novo TSHR antibody production,” said Dr. Kahaly. Inhibition of T cell–dependent antibody response was seen when iscalimab was given at a dose of 3 mg/kg in healthy human study participants.
The study results presented by Dr. Kahaly were drawn from a single-arm, proof-of-concept study that enrolled 15 patients with Graves disease to 12 weeks of treatment with iscalimab. The participants were followed for an additional 24 weeks after receiving intravenous iscalimab at 10 mg/kg on study days 1, 15, 29, 57, and 85.
All participants were receiving beta blockers at enrollment; four patients had new-onset Graves disease, and the rest were experiencing a treatment relapse.
The participants were a median 49 years old, and all but two were female. One patient was Asian, and the remainder were white. They were mostly normal weight, with a mean body mass index of about 23 kg/m2.
A group of seven patients who were clear responders to iscalimab saw normalization of FT4 levels; of the eight patients considered to be nonresponders, six required rescue medication with antithyroid drugs.
For responders, the initial mean FT4 level was 33.5 pmol/L, whereas for nonresponders, it was 51.3 pmol/L (P less than .05). Similarly, mean FT3 levels were 13.6 pmol/L in responders, compared with 22 pmol/L in nonresponders (P less than .05).
Mean thyroid volume was 14.5 ml in responders, compared with 26 ml in nonresponders (P less than .005).
A subgroup of four patients within the responder group became TSHR-Ab negative, with sustained low antibody levels seen during the follow-up period. All but one of the eight nonresponders had initial TSHR-Ab levels of more than 20 U/L, whereas the seven responders began with TSHR-Ab levels of about 10 U/L or less. Mean TSHR-Ab levels at baseline were 5.6 IU/L for responders, compared with 27.3 IU/L for nonresponders (P less than .001).
Most responders also had lower initial levels of antithyroid peroxidase IgG antibodies, compared with the nonresponder group.
Levels of chemokine (motif C-X-C) ligand 13 (CXCL13) fell throughout the study period. Higher CXCL13 levels are associated with lymphocytic infiltrates seen in autoimmune thyroiditis.
Occupancy of CD40 was initially measured at week 4 of the study and it remained high until week 16, when free CD40 receptors rose rapidly for several participants in both the responder and nonresponder groups. “The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks,” wrote Dr. Kahaly and colleagues in the abstract accompanying the presentation.
In assessing CD40 target engagement, the investigators found that total soluble CD40 levels climbed during the treatment period, reaching peaks as high as 400-500 ng/mL, and then plummeted back to zero by study’s end for all participants.
A pharmacokinetic analysis revealed expected peaks of serum iscalimab after treatments, with levels dropping sharply at the end of the study period and falling to levels approaching zero by week 24 for most participants.
In terms of safety, 12 patients experienced at least one adverse event, with 3 participants reporting an episode of cystitis during the study. Fatigue, headache, insomnia, nausea, and viral upper respiratory infection were each reported by 2 patients. No injection site reactions were seen. All adverse events were mild or moderate, did not result in study withdrawal, and resolved by the end of the study period, Dr. Kahaly noted.
“These encouraging results suggest that iscalimab should be tested further to understand better its potential therapeutic benefit,” the investigators wrote.
The study was funded by Novartis, which is developing iscalimab for Graves disease, other autoimmune disorders, and as an antirejection drug for patients with kidney transplants.
CHICAGO – The investigational monoclonal antibody iscalimab reduced levels of thyroid hormone and thyroid-stimulating hormone–receptor antibodies (TSHR-Ab) in some patients with Graves disease in a small study.
Of 15 patients with Graves disease, 7 patients, or 47%, saw their thyroid hormone levels normalize, and levels of TSHR-Ab normalized in 4 patients, or 27% of the cohort. In addition, mean levels of a chemokine associated with Graves disease activity dropped.
“These results suggest that iscalimab may be an effective and attractive immunomodulation strategy for Graves disease,” said George Kahaly, MD, PhD, in his presentation of the phase 2 results at the annual meeting of the American Thyroid Association (J Clin Endocrinol Metab. 2019 Sep 12. doi: 10.1210/clinem/dgz013).
Overall, patients who responded had lower levels of free triiodothyronine (FT3), free thyroxine (FT4), and TSHR-Ab and lower thyroid volume at baseline.
Iscalimab is a fully human monoclonal antibody that is active against the costimulatory protein CD40 that is present on the surface of antigen-presenting cells. Dr. Kahaly, professor of endocrinology at Johannes Gutenberg University Medical Center, Mainz, Germany, explained that in primate studies, iscalimab inhibits the T cell–dependent antibody response to an antigen, without depletion of B cells. However, iscalimab would be expected to block B-cell activation and differentiation, “leading to reduced de novo TSHR antibody production,” said Dr. Kahaly. Inhibition of T cell–dependent antibody response was seen when iscalimab was given at a dose of 3 mg/kg in healthy human study participants.
The study results presented by Dr. Kahaly were drawn from a single-arm, proof-of-concept study that enrolled 15 patients with Graves disease to 12 weeks of treatment with iscalimab. The participants were followed for an additional 24 weeks after receiving intravenous iscalimab at 10 mg/kg on study days 1, 15, 29, 57, and 85.
All participants were receiving beta blockers at enrollment; four patients had new-onset Graves disease, and the rest were experiencing a treatment relapse.
The participants were a median 49 years old, and all but two were female. One patient was Asian, and the remainder were white. They were mostly normal weight, with a mean body mass index of about 23 kg/m2.
A group of seven patients who were clear responders to iscalimab saw normalization of FT4 levels; of the eight patients considered to be nonresponders, six required rescue medication with antithyroid drugs.
For responders, the initial mean FT4 level was 33.5 pmol/L, whereas for nonresponders, it was 51.3 pmol/L (P less than .05). Similarly, mean FT3 levels were 13.6 pmol/L in responders, compared with 22 pmol/L in nonresponders (P less than .05).
Mean thyroid volume was 14.5 ml in responders, compared with 26 ml in nonresponders (P less than .005).
A subgroup of four patients within the responder group became TSHR-Ab negative, with sustained low antibody levels seen during the follow-up period. All but one of the eight nonresponders had initial TSHR-Ab levels of more than 20 U/L, whereas the seven responders began with TSHR-Ab levels of about 10 U/L or less. Mean TSHR-Ab levels at baseline were 5.6 IU/L for responders, compared with 27.3 IU/L for nonresponders (P less than .001).
Most responders also had lower initial levels of antithyroid peroxidase IgG antibodies, compared with the nonresponder group.
Levels of chemokine (motif C-X-C) ligand 13 (CXCL13) fell throughout the study period. Higher CXCL13 levels are associated with lymphocytic infiltrates seen in autoimmune thyroiditis.
Occupancy of CD40 was initially measured at week 4 of the study and it remained high until week 16, when free CD40 receptors rose rapidly for several participants in both the responder and nonresponder groups. “The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks,” wrote Dr. Kahaly and colleagues in the abstract accompanying the presentation.
In assessing CD40 target engagement, the investigators found that total soluble CD40 levels climbed during the treatment period, reaching peaks as high as 400-500 ng/mL, and then plummeted back to zero by study’s end for all participants.
A pharmacokinetic analysis revealed expected peaks of serum iscalimab after treatments, with levels dropping sharply at the end of the study period and falling to levels approaching zero by week 24 for most participants.
In terms of safety, 12 patients experienced at least one adverse event, with 3 participants reporting an episode of cystitis during the study. Fatigue, headache, insomnia, nausea, and viral upper respiratory infection were each reported by 2 patients. No injection site reactions were seen. All adverse events were mild or moderate, did not result in study withdrawal, and resolved by the end of the study period, Dr. Kahaly noted.
“These encouraging results suggest that iscalimab should be tested further to understand better its potential therapeutic benefit,” the investigators wrote.
The study was funded by Novartis, which is developing iscalimab for Graves disease, other autoimmune disorders, and as an antirejection drug for patients with kidney transplants.
CHICAGO – The investigational monoclonal antibody iscalimab reduced levels of thyroid hormone and thyroid-stimulating hormone–receptor antibodies (TSHR-Ab) in some patients with Graves disease in a small study.
Of 15 patients with Graves disease, 7 patients, or 47%, saw their thyroid hormone levels normalize, and levels of TSHR-Ab normalized in 4 patients, or 27% of the cohort. In addition, mean levels of a chemokine associated with Graves disease activity dropped.
“These results suggest that iscalimab may be an effective and attractive immunomodulation strategy for Graves disease,” said George Kahaly, MD, PhD, in his presentation of the phase 2 results at the annual meeting of the American Thyroid Association (J Clin Endocrinol Metab. 2019 Sep 12. doi: 10.1210/clinem/dgz013).
Overall, patients who responded had lower levels of free triiodothyronine (FT3), free thyroxine (FT4), and TSHR-Ab and lower thyroid volume at baseline.
Iscalimab is a fully human monoclonal antibody that is active against the costimulatory protein CD40 that is present on the surface of antigen-presenting cells. Dr. Kahaly, professor of endocrinology at Johannes Gutenberg University Medical Center, Mainz, Germany, explained that in primate studies, iscalimab inhibits the T cell–dependent antibody response to an antigen, without depletion of B cells. However, iscalimab would be expected to block B-cell activation and differentiation, “leading to reduced de novo TSHR antibody production,” said Dr. Kahaly. Inhibition of T cell–dependent antibody response was seen when iscalimab was given at a dose of 3 mg/kg in healthy human study participants.
The study results presented by Dr. Kahaly were drawn from a single-arm, proof-of-concept study that enrolled 15 patients with Graves disease to 12 weeks of treatment with iscalimab. The participants were followed for an additional 24 weeks after receiving intravenous iscalimab at 10 mg/kg on study days 1, 15, 29, 57, and 85.
All participants were receiving beta blockers at enrollment; four patients had new-onset Graves disease, and the rest were experiencing a treatment relapse.
The participants were a median 49 years old, and all but two were female. One patient was Asian, and the remainder were white. They were mostly normal weight, with a mean body mass index of about 23 kg/m2.
A group of seven patients who were clear responders to iscalimab saw normalization of FT4 levels; of the eight patients considered to be nonresponders, six required rescue medication with antithyroid drugs.
For responders, the initial mean FT4 level was 33.5 pmol/L, whereas for nonresponders, it was 51.3 pmol/L (P less than .05). Similarly, mean FT3 levels were 13.6 pmol/L in responders, compared with 22 pmol/L in nonresponders (P less than .05).
Mean thyroid volume was 14.5 ml in responders, compared with 26 ml in nonresponders (P less than .005).
A subgroup of four patients within the responder group became TSHR-Ab negative, with sustained low antibody levels seen during the follow-up period. All but one of the eight nonresponders had initial TSHR-Ab levels of more than 20 U/L, whereas the seven responders began with TSHR-Ab levels of about 10 U/L or less. Mean TSHR-Ab levels at baseline were 5.6 IU/L for responders, compared with 27.3 IU/L for nonresponders (P less than .001).
Most responders also had lower initial levels of antithyroid peroxidase IgG antibodies, compared with the nonresponder group.
Levels of chemokine (motif C-X-C) ligand 13 (CXCL13) fell throughout the study period. Higher CXCL13 levels are associated with lymphocytic infiltrates seen in autoimmune thyroiditis.
Occupancy of CD40 was initially measured at week 4 of the study and it remained high until week 16, when free CD40 receptors rose rapidly for several participants in both the responder and nonresponder groups. “The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks,” wrote Dr. Kahaly and colleagues in the abstract accompanying the presentation.
In assessing CD40 target engagement, the investigators found that total soluble CD40 levels climbed during the treatment period, reaching peaks as high as 400-500 ng/mL, and then plummeted back to zero by study’s end for all participants.
A pharmacokinetic analysis revealed expected peaks of serum iscalimab after treatments, with levels dropping sharply at the end of the study period and falling to levels approaching zero by week 24 for most participants.
In terms of safety, 12 patients experienced at least one adverse event, with 3 participants reporting an episode of cystitis during the study. Fatigue, headache, insomnia, nausea, and viral upper respiratory infection were each reported by 2 patients. No injection site reactions were seen. All adverse events were mild or moderate, did not result in study withdrawal, and resolved by the end of the study period, Dr. Kahaly noted.
“These encouraging results suggest that iscalimab should be tested further to understand better its potential therapeutic benefit,” the investigators wrote.
The study was funded by Novartis, which is developing iscalimab for Graves disease, other autoimmune disorders, and as an antirejection drug for patients with kidney transplants.
REPORTING FROM ATA 2019
Drug recall in U.S. causes extreme hardship for hypoparathyroid patients
The recall of injectable recombinant parathyroid hormone (PTH; Natpara) in the United States over safety concerns about the product is gravely affecting the lives of American patients with severe hypoparathyroidism who need replacement PTH therapy to adequately control symptoms.
Approximately 2,700 patients in the United States have been affected by the recall of Natpara, according to one of the manufacturers, Takeda. Those who were taking it have had to transition back to controlling their symptoms with just oral medications, including active vitamin D or calcitriol (Rocaltrol) plus calcium supplements, which has had a negative impact on the management of their disease in most cases, with some patients hospitalized because of severe hypocalcemia.
One patient related in an interview that even if the transition from injectable PTH back to calcium supplements and calcitriol goes smoothly, individuals can still feel pretty awful because the benefits of the Natpara are subtle – patients just feel better on it. And one report indicates at least 100 patients who had to stop Natpara because of the Food and Drug Administration recall have been hospitalized.
“It’s been a rough time for all patients previously on Natpara adjusting to oral medications after they have been on a replacement therapy,” endocrinologist Dolores Shoback, MD, University of California, San Francisco, said in an email.
Aliya Khan, MD, agrees: “This molecule ... is life changing ... [It] makes a huge difference in patients’ quality of life and in their ability to function normally.”
“The FDA in the United States made the recall decision, and we have to respect that,” added Dr. Khan, a professor of clinical medicine at McMaster University in Hamilton, Ontario.
“We need to address patients’ needs and [try to] reinstate it,” Dr. Khan added, who is the lead author of recent guidelines on the treatment of hypoparathyroidism and who has received research funding from Takeda and Ascendis Pharma, both of which make injectable PTH.
Dr. Kahn also has advice for U.S. endocrinologists who are having to deal with patients who were previously on Natpara and no longer have access to the drug.
She explains how they can transition patients back to other available therapies.
Oral treatments a 'Band-Aid'
Hypoparathyroidism is a rare endocrine disorder that affects approximately 60,000 people in the United States. The FDA approved Natpara as an orphan drug and as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism in January 2015.
The FDA issued the recall for Natpara in September, out of concern that rubber particulate matter originating from the rubber septum of the drug’s cartridge might be contaminating the product.
But the European Medicines Agency, which approved the product under the brand name Natpar in 2017, has not reached the same decision as the FDA; patients in Europe who qualify for injectable PTH still have access to the drug.
As Dr. Khan explained in an interview, PTH is critical for the control of calcium and phosphate homeostasis.
When functioning normally, the parathyroid glands are able to regulate blood calcium levels very finely, sensing how much calcium is being resorbed through the kidney, how much is going in and out of bone, how active vitamin D levels are, and the amount the body is absorbing from the bowel and bone. “It’s all being very carefully fine-tuned continuously,” she said.
Patients with hypoparathyroidism suffer from very low levels of serum calcium, which can, in turn, lead to seizures and cardiac irregularities as well as bronchospasm and even respiratory failure. Magnesium levels can also be dysregulated by hypocalcemia.
“All these are serious results of very low calcium levels,” Dr. Khan emphasized.
These patients “are also not able to eliminate phosphate through the kidneys so their phosphate levels rise,” she added.
Standard treatment for hypoparathyroidism is active vitamin D or calcitriol plus oral calcium supplements.
However, for patients with severe hypoparathyroidism, for whom injectable PTH is indicated, standard treatment is like a “Band-Aid” because what they really need is replacement PTH to help them regulate calcium levels as finely as possible, Dr. Khan said.
High risk for severe hypocalcemia
If PTH is stopped abruptly, calcium levels will likely plummet, a phenomenon sometimes referred to as hungry bone syndrome, placing patients at risk for the consequences of severe hypocalcemia, Dr. Khan added.
(Hungry bone syndrome refers to the rapid, profound, and prolonged hypocalcemia associated with hypophosphatemia and hypomagnesemia, which is exacerbated by suppressed PTH).
One report suggests at least 100 patients who had to stop Natpara because of the FDA recall had to seek hospitalization to have calcium levels restored intravenously.
And even if the transition from injectable PTH back to calcium supplements and calcitriol goes smoothly, patients can still feel pretty awful.
“When you look at my blood levels on and off Natpara, they look very similar,” Danette Astolfi, a former Natpara user in the United States who recently transitioned from the injectable to standard of care, said in an interview.
“But I felt much, much better on Natpara, so this is an interesting ‘wild card’ that patients have with this drug – they just feel better on it. They don’t have the fatigue, they don’t have the brain fog, they don’t have the aches and pains even if their calcium levels are normal,” Ms. Astolfi said.
So patients who are candidates for injectable PTH therapy are by definition those who do not do very well on standard-of-care calcium and calcitriol.
“With the recall, patients are going back to this regimen they already did not have great success with,” Ms. Astolfi explained. “And that’s the tricky part because if you fall into this category, as I do, there is not much you can do about it.”
Ms. Astolfi, who is also on the board of directors of the Hypoparathyroidism Association in Pennsylvania, was lucky because she did not have to stop treatment with injectable PTH abruptly.
“I was fortunate. My physician did not want me to stop the drug right away, so we had time to develop a discontinuation plan,” she noted.
Transitioning safely to other therapies
Dr. Khan has advice for endocrinologists dealing with patients who were previously on Natpara and no longer have access to the drug.
First, “endocrinologists need to be aware that when you stop PTH treatment suddenly, patients’ need for calcium supplements and calcitriol may be as high as two times what they were on before they started PTH therapy,” she noted.
Physicians also need to follow patients closely by monitoring not only calcium and vitamin D levels but also phosphate and magnesium almost daily.
Dr. Khan said she does this because it’s difficult to predict how much calcium and calcitriol a patient will require and doses will likely have to be titrated up or down based on lab results.
It is noteworthy that a joint statement on the Natpara recall by the Endocrine Society and the American Society of Bone and Mineral Research (ASBMR) also emphasizes these points.
And Dr. Khan – as well as the Endocrine Society and ASBMR – also point out that patients may be transitioned from Natpara to teriparatide (Forteo), another recombinant form of PTH that is licensed for use in osteoporosis but has not been approved for hypoparathyroidism.
In Dr. Khan’s experience, patients often do quite well on teriparatide.
The big downside of prescribing teriparatide in the United States, however, is that the drug has to be used off label, and as such, insurance companies are unlikely to pick up the tab for what is an expensive treatment, she explained.
Furthermore, teriparatide has a very short shelf-life once injected so patients may need to use up to four needles a day to stabilize calcium levels.
If teriparatide is prescribed, subcutaneous injections given in the thigh are recommended for the treatment of hypoparathyroidism, according to the joint Endocrine Society/ASBMR statement.
Takeda vs. FDA
In the meantime, Takeda says it has been in regular contact with the FDA to try and work out how to bring Natpara back to U.S. patients who require it for symptom control.
Current outstanding issues between the company and FDA involve considerations related to dose accuracy, safety, and supply continuity, which the company hopes will be resolved in a timely manner.
Furthermore, shortly after the recall order, the company created a special use program that continues to support patients previously prescribed Natpara who would otherwise be at extreme risk of serious complications if forced to stop taking the drug.
“Originally intended for an extremely limited number of patients, the special use program has now enrolled approximately 300 patients,” Cheryl Schwartz, head, U.S. Hematology & Rare Business Unit, Takeda, said in a letter to members of the U.S. Hypoparathyroidism Association on Nov. 21.
The number is higher than expected and reflects the significant treatment needs of patients with serious disease, Ms. Schwartz noted.
“I want to reiterate that we do understand and sincerely regret the impact the Natpara recall is having on patients. We will provide another update as soon as we have more information to share. We continue to work around the clock to find ways to bring Natpara back to the broader hypoparathyroidism community,” she added.
“Patient safety always has been, and continues to be, the highest priority for Takeda,” she said.
Final efforts
Dr. Khan is currently involved in clinical trials evaluating Natpara in Canada (where it is not yet approved).
She was also involved in some of the pivotal studies that helped gain support of the product in the United States and European Union, including REPLACE, which showed that the injectable PTH molecule maintained serum calcium while reducing or eliminating requirements for calcium and active vitamin D supplementation.
“We now have 8 years of experience with this molecule, so we know that it’s safe and effective,” Dr. Khan emphasized.
Health Canada has not deemed Natpara problematic enough to stop the ongoing research program into injectable PTH therapies there, which is being headed up by Dr. Khan at McMaster University.
“The company has not yet applied for approval here, but when they do apply, I am sure they will have fixed this problem by then,” Dr. Khan said. “And I expect it will be fixed momentarily in the United States, where patients have been most affected.”
Asked if she was looking forward to getting Natpara back on track, Ms. Astolfi said “absolutely” several times.
“This recall has really had a large impact on our community,” she stressed. “And while it’s good that critically ill patients have access to the drug through the special-use program, we want to get everyone back to their best life and feeling great.”
A version of this story originally appeared on Medscape.com.
The recall of injectable recombinant parathyroid hormone (PTH; Natpara) in the United States over safety concerns about the product is gravely affecting the lives of American patients with severe hypoparathyroidism who need replacement PTH therapy to adequately control symptoms.
Approximately 2,700 patients in the United States have been affected by the recall of Natpara, according to one of the manufacturers, Takeda. Those who were taking it have had to transition back to controlling their symptoms with just oral medications, including active vitamin D or calcitriol (Rocaltrol) plus calcium supplements, which has had a negative impact on the management of their disease in most cases, with some patients hospitalized because of severe hypocalcemia.
One patient related in an interview that even if the transition from injectable PTH back to calcium supplements and calcitriol goes smoothly, individuals can still feel pretty awful because the benefits of the Natpara are subtle – patients just feel better on it. And one report indicates at least 100 patients who had to stop Natpara because of the Food and Drug Administration recall have been hospitalized.
“It’s been a rough time for all patients previously on Natpara adjusting to oral medications after they have been on a replacement therapy,” endocrinologist Dolores Shoback, MD, University of California, San Francisco, said in an email.
Aliya Khan, MD, agrees: “This molecule ... is life changing ... [It] makes a huge difference in patients’ quality of life and in their ability to function normally.”
“The FDA in the United States made the recall decision, and we have to respect that,” added Dr. Khan, a professor of clinical medicine at McMaster University in Hamilton, Ontario.
“We need to address patients’ needs and [try to] reinstate it,” Dr. Khan added, who is the lead author of recent guidelines on the treatment of hypoparathyroidism and who has received research funding from Takeda and Ascendis Pharma, both of which make injectable PTH.
Dr. Kahn also has advice for U.S. endocrinologists who are having to deal with patients who were previously on Natpara and no longer have access to the drug.
She explains how they can transition patients back to other available therapies.
Oral treatments a 'Band-Aid'
Hypoparathyroidism is a rare endocrine disorder that affects approximately 60,000 people in the United States. The FDA approved Natpara as an orphan drug and as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism in January 2015.
The FDA issued the recall for Natpara in September, out of concern that rubber particulate matter originating from the rubber septum of the drug’s cartridge might be contaminating the product.
But the European Medicines Agency, which approved the product under the brand name Natpar in 2017, has not reached the same decision as the FDA; patients in Europe who qualify for injectable PTH still have access to the drug.
As Dr. Khan explained in an interview, PTH is critical for the control of calcium and phosphate homeostasis.
When functioning normally, the parathyroid glands are able to regulate blood calcium levels very finely, sensing how much calcium is being resorbed through the kidney, how much is going in and out of bone, how active vitamin D levels are, and the amount the body is absorbing from the bowel and bone. “It’s all being very carefully fine-tuned continuously,” she said.
Patients with hypoparathyroidism suffer from very low levels of serum calcium, which can, in turn, lead to seizures and cardiac irregularities as well as bronchospasm and even respiratory failure. Magnesium levels can also be dysregulated by hypocalcemia.
“All these are serious results of very low calcium levels,” Dr. Khan emphasized.
These patients “are also not able to eliminate phosphate through the kidneys so their phosphate levels rise,” she added.
Standard treatment for hypoparathyroidism is active vitamin D or calcitriol plus oral calcium supplements.
However, for patients with severe hypoparathyroidism, for whom injectable PTH is indicated, standard treatment is like a “Band-Aid” because what they really need is replacement PTH to help them regulate calcium levels as finely as possible, Dr. Khan said.
High risk for severe hypocalcemia
If PTH is stopped abruptly, calcium levels will likely plummet, a phenomenon sometimes referred to as hungry bone syndrome, placing patients at risk for the consequences of severe hypocalcemia, Dr. Khan added.
(Hungry bone syndrome refers to the rapid, profound, and prolonged hypocalcemia associated with hypophosphatemia and hypomagnesemia, which is exacerbated by suppressed PTH).
One report suggests at least 100 patients who had to stop Natpara because of the FDA recall had to seek hospitalization to have calcium levels restored intravenously.
And even if the transition from injectable PTH back to calcium supplements and calcitriol goes smoothly, patients can still feel pretty awful.
“When you look at my blood levels on and off Natpara, they look very similar,” Danette Astolfi, a former Natpara user in the United States who recently transitioned from the injectable to standard of care, said in an interview.
“But I felt much, much better on Natpara, so this is an interesting ‘wild card’ that patients have with this drug – they just feel better on it. They don’t have the fatigue, they don’t have the brain fog, they don’t have the aches and pains even if their calcium levels are normal,” Ms. Astolfi said.
So patients who are candidates for injectable PTH therapy are by definition those who do not do very well on standard-of-care calcium and calcitriol.
“With the recall, patients are going back to this regimen they already did not have great success with,” Ms. Astolfi explained. “And that’s the tricky part because if you fall into this category, as I do, there is not much you can do about it.”
Ms. Astolfi, who is also on the board of directors of the Hypoparathyroidism Association in Pennsylvania, was lucky because she did not have to stop treatment with injectable PTH abruptly.
“I was fortunate. My physician did not want me to stop the drug right away, so we had time to develop a discontinuation plan,” she noted.
Transitioning safely to other therapies
Dr. Khan has advice for endocrinologists dealing with patients who were previously on Natpara and no longer have access to the drug.
First, “endocrinologists need to be aware that when you stop PTH treatment suddenly, patients’ need for calcium supplements and calcitriol may be as high as two times what they were on before they started PTH therapy,” she noted.
Physicians also need to follow patients closely by monitoring not only calcium and vitamin D levels but also phosphate and magnesium almost daily.
Dr. Khan said she does this because it’s difficult to predict how much calcium and calcitriol a patient will require and doses will likely have to be titrated up or down based on lab results.
It is noteworthy that a joint statement on the Natpara recall by the Endocrine Society and the American Society of Bone and Mineral Research (ASBMR) also emphasizes these points.
And Dr. Khan – as well as the Endocrine Society and ASBMR – also point out that patients may be transitioned from Natpara to teriparatide (Forteo), another recombinant form of PTH that is licensed for use in osteoporosis but has not been approved for hypoparathyroidism.
In Dr. Khan’s experience, patients often do quite well on teriparatide.
The big downside of prescribing teriparatide in the United States, however, is that the drug has to be used off label, and as such, insurance companies are unlikely to pick up the tab for what is an expensive treatment, she explained.
Furthermore, teriparatide has a very short shelf-life once injected so patients may need to use up to four needles a day to stabilize calcium levels.
If teriparatide is prescribed, subcutaneous injections given in the thigh are recommended for the treatment of hypoparathyroidism, according to the joint Endocrine Society/ASBMR statement.
Takeda vs. FDA
In the meantime, Takeda says it has been in regular contact with the FDA to try and work out how to bring Natpara back to U.S. patients who require it for symptom control.
Current outstanding issues between the company and FDA involve considerations related to dose accuracy, safety, and supply continuity, which the company hopes will be resolved in a timely manner.
Furthermore, shortly after the recall order, the company created a special use program that continues to support patients previously prescribed Natpara who would otherwise be at extreme risk of serious complications if forced to stop taking the drug.
“Originally intended for an extremely limited number of patients, the special use program has now enrolled approximately 300 patients,” Cheryl Schwartz, head, U.S. Hematology & Rare Business Unit, Takeda, said in a letter to members of the U.S. Hypoparathyroidism Association on Nov. 21.
The number is higher than expected and reflects the significant treatment needs of patients with serious disease, Ms. Schwartz noted.
“I want to reiterate that we do understand and sincerely regret the impact the Natpara recall is having on patients. We will provide another update as soon as we have more information to share. We continue to work around the clock to find ways to bring Natpara back to the broader hypoparathyroidism community,” she added.
“Patient safety always has been, and continues to be, the highest priority for Takeda,” she said.
Final efforts
Dr. Khan is currently involved in clinical trials evaluating Natpara in Canada (where it is not yet approved).
She was also involved in some of the pivotal studies that helped gain support of the product in the United States and European Union, including REPLACE, which showed that the injectable PTH molecule maintained serum calcium while reducing or eliminating requirements for calcium and active vitamin D supplementation.
“We now have 8 years of experience with this molecule, so we know that it’s safe and effective,” Dr. Khan emphasized.
Health Canada has not deemed Natpara problematic enough to stop the ongoing research program into injectable PTH therapies there, which is being headed up by Dr. Khan at McMaster University.
“The company has not yet applied for approval here, but when they do apply, I am sure they will have fixed this problem by then,” Dr. Khan said. “And I expect it will be fixed momentarily in the United States, where patients have been most affected.”
Asked if she was looking forward to getting Natpara back on track, Ms. Astolfi said “absolutely” several times.
“This recall has really had a large impact on our community,” she stressed. “And while it’s good that critically ill patients have access to the drug through the special-use program, we want to get everyone back to their best life and feeling great.”
A version of this story originally appeared on Medscape.com.
The recall of injectable recombinant parathyroid hormone (PTH; Natpara) in the United States over safety concerns about the product is gravely affecting the lives of American patients with severe hypoparathyroidism who need replacement PTH therapy to adequately control symptoms.
Approximately 2,700 patients in the United States have been affected by the recall of Natpara, according to one of the manufacturers, Takeda. Those who were taking it have had to transition back to controlling their symptoms with just oral medications, including active vitamin D or calcitriol (Rocaltrol) plus calcium supplements, which has had a negative impact on the management of their disease in most cases, with some patients hospitalized because of severe hypocalcemia.
One patient related in an interview that even if the transition from injectable PTH back to calcium supplements and calcitriol goes smoothly, individuals can still feel pretty awful because the benefits of the Natpara are subtle – patients just feel better on it. And one report indicates at least 100 patients who had to stop Natpara because of the Food and Drug Administration recall have been hospitalized.
“It’s been a rough time for all patients previously on Natpara adjusting to oral medications after they have been on a replacement therapy,” endocrinologist Dolores Shoback, MD, University of California, San Francisco, said in an email.
Aliya Khan, MD, agrees: “This molecule ... is life changing ... [It] makes a huge difference in patients’ quality of life and in their ability to function normally.”
“The FDA in the United States made the recall decision, and we have to respect that,” added Dr. Khan, a professor of clinical medicine at McMaster University in Hamilton, Ontario.
“We need to address patients’ needs and [try to] reinstate it,” Dr. Khan added, who is the lead author of recent guidelines on the treatment of hypoparathyroidism and who has received research funding from Takeda and Ascendis Pharma, both of which make injectable PTH.
Dr. Kahn also has advice for U.S. endocrinologists who are having to deal with patients who were previously on Natpara and no longer have access to the drug.
She explains how they can transition patients back to other available therapies.
Oral treatments a 'Band-Aid'
Hypoparathyroidism is a rare endocrine disorder that affects approximately 60,000 people in the United States. The FDA approved Natpara as an orphan drug and as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism in January 2015.
The FDA issued the recall for Natpara in September, out of concern that rubber particulate matter originating from the rubber septum of the drug’s cartridge might be contaminating the product.
But the European Medicines Agency, which approved the product under the brand name Natpar in 2017, has not reached the same decision as the FDA; patients in Europe who qualify for injectable PTH still have access to the drug.
As Dr. Khan explained in an interview, PTH is critical for the control of calcium and phosphate homeostasis.
When functioning normally, the parathyroid glands are able to regulate blood calcium levels very finely, sensing how much calcium is being resorbed through the kidney, how much is going in and out of bone, how active vitamin D levels are, and the amount the body is absorbing from the bowel and bone. “It’s all being very carefully fine-tuned continuously,” she said.
Patients with hypoparathyroidism suffer from very low levels of serum calcium, which can, in turn, lead to seizures and cardiac irregularities as well as bronchospasm and even respiratory failure. Magnesium levels can also be dysregulated by hypocalcemia.
“All these are serious results of very low calcium levels,” Dr. Khan emphasized.
These patients “are also not able to eliminate phosphate through the kidneys so their phosphate levels rise,” she added.
Standard treatment for hypoparathyroidism is active vitamin D or calcitriol plus oral calcium supplements.
However, for patients with severe hypoparathyroidism, for whom injectable PTH is indicated, standard treatment is like a “Band-Aid” because what they really need is replacement PTH to help them regulate calcium levels as finely as possible, Dr. Khan said.
High risk for severe hypocalcemia
If PTH is stopped abruptly, calcium levels will likely plummet, a phenomenon sometimes referred to as hungry bone syndrome, placing patients at risk for the consequences of severe hypocalcemia, Dr. Khan added.
(Hungry bone syndrome refers to the rapid, profound, and prolonged hypocalcemia associated with hypophosphatemia and hypomagnesemia, which is exacerbated by suppressed PTH).
One report suggests at least 100 patients who had to stop Natpara because of the FDA recall had to seek hospitalization to have calcium levels restored intravenously.
And even if the transition from injectable PTH back to calcium supplements and calcitriol goes smoothly, patients can still feel pretty awful.
“When you look at my blood levels on and off Natpara, they look very similar,” Danette Astolfi, a former Natpara user in the United States who recently transitioned from the injectable to standard of care, said in an interview.
“But I felt much, much better on Natpara, so this is an interesting ‘wild card’ that patients have with this drug – they just feel better on it. They don’t have the fatigue, they don’t have the brain fog, they don’t have the aches and pains even if their calcium levels are normal,” Ms. Astolfi said.
So patients who are candidates for injectable PTH therapy are by definition those who do not do very well on standard-of-care calcium and calcitriol.
“With the recall, patients are going back to this regimen they already did not have great success with,” Ms. Astolfi explained. “And that’s the tricky part because if you fall into this category, as I do, there is not much you can do about it.”
Ms. Astolfi, who is also on the board of directors of the Hypoparathyroidism Association in Pennsylvania, was lucky because she did not have to stop treatment with injectable PTH abruptly.
“I was fortunate. My physician did not want me to stop the drug right away, so we had time to develop a discontinuation plan,” she noted.
Transitioning safely to other therapies
Dr. Khan has advice for endocrinologists dealing with patients who were previously on Natpara and no longer have access to the drug.
First, “endocrinologists need to be aware that when you stop PTH treatment suddenly, patients’ need for calcium supplements and calcitriol may be as high as two times what they were on before they started PTH therapy,” she noted.
Physicians also need to follow patients closely by monitoring not only calcium and vitamin D levels but also phosphate and magnesium almost daily.
Dr. Khan said she does this because it’s difficult to predict how much calcium and calcitriol a patient will require and doses will likely have to be titrated up or down based on lab results.
It is noteworthy that a joint statement on the Natpara recall by the Endocrine Society and the American Society of Bone and Mineral Research (ASBMR) also emphasizes these points.
And Dr. Khan – as well as the Endocrine Society and ASBMR – also point out that patients may be transitioned from Natpara to teriparatide (Forteo), another recombinant form of PTH that is licensed for use in osteoporosis but has not been approved for hypoparathyroidism.
In Dr. Khan’s experience, patients often do quite well on teriparatide.
The big downside of prescribing teriparatide in the United States, however, is that the drug has to be used off label, and as such, insurance companies are unlikely to pick up the tab for what is an expensive treatment, she explained.
Furthermore, teriparatide has a very short shelf-life once injected so patients may need to use up to four needles a day to stabilize calcium levels.
If teriparatide is prescribed, subcutaneous injections given in the thigh are recommended for the treatment of hypoparathyroidism, according to the joint Endocrine Society/ASBMR statement.
Takeda vs. FDA
In the meantime, Takeda says it has been in regular contact with the FDA to try and work out how to bring Natpara back to U.S. patients who require it for symptom control.
Current outstanding issues between the company and FDA involve considerations related to dose accuracy, safety, and supply continuity, which the company hopes will be resolved in a timely manner.
Furthermore, shortly after the recall order, the company created a special use program that continues to support patients previously prescribed Natpara who would otherwise be at extreme risk of serious complications if forced to stop taking the drug.
“Originally intended for an extremely limited number of patients, the special use program has now enrolled approximately 300 patients,” Cheryl Schwartz, head, U.S. Hematology & Rare Business Unit, Takeda, said in a letter to members of the U.S. Hypoparathyroidism Association on Nov. 21.
The number is higher than expected and reflects the significant treatment needs of patients with serious disease, Ms. Schwartz noted.
“I want to reiterate that we do understand and sincerely regret the impact the Natpara recall is having on patients. We will provide another update as soon as we have more information to share. We continue to work around the clock to find ways to bring Natpara back to the broader hypoparathyroidism community,” she added.
“Patient safety always has been, and continues to be, the highest priority for Takeda,” she said.
Final efforts
Dr. Khan is currently involved in clinical trials evaluating Natpara in Canada (where it is not yet approved).
She was also involved in some of the pivotal studies that helped gain support of the product in the United States and European Union, including REPLACE, which showed that the injectable PTH molecule maintained serum calcium while reducing or eliminating requirements for calcium and active vitamin D supplementation.
“We now have 8 years of experience with this molecule, so we know that it’s safe and effective,” Dr. Khan emphasized.
Health Canada has not deemed Natpara problematic enough to stop the ongoing research program into injectable PTH therapies there, which is being headed up by Dr. Khan at McMaster University.
“The company has not yet applied for approval here, but when they do apply, I am sure they will have fixed this problem by then,” Dr. Khan said. “And I expect it will be fixed momentarily in the United States, where patients have been most affected.”
Asked if she was looking forward to getting Natpara back on track, Ms. Astolfi said “absolutely” several times.
“This recall has really had a large impact on our community,” she stressed. “And while it’s good that critically ill patients have access to the drug through the special-use program, we want to get everyone back to their best life and feeling great.”
A version of this story originally appeared on Medscape.com.
Bethesda system underpredicts malignancy in pediatric thyroid tumors
CHICAGO –
Especially for nodules that fall into indeterminate categories, “the rate of malignancy in thyroid nodules is higher [in pediatric patients] than that reported in adults,” said Wen Jiang, MD, of the University of California San Diego and Rady Children’s Hospital, also in San Diego.
Current pediatric guidelines recommend that thyroid fine-needle aspiration (FNA) be performed only under ultrasound guidance, noted Dr. Jiang, a pediatric otolaryngologist, at the annual meeting of the American Thyroid Association. In addition, the Bethesda thyroid cytopathology system should be used to report FNA cytology results, and when cytopathology of FNA for a thyroid nodule is indeterminate, thyroid lobectomy is preferred over repeat FNA for most children with thyroid nodules.
To assess how well pediatric patients fared using the Bethesda system for thyroid cytopathology, Dr. Jiang and colleagues performed a retrospective review of children with thyroid nodules who received FNA at Rady Children’s Hospital during 2002-2018. The investigators used the Bethesda system to classify FNA results.
In addition to collecting the initial cytologic findings and demographic data, Dr. Jiang and colleagues also tracked repeat cytology and histopathology, as well as any radiographic and clinical follow-up data that were available.
A total of 203 cytologic samples were available from 171 patients. In all, 50 patients (29.2%) had malignancy. The mean age was about 15 years (range, 6-18 years), and the ratio of 140 female to 31 male participants was 4.5:1.
All but 21 of the samples were performed under ultrasound guidance. The nondiagnostic rate for ultrasound-guided samples was 11.5%, and for those obtained without use of ultrasound – which occurred in older cases – the nondiagnostic rate was 38.5%. “Ultrasound guidance improves the diagnostic rate,” said Dr. Jiang, adding that incorporation of on-site adequacy testing also “significantly decreased the nondiagnostic rate over the study period.”
The Bethesda system has the following six diagnostic categories, with each accompanied by follow-up recommendations in the adult population.
- Category I is nondiagnostic, and a repeat ultrasound-guided FNA is recommended for adults in this category.
- Category II is benign. Patients with these nodules should receive clinical follow-up and repeat ultrasound examination.
- Category III nodules may show atypia of undetermined significance or be judged a follicular lesion of undetermined significance. Here, adult management options include repeat FNA, molecular testing, or thyroid lobectomy.
- Category IV nodules may be assessed as follicular neoplasm or as suspicious for follicular neoplasm. Molecular testing or lobectomy are the adult management options.
- Category V describes nodules suspicious for malignancy. Either lobectomy or total thyroidectomy are options for adult management.
- Category VI is reserved for clearly malignant nodules. Again, lobectomy or total thyroidectomy are the adult management options.
In terms of the real-world outcomes in this cohort of pediatric patients with nodules, 14.8% of the 29 nodules with Bethesda category I – nondiagnostic – status were later found to be malignant, a higher rate than the 5%-10% expected in adults. Of 106 Bethesda category II – benign – nodules, 4% were malignant. In adults, 0%-3% of category II nodules turn out to be malignant.
Cytopathology from FNA of 22 nodules fell into the Bethesda category III, and 25% were malignant, which was within the expected range of 10%-30% for adults. “Bethesda class II accurately identified benign nodules with low risk of subsequent malignancy,” said Dr. Jiang.
Fourteen nodules were Bethesda category IV, and of those, 42.9% were malignant, again slightly higher than the 25%-40% expected in adults.
Just six nodules had FNA results falling into Bethesda category V, of which 83.3% were malignant, a higher rate than the 50%-75% expected for adult category V cytopathology results. All category V nodules were papillary thyroid carcinoma.
All 26 Bethesda category VI nodules were malignant; in adult category VI nodules, 97%-99% are expected to be malignant. All but four of the cases were found to be papillary thyroid carcinoma.
Dr. Jiang explained that at Rady Children’s Hospital, all FNA cytology slides received a second-opinion assessment by pathologists at the University of California San Diego. Of all the samples assessed in the study, there was disagreement about one slide, with a difference of one Bethesda category. “Malignant class cytology is quite reliable,” she said, adding the caveat that “second-opinion confirmation adds additional confidence to the cytologic diagnosis.”
She emphasized again that the initiation of on-site testing for sample adequacy significantly decreased the nondiagnostic rate seen over the course of the study.
Dr. Jiang reported no relevant conflicts of interest and no outside sources of funding.
SOURCE: Jiang W et al. ATA 2019, Oral Abstract 34.
CHICAGO –
Especially for nodules that fall into indeterminate categories, “the rate of malignancy in thyroid nodules is higher [in pediatric patients] than that reported in adults,” said Wen Jiang, MD, of the University of California San Diego and Rady Children’s Hospital, also in San Diego.
Current pediatric guidelines recommend that thyroid fine-needle aspiration (FNA) be performed only under ultrasound guidance, noted Dr. Jiang, a pediatric otolaryngologist, at the annual meeting of the American Thyroid Association. In addition, the Bethesda thyroid cytopathology system should be used to report FNA cytology results, and when cytopathology of FNA for a thyroid nodule is indeterminate, thyroid lobectomy is preferred over repeat FNA for most children with thyroid nodules.
To assess how well pediatric patients fared using the Bethesda system for thyroid cytopathology, Dr. Jiang and colleagues performed a retrospective review of children with thyroid nodules who received FNA at Rady Children’s Hospital during 2002-2018. The investigators used the Bethesda system to classify FNA results.
In addition to collecting the initial cytologic findings and demographic data, Dr. Jiang and colleagues also tracked repeat cytology and histopathology, as well as any radiographic and clinical follow-up data that were available.
A total of 203 cytologic samples were available from 171 patients. In all, 50 patients (29.2%) had malignancy. The mean age was about 15 years (range, 6-18 years), and the ratio of 140 female to 31 male participants was 4.5:1.
All but 21 of the samples were performed under ultrasound guidance. The nondiagnostic rate for ultrasound-guided samples was 11.5%, and for those obtained without use of ultrasound – which occurred in older cases – the nondiagnostic rate was 38.5%. “Ultrasound guidance improves the diagnostic rate,” said Dr. Jiang, adding that incorporation of on-site adequacy testing also “significantly decreased the nondiagnostic rate over the study period.”
The Bethesda system has the following six diagnostic categories, with each accompanied by follow-up recommendations in the adult population.
- Category I is nondiagnostic, and a repeat ultrasound-guided FNA is recommended for adults in this category.
- Category II is benign. Patients with these nodules should receive clinical follow-up and repeat ultrasound examination.
- Category III nodules may show atypia of undetermined significance or be judged a follicular lesion of undetermined significance. Here, adult management options include repeat FNA, molecular testing, or thyroid lobectomy.
- Category IV nodules may be assessed as follicular neoplasm or as suspicious for follicular neoplasm. Molecular testing or lobectomy are the adult management options.
- Category V describes nodules suspicious for malignancy. Either lobectomy or total thyroidectomy are options for adult management.
- Category VI is reserved for clearly malignant nodules. Again, lobectomy or total thyroidectomy are the adult management options.
In terms of the real-world outcomes in this cohort of pediatric patients with nodules, 14.8% of the 29 nodules with Bethesda category I – nondiagnostic – status were later found to be malignant, a higher rate than the 5%-10% expected in adults. Of 106 Bethesda category II – benign – nodules, 4% were malignant. In adults, 0%-3% of category II nodules turn out to be malignant.
Cytopathology from FNA of 22 nodules fell into the Bethesda category III, and 25% were malignant, which was within the expected range of 10%-30% for adults. “Bethesda class II accurately identified benign nodules with low risk of subsequent malignancy,” said Dr. Jiang.
Fourteen nodules were Bethesda category IV, and of those, 42.9% were malignant, again slightly higher than the 25%-40% expected in adults.
Just six nodules had FNA results falling into Bethesda category V, of which 83.3% were malignant, a higher rate than the 50%-75% expected for adult category V cytopathology results. All category V nodules were papillary thyroid carcinoma.
All 26 Bethesda category VI nodules were malignant; in adult category VI nodules, 97%-99% are expected to be malignant. All but four of the cases were found to be papillary thyroid carcinoma.
Dr. Jiang explained that at Rady Children’s Hospital, all FNA cytology slides received a second-opinion assessment by pathologists at the University of California San Diego. Of all the samples assessed in the study, there was disagreement about one slide, with a difference of one Bethesda category. “Malignant class cytology is quite reliable,” she said, adding the caveat that “second-opinion confirmation adds additional confidence to the cytologic diagnosis.”
She emphasized again that the initiation of on-site testing for sample adequacy significantly decreased the nondiagnostic rate seen over the course of the study.
Dr. Jiang reported no relevant conflicts of interest and no outside sources of funding.
SOURCE: Jiang W et al. ATA 2019, Oral Abstract 34.
CHICAGO –
Especially for nodules that fall into indeterminate categories, “the rate of malignancy in thyroid nodules is higher [in pediatric patients] than that reported in adults,” said Wen Jiang, MD, of the University of California San Diego and Rady Children’s Hospital, also in San Diego.
Current pediatric guidelines recommend that thyroid fine-needle aspiration (FNA) be performed only under ultrasound guidance, noted Dr. Jiang, a pediatric otolaryngologist, at the annual meeting of the American Thyroid Association. In addition, the Bethesda thyroid cytopathology system should be used to report FNA cytology results, and when cytopathology of FNA for a thyroid nodule is indeterminate, thyroid lobectomy is preferred over repeat FNA for most children with thyroid nodules.
To assess how well pediatric patients fared using the Bethesda system for thyroid cytopathology, Dr. Jiang and colleagues performed a retrospective review of children with thyroid nodules who received FNA at Rady Children’s Hospital during 2002-2018. The investigators used the Bethesda system to classify FNA results.
In addition to collecting the initial cytologic findings and demographic data, Dr. Jiang and colleagues also tracked repeat cytology and histopathology, as well as any radiographic and clinical follow-up data that were available.
A total of 203 cytologic samples were available from 171 patients. In all, 50 patients (29.2%) had malignancy. The mean age was about 15 years (range, 6-18 years), and the ratio of 140 female to 31 male participants was 4.5:1.
All but 21 of the samples were performed under ultrasound guidance. The nondiagnostic rate for ultrasound-guided samples was 11.5%, and for those obtained without use of ultrasound – which occurred in older cases – the nondiagnostic rate was 38.5%. “Ultrasound guidance improves the diagnostic rate,” said Dr. Jiang, adding that incorporation of on-site adequacy testing also “significantly decreased the nondiagnostic rate over the study period.”
The Bethesda system has the following six diagnostic categories, with each accompanied by follow-up recommendations in the adult population.
- Category I is nondiagnostic, and a repeat ultrasound-guided FNA is recommended for adults in this category.
- Category II is benign. Patients with these nodules should receive clinical follow-up and repeat ultrasound examination.
- Category III nodules may show atypia of undetermined significance or be judged a follicular lesion of undetermined significance. Here, adult management options include repeat FNA, molecular testing, or thyroid lobectomy.
- Category IV nodules may be assessed as follicular neoplasm or as suspicious for follicular neoplasm. Molecular testing or lobectomy are the adult management options.
- Category V describes nodules suspicious for malignancy. Either lobectomy or total thyroidectomy are options for adult management.
- Category VI is reserved for clearly malignant nodules. Again, lobectomy or total thyroidectomy are the adult management options.
In terms of the real-world outcomes in this cohort of pediatric patients with nodules, 14.8% of the 29 nodules with Bethesda category I – nondiagnostic – status were later found to be malignant, a higher rate than the 5%-10% expected in adults. Of 106 Bethesda category II – benign – nodules, 4% were malignant. In adults, 0%-3% of category II nodules turn out to be malignant.
Cytopathology from FNA of 22 nodules fell into the Bethesda category III, and 25% were malignant, which was within the expected range of 10%-30% for adults. “Bethesda class II accurately identified benign nodules with low risk of subsequent malignancy,” said Dr. Jiang.
Fourteen nodules were Bethesda category IV, and of those, 42.9% were malignant, again slightly higher than the 25%-40% expected in adults.
Just six nodules had FNA results falling into Bethesda category V, of which 83.3% were malignant, a higher rate than the 50%-75% expected for adult category V cytopathology results. All category V nodules were papillary thyroid carcinoma.
All 26 Bethesda category VI nodules were malignant; in adult category VI nodules, 97%-99% are expected to be malignant. All but four of the cases were found to be papillary thyroid carcinoma.
Dr. Jiang explained that at Rady Children’s Hospital, all FNA cytology slides received a second-opinion assessment by pathologists at the University of California San Diego. Of all the samples assessed in the study, there was disagreement about one slide, with a difference of one Bethesda category. “Malignant class cytology is quite reliable,” she said, adding the caveat that “second-opinion confirmation adds additional confidence to the cytologic diagnosis.”
She emphasized again that the initiation of on-site testing for sample adequacy significantly decreased the nondiagnostic rate seen over the course of the study.
Dr. Jiang reported no relevant conflicts of interest and no outside sources of funding.
SOURCE: Jiang W et al. ATA 2019, Oral Abstract 34.
REPORTING FROM ATA 2019
Key clinical point: Pediatric thyroid nodule cytopathology classified according to the Bethesda system showed a higher rate of malignancy than that reported in adults.
Major finding: Of 203 nodules, 14 were Bethesda category IV (follicular neoplasm or suspicious for neoplasm), and 42.9% of those were malignant, compared with the 25%-40% expected in adults.
Study details: Retrospective, single-center review of 203 fine needle–aspirated samples from 171 pediatric patients with thyroid nodules tracked over a 16-year period.
Disclosures: Dr. Jiang reported no relevant conflicts of interest and no outside sources of funding.
Source: Johnson T et al. ATA 2019, Oral Abstract 34.
Findings confirm link between methimazole and risk for acute pancreatitis
CHICAGO –
After 6 months of methimazole use, the odds ratio for acute pancreatitis was 2.02, with a nonsignificant risk elevation for propylthiouracil use after a similar duration, Laszlo Hegedüs, MD, reported at the annual meeting of the American Thyroid Association.
“Ongoing methimazole, but not propylthiouracil, use is associated with an increased risk of acute pancreatitis,” he said.
Dr. Hegedüs, professor of endocrinology and metabolism at the University of Southern Denmark, Odense, said that the European Medicines Agency has noted a few postmarketing reports of acute pancreatitis in patients who received the antithyroid drug methimazole, as well as its prodrug, carbimazole. The agency has accordingly contraindicated antithyroid drug use for patients who previously experienced acute pancreatitis after receiving this drug, advising that methimazole should be “discontinued immediately” should a patient develop acute pancreatitis.
However, investigation of the antithyroid drug–pancreatitis association had been limited to aggregating those case reports, so Dr. Hegedüs and colleagues decided to use Danish medical record and registry data to investigate the association in a nationwide, controlled study that looked at both duration of therapy and total antithyroid drug use.
During the period from 1995-2018, a total of 118,649 patients who used antithyroid drugs were found in the 5.5 million individuals in the Statistics Denmark registry. Dr. Hegedüs and his colleagues also pulled in patient registry and national prescription registry data, as well as civil vital statistics data.
Of those who used antithyroid drugs, 103,825 patients used methimazole, and 14,824 used propylthiouracil. The researchers found 43,580 instances of hospitalization for first-time acute pancreatitis in the pooled antithyroid drug data. Of those, however, just 226 (0.5%) occurred in patients using methimazole, and 19 (0.04%) in those using propylthiouracil at the time of pancreatitis onset.
To ascertain the risk of acute pancreatitis in patients using antithyroid drugs for various durations, Dr. Hegedüs and his colleagues used a case-crossover study design. In the case-crossover technique, patients served as their own controls, because each patient was both exposed and not exposed to antithyroid drugs at some point during the study period. Antithyroid drugs are well suited to this study design, explained Dr. Hegedüs, because they are given for a limited time. A case-crossover design can be used with a small sample size and effectively controls for potentially confounding variables.
The odds ratio for acute pancreatitis in methimazole users after 3 months of exposure was 1.51, with a 95% confidence interval of 1.12-2.02. After 3 months of propylthiouracil exposure, the odds ratio for acute pancreatitis was 1.16 (95% CI 0.46-2.3). At 6 months, the odds ratio of 2.02 for methimazole was similarly statistically significant (95% CI, 1.50-2.78), whereas the odds ratio of 1.40 for propylthiouracil use was not significant (95% CI, 0.58-3.34).
The researchers also wanted to find out whether the cumulative drug dose affected the risk of acute pancreatitis, so they drew from the antithyroid drug population to conduct a case-control study. Here, the investigators matched data from four control patients to each case of acute pancreatitis. The researchers also controlled for sex, age, comorbidities, and prior use of drugs associated with pancreatitis.
Overall, 20% of the 692 methimazole users and their controls were men, as were 16% of the 108 propylthiouracil users, in the case-control study.
Just more than half of patients overall had a total dose exposure of 200 to 1,200 defined daily dose (DDD) – a measure developed by the World Health Organization to denote the assumed average adult dose per day of a medication – with about a quarter of patients receiving a total antithyroid drug dose more than 1,200 DDD and about 20% receiving a dose exposure of less than 200 DDD. The risk of acute pancreatitis did not increase with increased total exposure to antithyroid drugs.
“There is no evidence of a cumulative dose effect of either methimazole or propylthiouracil on the risk of acute pancreatitis,” said Dr. Hegedüs. However, “the warning of the European Medicines Agency seems justified,” he added. “The frequency of acute pancreatitis in acute methimazole users is of a similar magnitude [to that] reported for agranulocytosis,” a known, dire complication of antithyroid drug use. Patients should be advised of the potential complication and informed of signs and symptoms of acute pancreatitis, he said.
Dr. Hegedüs noted that the study had the advantage of using validated epidemiologic methods to look at drug exposure and outcomes at a nationwide scale. However, the registries from which the data were drawn also have limitations. The investigators could not determine the severity of hyperthyroidism, he said, and the relatively rare occurrence of acute pancreatitis meant that there was not sufficient statistical power to look at the subgroup of individuals who had Graves disease and to compare them with those with nodular toxic goiter.
He advised conducting a confirmatory study in an independent cohort, as well as further investigating the yet unknown mechanism of action for the link between the antithyroid drug and acute pancreatitis.
Dr. Hegedüs reported that he had no relevant conflicts of interest and reported no outside sources of funding.
SOURCE: Hegedüs, L. et al. ATA 2019, Short Call Oral Abstract 6 .
CHICAGO –
After 6 months of methimazole use, the odds ratio for acute pancreatitis was 2.02, with a nonsignificant risk elevation for propylthiouracil use after a similar duration, Laszlo Hegedüs, MD, reported at the annual meeting of the American Thyroid Association.
“Ongoing methimazole, but not propylthiouracil, use is associated with an increased risk of acute pancreatitis,” he said.
Dr. Hegedüs, professor of endocrinology and metabolism at the University of Southern Denmark, Odense, said that the European Medicines Agency has noted a few postmarketing reports of acute pancreatitis in patients who received the antithyroid drug methimazole, as well as its prodrug, carbimazole. The agency has accordingly contraindicated antithyroid drug use for patients who previously experienced acute pancreatitis after receiving this drug, advising that methimazole should be “discontinued immediately” should a patient develop acute pancreatitis.
However, investigation of the antithyroid drug–pancreatitis association had been limited to aggregating those case reports, so Dr. Hegedüs and colleagues decided to use Danish medical record and registry data to investigate the association in a nationwide, controlled study that looked at both duration of therapy and total antithyroid drug use.
During the period from 1995-2018, a total of 118,649 patients who used antithyroid drugs were found in the 5.5 million individuals in the Statistics Denmark registry. Dr. Hegedüs and his colleagues also pulled in patient registry and national prescription registry data, as well as civil vital statistics data.
Of those who used antithyroid drugs, 103,825 patients used methimazole, and 14,824 used propylthiouracil. The researchers found 43,580 instances of hospitalization for first-time acute pancreatitis in the pooled antithyroid drug data. Of those, however, just 226 (0.5%) occurred in patients using methimazole, and 19 (0.04%) in those using propylthiouracil at the time of pancreatitis onset.
To ascertain the risk of acute pancreatitis in patients using antithyroid drugs for various durations, Dr. Hegedüs and his colleagues used a case-crossover study design. In the case-crossover technique, patients served as their own controls, because each patient was both exposed and not exposed to antithyroid drugs at some point during the study period. Antithyroid drugs are well suited to this study design, explained Dr. Hegedüs, because they are given for a limited time. A case-crossover design can be used with a small sample size and effectively controls for potentially confounding variables.
The odds ratio for acute pancreatitis in methimazole users after 3 months of exposure was 1.51, with a 95% confidence interval of 1.12-2.02. After 3 months of propylthiouracil exposure, the odds ratio for acute pancreatitis was 1.16 (95% CI 0.46-2.3). At 6 months, the odds ratio of 2.02 for methimazole was similarly statistically significant (95% CI, 1.50-2.78), whereas the odds ratio of 1.40 for propylthiouracil use was not significant (95% CI, 0.58-3.34).
The researchers also wanted to find out whether the cumulative drug dose affected the risk of acute pancreatitis, so they drew from the antithyroid drug population to conduct a case-control study. Here, the investigators matched data from four control patients to each case of acute pancreatitis. The researchers also controlled for sex, age, comorbidities, and prior use of drugs associated with pancreatitis.
Overall, 20% of the 692 methimazole users and their controls were men, as were 16% of the 108 propylthiouracil users, in the case-control study.
Just more than half of patients overall had a total dose exposure of 200 to 1,200 defined daily dose (DDD) – a measure developed by the World Health Organization to denote the assumed average adult dose per day of a medication – with about a quarter of patients receiving a total antithyroid drug dose more than 1,200 DDD and about 20% receiving a dose exposure of less than 200 DDD. The risk of acute pancreatitis did not increase with increased total exposure to antithyroid drugs.
“There is no evidence of a cumulative dose effect of either methimazole or propylthiouracil on the risk of acute pancreatitis,” said Dr. Hegedüs. However, “the warning of the European Medicines Agency seems justified,” he added. “The frequency of acute pancreatitis in acute methimazole users is of a similar magnitude [to that] reported for agranulocytosis,” a known, dire complication of antithyroid drug use. Patients should be advised of the potential complication and informed of signs and symptoms of acute pancreatitis, he said.
Dr. Hegedüs noted that the study had the advantage of using validated epidemiologic methods to look at drug exposure and outcomes at a nationwide scale. However, the registries from which the data were drawn also have limitations. The investigators could not determine the severity of hyperthyroidism, he said, and the relatively rare occurrence of acute pancreatitis meant that there was not sufficient statistical power to look at the subgroup of individuals who had Graves disease and to compare them with those with nodular toxic goiter.
He advised conducting a confirmatory study in an independent cohort, as well as further investigating the yet unknown mechanism of action for the link between the antithyroid drug and acute pancreatitis.
Dr. Hegedüs reported that he had no relevant conflicts of interest and reported no outside sources of funding.
SOURCE: Hegedüs, L. et al. ATA 2019, Short Call Oral Abstract 6 .
CHICAGO –
After 6 months of methimazole use, the odds ratio for acute pancreatitis was 2.02, with a nonsignificant risk elevation for propylthiouracil use after a similar duration, Laszlo Hegedüs, MD, reported at the annual meeting of the American Thyroid Association.
“Ongoing methimazole, but not propylthiouracil, use is associated with an increased risk of acute pancreatitis,” he said.
Dr. Hegedüs, professor of endocrinology and metabolism at the University of Southern Denmark, Odense, said that the European Medicines Agency has noted a few postmarketing reports of acute pancreatitis in patients who received the antithyroid drug methimazole, as well as its prodrug, carbimazole. The agency has accordingly contraindicated antithyroid drug use for patients who previously experienced acute pancreatitis after receiving this drug, advising that methimazole should be “discontinued immediately” should a patient develop acute pancreatitis.
However, investigation of the antithyroid drug–pancreatitis association had been limited to aggregating those case reports, so Dr. Hegedüs and colleagues decided to use Danish medical record and registry data to investigate the association in a nationwide, controlled study that looked at both duration of therapy and total antithyroid drug use.
During the period from 1995-2018, a total of 118,649 patients who used antithyroid drugs were found in the 5.5 million individuals in the Statistics Denmark registry. Dr. Hegedüs and his colleagues also pulled in patient registry and national prescription registry data, as well as civil vital statistics data.
Of those who used antithyroid drugs, 103,825 patients used methimazole, and 14,824 used propylthiouracil. The researchers found 43,580 instances of hospitalization for first-time acute pancreatitis in the pooled antithyroid drug data. Of those, however, just 226 (0.5%) occurred in patients using methimazole, and 19 (0.04%) in those using propylthiouracil at the time of pancreatitis onset.
To ascertain the risk of acute pancreatitis in patients using antithyroid drugs for various durations, Dr. Hegedüs and his colleagues used a case-crossover study design. In the case-crossover technique, patients served as their own controls, because each patient was both exposed and not exposed to antithyroid drugs at some point during the study period. Antithyroid drugs are well suited to this study design, explained Dr. Hegedüs, because they are given for a limited time. A case-crossover design can be used with a small sample size and effectively controls for potentially confounding variables.
The odds ratio for acute pancreatitis in methimazole users after 3 months of exposure was 1.51, with a 95% confidence interval of 1.12-2.02. After 3 months of propylthiouracil exposure, the odds ratio for acute pancreatitis was 1.16 (95% CI 0.46-2.3). At 6 months, the odds ratio of 2.02 for methimazole was similarly statistically significant (95% CI, 1.50-2.78), whereas the odds ratio of 1.40 for propylthiouracil use was not significant (95% CI, 0.58-3.34).
The researchers also wanted to find out whether the cumulative drug dose affected the risk of acute pancreatitis, so they drew from the antithyroid drug population to conduct a case-control study. Here, the investigators matched data from four control patients to each case of acute pancreatitis. The researchers also controlled for sex, age, comorbidities, and prior use of drugs associated with pancreatitis.
Overall, 20% of the 692 methimazole users and their controls were men, as were 16% of the 108 propylthiouracil users, in the case-control study.
Just more than half of patients overall had a total dose exposure of 200 to 1,200 defined daily dose (DDD) – a measure developed by the World Health Organization to denote the assumed average adult dose per day of a medication – with about a quarter of patients receiving a total antithyroid drug dose more than 1,200 DDD and about 20% receiving a dose exposure of less than 200 DDD. The risk of acute pancreatitis did not increase with increased total exposure to antithyroid drugs.
“There is no evidence of a cumulative dose effect of either methimazole or propylthiouracil on the risk of acute pancreatitis,” said Dr. Hegedüs. However, “the warning of the European Medicines Agency seems justified,” he added. “The frequency of acute pancreatitis in acute methimazole users is of a similar magnitude [to that] reported for agranulocytosis,” a known, dire complication of antithyroid drug use. Patients should be advised of the potential complication and informed of signs and symptoms of acute pancreatitis, he said.
Dr. Hegedüs noted that the study had the advantage of using validated epidemiologic methods to look at drug exposure and outcomes at a nationwide scale. However, the registries from which the data were drawn also have limitations. The investigators could not determine the severity of hyperthyroidism, he said, and the relatively rare occurrence of acute pancreatitis meant that there was not sufficient statistical power to look at the subgroup of individuals who had Graves disease and to compare them with those with nodular toxic goiter.
He advised conducting a confirmatory study in an independent cohort, as well as further investigating the yet unknown mechanism of action for the link between the antithyroid drug and acute pancreatitis.
Dr. Hegedüs reported that he had no relevant conflicts of interest and reported no outside sources of funding.
SOURCE: Hegedüs, L. et al. ATA 2019, Short Call Oral Abstract 6 .
REPORTING FROM ATA 2019
Multimodal therapies almost double survival in anaplastic thyroid cancer
CHICAGO –
Median survival for participants in a specialized program who have been able to benefit from targeted therapy and immunotherapy now stands at 16 months, with 43% of patients surviving 2 years or more, said Anastasios Maniakas, MD, at the annual meeting of the American Thyroid Association.
Median survival was 8 months during 2000-2013, before the program, dubbed FAST (Facilitating Anaplastic Thyroid Cancer Specialized Treatment), was initiated at the University of Texas MD Anderson Cancer Center, Houston.
These increased survival rates were driven primarily by better targeting of mutation-specific therapy and by immunotherapy, said Dr. Maniakas, a fellow in head and neck surgery at the center. This targeting, in turn, was facilitated by timely staging and genetic work-up, as well as appropriate clinical trial enrollment.
As word has spread about the program, referrals went up by 44%, said Dr. Maniakas. Members of the FAST team include representatives from oncologic endocrinology, head and neck surgery, radiation oncology, pathology, and basic science.
Historically, anaplastic thyroid cancer (ATC) has had a 12-month overall survival rate of less than 30% for patients who have advanced disease, said Dr. Maniakas, citing a recent analysis showing that, in 1,567 ATC cases, the median survival was just 4 months, and the 6-month survival rate was 35%.
The FAST team’s engagement starts with rapid intake whereby patients see a physician within 3-5 days of initial contact with the center, explained Dr. Maniakas. A prescheduled work-up is completed within another 3-7 days. It includes basic lab work, cell-free DNA testing, BRAF immunohistochemistry, and molecular testing. Additional consults and appropriate medical imaging for staging are also included in the initial work-up.
With these data in hand, physicians meet again with patients in a treatment-planning clinic to assess eligibility for participation in a clinical trial. Patients will otherwise receive standard-of-care therapy that may include surgery or BRAF-directed therapy. However, said Dr. Maniakas, the FAST approach has resulted in a boost of more than 30% in clinical trial participation by ATC patients. Adjunctive therapies are also tailored to patients under the care of the FAST team, which may include stereotactic body-radiation therapy, surgery, and immunotherapy.
The team is tracking a cohort of patients who received surgery with or without radiation therapy, preceded by neoadjuvant BRAF/MEK inhibitor therapy – an approach used since 2017. Of 20 patients who were positive for BRAF-V600E, 16 are still alive at a median 1.21 years of follow-up since diagnosis, said Dr. Maniakas. The median survival time for those who did not receive surgery is 0.8 years, whereas the median survival has not been reached for those who also had surgery.
Molecular testing and initial screening of ATC patients is an essential component of the cancer center’s precision medicine approach, said Dr. Maniakas. “Genetic profiling has become a key player in ATC management and survival.”
In looking at outcomes at the cancer center, Dr. Maniakas and his collaborators divided the patients into three groups. The first included 227 patients seen during 2000-2013, before the program was initiated. The 100 participants in the second group initiated treatment sometime during 2014-2016, after the program was launched but before the targeted therapy and immunotherapy trial was fully implemented. Since 2017, 152 participants in the third group have had the opportunity to participate in the clinical trial, as well as receiving surgery with or without radiation therapy after neoadjuvant immunotherapy.
Since 2017, 97% of ATC patients have had genetic profiling done. Most patients are receiving rapid determination of BRAF-V600E status with immunohistochemistry, with results available in a few days, followed by liquid biopsy (available in about 2 weeks), and then next-generation sequencing. Results for the latter, considered the gold standard, can take up to 3 weeks.
Patients participating in the program were aged a mean 65 years at diagnosis, and just over half were men. The number of patients receiving targeted therapy has continued to rise, said Dr. Maniakas. From 2000 to 2013, just 9% of patients received targeted therapy; from 2014 to 2016, that figure rose to 43%; and since 2017, 61% of patients have received targeted therapy (P less than .001).
“Landmark changes in the management of ATC patients as a whole have had a direct impact to the significant increase in overall survival,” said Dr. Maniakas.
He added that the cancer center’s experience could inform future ATC guidelines. Patients with this deadliest of thyroid cancers should all have rapid molecular testing, followed by timely, targeted therapy. Clinical trial eligibility should be considered for all patients. Finally, guideline authors should take note of the ongoing favorable survival rates seen for patients receiving surgery after neoadjuvant therapy.
Dr. Maniakas reported no outside sources of funding and that he had no relevant disclosures.
SOURCE: Maniakas A et al. ATA 2019, Short Call Oral Abstract 9.
CHICAGO –
Median survival for participants in a specialized program who have been able to benefit from targeted therapy and immunotherapy now stands at 16 months, with 43% of patients surviving 2 years or more, said Anastasios Maniakas, MD, at the annual meeting of the American Thyroid Association.
Median survival was 8 months during 2000-2013, before the program, dubbed FAST (Facilitating Anaplastic Thyroid Cancer Specialized Treatment), was initiated at the University of Texas MD Anderson Cancer Center, Houston.
These increased survival rates were driven primarily by better targeting of mutation-specific therapy and by immunotherapy, said Dr. Maniakas, a fellow in head and neck surgery at the center. This targeting, in turn, was facilitated by timely staging and genetic work-up, as well as appropriate clinical trial enrollment.
As word has spread about the program, referrals went up by 44%, said Dr. Maniakas. Members of the FAST team include representatives from oncologic endocrinology, head and neck surgery, radiation oncology, pathology, and basic science.
Historically, anaplastic thyroid cancer (ATC) has had a 12-month overall survival rate of less than 30% for patients who have advanced disease, said Dr. Maniakas, citing a recent analysis showing that, in 1,567 ATC cases, the median survival was just 4 months, and the 6-month survival rate was 35%.
The FAST team’s engagement starts with rapid intake whereby patients see a physician within 3-5 days of initial contact with the center, explained Dr. Maniakas. A prescheduled work-up is completed within another 3-7 days. It includes basic lab work, cell-free DNA testing, BRAF immunohistochemistry, and molecular testing. Additional consults and appropriate medical imaging for staging are also included in the initial work-up.
With these data in hand, physicians meet again with patients in a treatment-planning clinic to assess eligibility for participation in a clinical trial. Patients will otherwise receive standard-of-care therapy that may include surgery or BRAF-directed therapy. However, said Dr. Maniakas, the FAST approach has resulted in a boost of more than 30% in clinical trial participation by ATC patients. Adjunctive therapies are also tailored to patients under the care of the FAST team, which may include stereotactic body-radiation therapy, surgery, and immunotherapy.
The team is tracking a cohort of patients who received surgery with or without radiation therapy, preceded by neoadjuvant BRAF/MEK inhibitor therapy – an approach used since 2017. Of 20 patients who were positive for BRAF-V600E, 16 are still alive at a median 1.21 years of follow-up since diagnosis, said Dr. Maniakas. The median survival time for those who did not receive surgery is 0.8 years, whereas the median survival has not been reached for those who also had surgery.
Molecular testing and initial screening of ATC patients is an essential component of the cancer center’s precision medicine approach, said Dr. Maniakas. “Genetic profiling has become a key player in ATC management and survival.”
In looking at outcomes at the cancer center, Dr. Maniakas and his collaborators divided the patients into three groups. The first included 227 patients seen during 2000-2013, before the program was initiated. The 100 participants in the second group initiated treatment sometime during 2014-2016, after the program was launched but before the targeted therapy and immunotherapy trial was fully implemented. Since 2017, 152 participants in the third group have had the opportunity to participate in the clinical trial, as well as receiving surgery with or without radiation therapy after neoadjuvant immunotherapy.
Since 2017, 97% of ATC patients have had genetic profiling done. Most patients are receiving rapid determination of BRAF-V600E status with immunohistochemistry, with results available in a few days, followed by liquid biopsy (available in about 2 weeks), and then next-generation sequencing. Results for the latter, considered the gold standard, can take up to 3 weeks.
Patients participating in the program were aged a mean 65 years at diagnosis, and just over half were men. The number of patients receiving targeted therapy has continued to rise, said Dr. Maniakas. From 2000 to 2013, just 9% of patients received targeted therapy; from 2014 to 2016, that figure rose to 43%; and since 2017, 61% of patients have received targeted therapy (P less than .001).
“Landmark changes in the management of ATC patients as a whole have had a direct impact to the significant increase in overall survival,” said Dr. Maniakas.
He added that the cancer center’s experience could inform future ATC guidelines. Patients with this deadliest of thyroid cancers should all have rapid molecular testing, followed by timely, targeted therapy. Clinical trial eligibility should be considered for all patients. Finally, guideline authors should take note of the ongoing favorable survival rates seen for patients receiving surgery after neoadjuvant therapy.
Dr. Maniakas reported no outside sources of funding and that he had no relevant disclosures.
SOURCE: Maniakas A et al. ATA 2019, Short Call Oral Abstract 9.
CHICAGO –
Median survival for participants in a specialized program who have been able to benefit from targeted therapy and immunotherapy now stands at 16 months, with 43% of patients surviving 2 years or more, said Anastasios Maniakas, MD, at the annual meeting of the American Thyroid Association.
Median survival was 8 months during 2000-2013, before the program, dubbed FAST (Facilitating Anaplastic Thyroid Cancer Specialized Treatment), was initiated at the University of Texas MD Anderson Cancer Center, Houston.
These increased survival rates were driven primarily by better targeting of mutation-specific therapy and by immunotherapy, said Dr. Maniakas, a fellow in head and neck surgery at the center. This targeting, in turn, was facilitated by timely staging and genetic work-up, as well as appropriate clinical trial enrollment.
As word has spread about the program, referrals went up by 44%, said Dr. Maniakas. Members of the FAST team include representatives from oncologic endocrinology, head and neck surgery, radiation oncology, pathology, and basic science.
Historically, anaplastic thyroid cancer (ATC) has had a 12-month overall survival rate of less than 30% for patients who have advanced disease, said Dr. Maniakas, citing a recent analysis showing that, in 1,567 ATC cases, the median survival was just 4 months, and the 6-month survival rate was 35%.
The FAST team’s engagement starts with rapid intake whereby patients see a physician within 3-5 days of initial contact with the center, explained Dr. Maniakas. A prescheduled work-up is completed within another 3-7 days. It includes basic lab work, cell-free DNA testing, BRAF immunohistochemistry, and molecular testing. Additional consults and appropriate medical imaging for staging are also included in the initial work-up.
With these data in hand, physicians meet again with patients in a treatment-planning clinic to assess eligibility for participation in a clinical trial. Patients will otherwise receive standard-of-care therapy that may include surgery or BRAF-directed therapy. However, said Dr. Maniakas, the FAST approach has resulted in a boost of more than 30% in clinical trial participation by ATC patients. Adjunctive therapies are also tailored to patients under the care of the FAST team, which may include stereotactic body-radiation therapy, surgery, and immunotherapy.
The team is tracking a cohort of patients who received surgery with or without radiation therapy, preceded by neoadjuvant BRAF/MEK inhibitor therapy – an approach used since 2017. Of 20 patients who were positive for BRAF-V600E, 16 are still alive at a median 1.21 years of follow-up since diagnosis, said Dr. Maniakas. The median survival time for those who did not receive surgery is 0.8 years, whereas the median survival has not been reached for those who also had surgery.
Molecular testing and initial screening of ATC patients is an essential component of the cancer center’s precision medicine approach, said Dr. Maniakas. “Genetic profiling has become a key player in ATC management and survival.”
In looking at outcomes at the cancer center, Dr. Maniakas and his collaborators divided the patients into three groups. The first included 227 patients seen during 2000-2013, before the program was initiated. The 100 participants in the second group initiated treatment sometime during 2014-2016, after the program was launched but before the targeted therapy and immunotherapy trial was fully implemented. Since 2017, 152 participants in the third group have had the opportunity to participate in the clinical trial, as well as receiving surgery with or without radiation therapy after neoadjuvant immunotherapy.
Since 2017, 97% of ATC patients have had genetic profiling done. Most patients are receiving rapid determination of BRAF-V600E status with immunohistochemistry, with results available in a few days, followed by liquid biopsy (available in about 2 weeks), and then next-generation sequencing. Results for the latter, considered the gold standard, can take up to 3 weeks.
Patients participating in the program were aged a mean 65 years at diagnosis, and just over half were men. The number of patients receiving targeted therapy has continued to rise, said Dr. Maniakas. From 2000 to 2013, just 9% of patients received targeted therapy; from 2014 to 2016, that figure rose to 43%; and since 2017, 61% of patients have received targeted therapy (P less than .001).
“Landmark changes in the management of ATC patients as a whole have had a direct impact to the significant increase in overall survival,” said Dr. Maniakas.
He added that the cancer center’s experience could inform future ATC guidelines. Patients with this deadliest of thyroid cancers should all have rapid molecular testing, followed by timely, targeted therapy. Clinical trial eligibility should be considered for all patients. Finally, guideline authors should take note of the ongoing favorable survival rates seen for patients receiving surgery after neoadjuvant therapy.
Dr. Maniakas reported no outside sources of funding and that he had no relevant disclosures.
SOURCE: Maniakas A et al. ATA 2019, Short Call Oral Abstract 9.
REPORTING FROM ATA 2019
Small nodules, big problems: AI's role in thyroid nodule diagnosis
CHICAGO – A new image-analysis algorithm for benign thyroid nodules that uses a technique similar to facial recognition showed good sensitivity and specificity, with the potential to reduce biopsies by more than 50%.
The negative predictive value of the ultrasound analysis algorithm was 93.2%, a figure approximating the false-negative rate of about 5% that is seen in fine-needle aspiration of thyroid nodules, said Johnson Thomas, MD, at the annual meeting of the American Thyroid Association.
“Millions of people have thyroid nodules,” many of which are detected incidentally, said Dr. Thomas, an endocrinologist with the Mercy health care system in Springfield, Mo. Fewer than 10% of thyroid nodules turn out to be malignant, but each year, millions of patients undergo biopsies to determine the status of their thyroid nodules.
Faced with evaluating a thyroid nodule, an endocrinologist can currently turn to a risk-stratification scheme, such as those developed by the American College of Radiology and the American Thyroid Association. However, there’s a big subjective component to risk stratification – significant inter- and intraobserver variation has been observed, said Dr. Thomas, and not all nodules are classifiable. The result is a system that still has low specificity and positive predictive value, he said.
Even after a decision to proceed to biopsy, one in seven thyroid nodule biopsies will not produce a definitive diagnosis, he said.
“We are doing millions of thyroid biopsies based on very subjective criteria to find thyroid cancer in a very small percentage of the population, with an invasive technique that may not be diagnostic one out of seven times,” Dr. Thomas said in summing up the current medical situation as he sees it.
Dr. Thomas, who writes his own computer code, said he was searching for a reliable and explainable noninvasive technique, and one that lacked subjective room for error, to address the thyroid nodule problem.
The question was whether an artificial intelligence (AI) algorithm could match radiologist performance in classifying thyroid nodules according to the characteristics of their ultrasound images.
Other algorithms use AI to predict which nodules are malignant, but they function as “black boxes” – a common criticism of AI. The outside observer cannot ordinarily see how the AI algorithm “knows” what it knows. This characteristic of AI poses at least a theoretical problem when such algorithms are used for diagnosis or medical decision making.
Dr. Thomas’s* approach was to use a set of training data to allow the algorithm he constructed to see 2,025 images from a total of 482 nodules. The thyroid nodules used for training had been subjected to biopsy or excised in surgery, so they all had a definitive status of being benign or malignant.
Then, after the algorithm was refined, a set of 103 nodules with known malignancy status was used to test the algorithm’s sensitivity and specificity.
The algorithm, dubbed AiBx, used a convolutional neural network to build a unique image vector for each nodule. The AiBx algorithm then looked at the training database to find the “nearest neighbors,” or the images it found to be the most similar to those of the nodule being examined.
For example, said Dr. Thomas, a test image of a benign nodule would have an output from the AiBx analysis of three similar images from the database – all benign. Hence, rather than making a black-box call of whether a nodule is benign or malignant, the algorithm merely says: “This nodule resembles a benign nodule in our database.” The interpreting physician can then use the algorithm as a decision aid with confidence.
The overall accuracy of AiBx was 81.5%, sensitivity was 87.8%, and specificity was 78.5%. Positive predictive value was 65.9%.
As more images are added to the database, AiBx can easily be retrained and refined, said Dr. Thomas.
“It’s intuitive and explainable,” he added, noting that the algorithm is also a good teaching tool for residents and fellows.
“This AI model can be deployed as an app, integrated with [medical imaging systems] or hosted as a website. By using image-similarity AI models we can eliminate subjectivity and decrease the number of unnecessary biopsies,” he explained in the abstract accompanying the presentation.
However, he said that the algorithm as it currently stands has limitations: It has been tested on only 103 images thus far, and there’s the potential for selection bias.
Dr. Thomas* reported that, although he developed the AiBx algorithm, he has not drawn income or royalties from it. He reported no other relevant conflicts of interest.
SOURCE: Thomas* J et al. ATA 2019, Oral Abstract 27.
*Correction, 21/11/2019: An earlier version of this story misstated Dr. Thomas's last name.
CHICAGO – A new image-analysis algorithm for benign thyroid nodules that uses a technique similar to facial recognition showed good sensitivity and specificity, with the potential to reduce biopsies by more than 50%.
The negative predictive value of the ultrasound analysis algorithm was 93.2%, a figure approximating the false-negative rate of about 5% that is seen in fine-needle aspiration of thyroid nodules, said Johnson Thomas, MD, at the annual meeting of the American Thyroid Association.
“Millions of people have thyroid nodules,” many of which are detected incidentally, said Dr. Thomas, an endocrinologist with the Mercy health care system in Springfield, Mo. Fewer than 10% of thyroid nodules turn out to be malignant, but each year, millions of patients undergo biopsies to determine the status of their thyroid nodules.
Faced with evaluating a thyroid nodule, an endocrinologist can currently turn to a risk-stratification scheme, such as those developed by the American College of Radiology and the American Thyroid Association. However, there’s a big subjective component to risk stratification – significant inter- and intraobserver variation has been observed, said Dr. Thomas, and not all nodules are classifiable. The result is a system that still has low specificity and positive predictive value, he said.
Even after a decision to proceed to biopsy, one in seven thyroid nodule biopsies will not produce a definitive diagnosis, he said.
“We are doing millions of thyroid biopsies based on very subjective criteria to find thyroid cancer in a very small percentage of the population, with an invasive technique that may not be diagnostic one out of seven times,” Dr. Thomas said in summing up the current medical situation as he sees it.
Dr. Thomas, who writes his own computer code, said he was searching for a reliable and explainable noninvasive technique, and one that lacked subjective room for error, to address the thyroid nodule problem.
The question was whether an artificial intelligence (AI) algorithm could match radiologist performance in classifying thyroid nodules according to the characteristics of their ultrasound images.
Other algorithms use AI to predict which nodules are malignant, but they function as “black boxes” – a common criticism of AI. The outside observer cannot ordinarily see how the AI algorithm “knows” what it knows. This characteristic of AI poses at least a theoretical problem when such algorithms are used for diagnosis or medical decision making.
Dr. Thomas’s* approach was to use a set of training data to allow the algorithm he constructed to see 2,025 images from a total of 482 nodules. The thyroid nodules used for training had been subjected to biopsy or excised in surgery, so they all had a definitive status of being benign or malignant.
Then, after the algorithm was refined, a set of 103 nodules with known malignancy status was used to test the algorithm’s sensitivity and specificity.
The algorithm, dubbed AiBx, used a convolutional neural network to build a unique image vector for each nodule. The AiBx algorithm then looked at the training database to find the “nearest neighbors,” or the images it found to be the most similar to those of the nodule being examined.
For example, said Dr. Thomas, a test image of a benign nodule would have an output from the AiBx analysis of three similar images from the database – all benign. Hence, rather than making a black-box call of whether a nodule is benign or malignant, the algorithm merely says: “This nodule resembles a benign nodule in our database.” The interpreting physician can then use the algorithm as a decision aid with confidence.
The overall accuracy of AiBx was 81.5%, sensitivity was 87.8%, and specificity was 78.5%. Positive predictive value was 65.9%.
As more images are added to the database, AiBx can easily be retrained and refined, said Dr. Thomas.
“It’s intuitive and explainable,” he added, noting that the algorithm is also a good teaching tool for residents and fellows.
“This AI model can be deployed as an app, integrated with [medical imaging systems] or hosted as a website. By using image-similarity AI models we can eliminate subjectivity and decrease the number of unnecessary biopsies,” he explained in the abstract accompanying the presentation.
However, he said that the algorithm as it currently stands has limitations: It has been tested on only 103 images thus far, and there’s the potential for selection bias.
Dr. Thomas* reported that, although he developed the AiBx algorithm, he has not drawn income or royalties from it. He reported no other relevant conflicts of interest.
SOURCE: Thomas* J et al. ATA 2019, Oral Abstract 27.
*Correction, 21/11/2019: An earlier version of this story misstated Dr. Thomas's last name.
CHICAGO – A new image-analysis algorithm for benign thyroid nodules that uses a technique similar to facial recognition showed good sensitivity and specificity, with the potential to reduce biopsies by more than 50%.
The negative predictive value of the ultrasound analysis algorithm was 93.2%, a figure approximating the false-negative rate of about 5% that is seen in fine-needle aspiration of thyroid nodules, said Johnson Thomas, MD, at the annual meeting of the American Thyroid Association.
“Millions of people have thyroid nodules,” many of which are detected incidentally, said Dr. Thomas, an endocrinologist with the Mercy health care system in Springfield, Mo. Fewer than 10% of thyroid nodules turn out to be malignant, but each year, millions of patients undergo biopsies to determine the status of their thyroid nodules.
Faced with evaluating a thyroid nodule, an endocrinologist can currently turn to a risk-stratification scheme, such as those developed by the American College of Radiology and the American Thyroid Association. However, there’s a big subjective component to risk stratification – significant inter- and intraobserver variation has been observed, said Dr. Thomas, and not all nodules are classifiable. The result is a system that still has low specificity and positive predictive value, he said.
Even after a decision to proceed to biopsy, one in seven thyroid nodule biopsies will not produce a definitive diagnosis, he said.
“We are doing millions of thyroid biopsies based on very subjective criteria to find thyroid cancer in a very small percentage of the population, with an invasive technique that may not be diagnostic one out of seven times,” Dr. Thomas said in summing up the current medical situation as he sees it.
Dr. Thomas, who writes his own computer code, said he was searching for a reliable and explainable noninvasive technique, and one that lacked subjective room for error, to address the thyroid nodule problem.
The question was whether an artificial intelligence (AI) algorithm could match radiologist performance in classifying thyroid nodules according to the characteristics of their ultrasound images.
Other algorithms use AI to predict which nodules are malignant, but they function as “black boxes” – a common criticism of AI. The outside observer cannot ordinarily see how the AI algorithm “knows” what it knows. This characteristic of AI poses at least a theoretical problem when such algorithms are used for diagnosis or medical decision making.
Dr. Thomas’s* approach was to use a set of training data to allow the algorithm he constructed to see 2,025 images from a total of 482 nodules. The thyroid nodules used for training had been subjected to biopsy or excised in surgery, so they all had a definitive status of being benign or malignant.
Then, after the algorithm was refined, a set of 103 nodules with known malignancy status was used to test the algorithm’s sensitivity and specificity.
The algorithm, dubbed AiBx, used a convolutional neural network to build a unique image vector for each nodule. The AiBx algorithm then looked at the training database to find the “nearest neighbors,” or the images it found to be the most similar to those of the nodule being examined.
For example, said Dr. Thomas, a test image of a benign nodule would have an output from the AiBx analysis of three similar images from the database – all benign. Hence, rather than making a black-box call of whether a nodule is benign or malignant, the algorithm merely says: “This nodule resembles a benign nodule in our database.” The interpreting physician can then use the algorithm as a decision aid with confidence.
The overall accuracy of AiBx was 81.5%, sensitivity was 87.8%, and specificity was 78.5%. Positive predictive value was 65.9%.
As more images are added to the database, AiBx can easily be retrained and refined, said Dr. Thomas.
“It’s intuitive and explainable,” he added, noting that the algorithm is also a good teaching tool for residents and fellows.
“This AI model can be deployed as an app, integrated with [medical imaging systems] or hosted as a website. By using image-similarity AI models we can eliminate subjectivity and decrease the number of unnecessary biopsies,” he explained in the abstract accompanying the presentation.
However, he said that the algorithm as it currently stands has limitations: It has been tested on only 103 images thus far, and there’s the potential for selection bias.
Dr. Thomas* reported that, although he developed the AiBx algorithm, he has not drawn income or royalties from it. He reported no other relevant conflicts of interest.
SOURCE: Thomas* J et al. ATA 2019, Oral Abstract 27.
*Correction, 21/11/2019: An earlier version of this story misstated Dr. Thomas's last name.
REPORTING FROM ATA 2019
Opioid-free regimen after neck dissection keeps patients comfortable
CHICAGO – Many patients with thyroid cancer can be sent home after lateral neck dissections with few or no opioids, in the experience of an institution that made a sea change in opioid prescribing practices.
Between 2012 to mid-2019, Oregon Health & Science University (OHSU), Portland, saw 243 patients who received lateral neck dissections for thyroid cancer and were opioid naive. Before a shift in prescribing practices in early 2017, 5.3% of patients were discharged without opioids after lateral neck dissections for thyroid cancer, whereas after the shift, 41.7% of patients went home on an opioid-free regimen, James Y. Lim, MD, an endocrine surgeon and assistant professor at the university, said during a poster presentation at the annual meeting of the American Thyroid Association.
The initiative, led by Maisie L. Shindo, MD, was started at the OHSU Thyroid and Parathyroid Center in late 2016 in an effort to reduce the number of opioid prescriptions in postoperative patients, Dr. Lim explained in an interview after his presentation. Dr. Shindo, coauthor of the study, directs the thyroid and parathyroid surgery department at the university.
“Before the initiative, standard postoperative pain control consisted of opioids. However, it was common for patients to mention that they did not need them at all,” said Dr. Lim. “Our prescribing practices today reflect the ability to maintain patient comfort without having to resort to opioids. We are able to keep more than 90% of our patients comfortable with a multimodal approach to pain,” he said.
Dr. Lim and colleagues used a retrospective record review to tally how many opioids were initially prescribed at discharge after lateral neck dissections for thyroid cancer, along with the number and quantity of refills for opioids after discharge. Opioid doses were converted to morphine milligram equivalents (MME), and dosing patterns were compared for the periods before and after Feb. 1, 2017, when operating surgeons changed opioid prescribing patterns. These two subgroups were termed group 1 and group 2, respectively.
In all, 143 of the total 243 patients included in the study were women, and the mean age at the time of surgery was 47 years. Patients in group 1 had 170 surgeries, and those in group 2 had 103 surgeries.
Group 1 patients received a mean 295.4 MME after surgery, and group 2 patients received a mean 85.89 MME, though there was wide variation in discharge prescribing within each group. The absolute difference between the pre- and postinitiative groups was 209.51 MME (95% confidence interval, 157.8-261.2), for an effect size of 1.08. The MME figures for each group reflected both discharge medication and any refills or rescue prescriptions that were required.
“Decreasing the volume of opioids prescribed at discharge will decrease waste and reduce potential for addiction,” the authors noted.
As far as is known, “this is the first study that seeks to identify the extent of opioid needs after an extensive neck dissection for thyroid cancer operation,” said Dr. Lim, who added that he has been surprised at how well patients do after surgery. He said he and other surgeons had expected patients to have more pain from lateral neck dissections than they seem to experience.
“There have been studies, including from our own institution, that reported the relatively small need for opioids after a central neck procedure, such as a total thyroidectomy,” Dr. Lim said. “Our study showed that those requirements remain low even with more extensive lateral neck dissections. In the last 8 months of the study, more than 70% of patients with lateral neck dissections did not require opioids on discharge.”
Dr. Lim said that he and the rest of the care team advise patients to ramp up nonpharmacologic options, including ibuprofen, acetaminophen, ice packs, and throat lozenges – all of which can make a big difference in postoperative comfort.
Paying attention to how patients fare during an inpatient stay or even same-day procedures can help physicians estimate postdischarge needs, said Dr. Lim: “For our lateral neck dissections, patients usually stay overnight, and we can get a pretty good estimate of how their pain is being managed off opioids. For same-day procedures, it requires evaluating the patient before discharge and reassessing the pain needs at that time.”
Helping patients and their families understand the postoperative course and what level of discomfort they can expect has helped in the effort to minimize opioid use, Dr. Lim said. Overall, patients, family, and staff have received the changes “very well,” he added.
Practices that are considering a move toward opioid-free or opioid-sparing regimens after surgery should know that “it does require buy-in from all members of the medical team as well as the patients,” Dr. Lim emphasized.
“It starts at the initial surgical consultation, with surgeons educating patients on what to expect in terms of postoperative discomfort and pain. Patients are informed that they will have some discomfort and mild pain that is generally controlled with nonopioid, over-the-counter medications and cold therapy to the surgical site,” he explained.
“It requires education of the nurses and residents to encourage moving away from using opioids as a first-line therapy,” but it’s worth the hard work to get to a point where patients are going home with few, or no, opioids, said Dr. Lim. “Ultimately, patients are happier and are often relieved that their pain can be controlled without opioids,” he said.
Dr. Shindo is the senior author of a related study examining opioid reduction in neck dissection for a variety of head and neck cancers. In that study, she and her coauthors found that opioid requirements vary by cancer type. In an upcoming manuscript, the researchers are aiming to characterize typical opioid requirements for commonly performed procedures, to provide surgeons with evidence-based baselines for appropriate, but not excessive, opioid prescribing.
Dr. Lim reported no outside sources of funding. He, Dr. Shindo, and a third author reported that they had no conflicts of interest.
SOURCE: Lim J et al. ATA 2019, Poster 401.
CHICAGO – Many patients with thyroid cancer can be sent home after lateral neck dissections with few or no opioids, in the experience of an institution that made a sea change in opioid prescribing practices.
Between 2012 to mid-2019, Oregon Health & Science University (OHSU), Portland, saw 243 patients who received lateral neck dissections for thyroid cancer and were opioid naive. Before a shift in prescribing practices in early 2017, 5.3% of patients were discharged without opioids after lateral neck dissections for thyroid cancer, whereas after the shift, 41.7% of patients went home on an opioid-free regimen, James Y. Lim, MD, an endocrine surgeon and assistant professor at the university, said during a poster presentation at the annual meeting of the American Thyroid Association.
The initiative, led by Maisie L. Shindo, MD, was started at the OHSU Thyroid and Parathyroid Center in late 2016 in an effort to reduce the number of opioid prescriptions in postoperative patients, Dr. Lim explained in an interview after his presentation. Dr. Shindo, coauthor of the study, directs the thyroid and parathyroid surgery department at the university.
“Before the initiative, standard postoperative pain control consisted of opioids. However, it was common for patients to mention that they did not need them at all,” said Dr. Lim. “Our prescribing practices today reflect the ability to maintain patient comfort without having to resort to opioids. We are able to keep more than 90% of our patients comfortable with a multimodal approach to pain,” he said.
Dr. Lim and colleagues used a retrospective record review to tally how many opioids were initially prescribed at discharge after lateral neck dissections for thyroid cancer, along with the number and quantity of refills for opioids after discharge. Opioid doses were converted to morphine milligram equivalents (MME), and dosing patterns were compared for the periods before and after Feb. 1, 2017, when operating surgeons changed opioid prescribing patterns. These two subgroups were termed group 1 and group 2, respectively.
In all, 143 of the total 243 patients included in the study were women, and the mean age at the time of surgery was 47 years. Patients in group 1 had 170 surgeries, and those in group 2 had 103 surgeries.
Group 1 patients received a mean 295.4 MME after surgery, and group 2 patients received a mean 85.89 MME, though there was wide variation in discharge prescribing within each group. The absolute difference between the pre- and postinitiative groups was 209.51 MME (95% confidence interval, 157.8-261.2), for an effect size of 1.08. The MME figures for each group reflected both discharge medication and any refills or rescue prescriptions that were required.
“Decreasing the volume of opioids prescribed at discharge will decrease waste and reduce potential for addiction,” the authors noted.
As far as is known, “this is the first study that seeks to identify the extent of opioid needs after an extensive neck dissection for thyroid cancer operation,” said Dr. Lim, who added that he has been surprised at how well patients do after surgery. He said he and other surgeons had expected patients to have more pain from lateral neck dissections than they seem to experience.
“There have been studies, including from our own institution, that reported the relatively small need for opioids after a central neck procedure, such as a total thyroidectomy,” Dr. Lim said. “Our study showed that those requirements remain low even with more extensive lateral neck dissections. In the last 8 months of the study, more than 70% of patients with lateral neck dissections did not require opioids on discharge.”
Dr. Lim said that he and the rest of the care team advise patients to ramp up nonpharmacologic options, including ibuprofen, acetaminophen, ice packs, and throat lozenges – all of which can make a big difference in postoperative comfort.
Paying attention to how patients fare during an inpatient stay or even same-day procedures can help physicians estimate postdischarge needs, said Dr. Lim: “For our lateral neck dissections, patients usually stay overnight, and we can get a pretty good estimate of how their pain is being managed off opioids. For same-day procedures, it requires evaluating the patient before discharge and reassessing the pain needs at that time.”
Helping patients and their families understand the postoperative course and what level of discomfort they can expect has helped in the effort to minimize opioid use, Dr. Lim said. Overall, patients, family, and staff have received the changes “very well,” he added.
Practices that are considering a move toward opioid-free or opioid-sparing regimens after surgery should know that “it does require buy-in from all members of the medical team as well as the patients,” Dr. Lim emphasized.
“It starts at the initial surgical consultation, with surgeons educating patients on what to expect in terms of postoperative discomfort and pain. Patients are informed that they will have some discomfort and mild pain that is generally controlled with nonopioid, over-the-counter medications and cold therapy to the surgical site,” he explained.
“It requires education of the nurses and residents to encourage moving away from using opioids as a first-line therapy,” but it’s worth the hard work to get to a point where patients are going home with few, or no, opioids, said Dr. Lim. “Ultimately, patients are happier and are often relieved that their pain can be controlled without opioids,” he said.
Dr. Shindo is the senior author of a related study examining opioid reduction in neck dissection for a variety of head and neck cancers. In that study, she and her coauthors found that opioid requirements vary by cancer type. In an upcoming manuscript, the researchers are aiming to characterize typical opioid requirements for commonly performed procedures, to provide surgeons with evidence-based baselines for appropriate, but not excessive, opioid prescribing.
Dr. Lim reported no outside sources of funding. He, Dr. Shindo, and a third author reported that they had no conflicts of interest.
SOURCE: Lim J et al. ATA 2019, Poster 401.
CHICAGO – Many patients with thyroid cancer can be sent home after lateral neck dissections with few or no opioids, in the experience of an institution that made a sea change in opioid prescribing practices.
Between 2012 to mid-2019, Oregon Health & Science University (OHSU), Portland, saw 243 patients who received lateral neck dissections for thyroid cancer and were opioid naive. Before a shift in prescribing practices in early 2017, 5.3% of patients were discharged without opioids after lateral neck dissections for thyroid cancer, whereas after the shift, 41.7% of patients went home on an opioid-free regimen, James Y. Lim, MD, an endocrine surgeon and assistant professor at the university, said during a poster presentation at the annual meeting of the American Thyroid Association.
The initiative, led by Maisie L. Shindo, MD, was started at the OHSU Thyroid and Parathyroid Center in late 2016 in an effort to reduce the number of opioid prescriptions in postoperative patients, Dr. Lim explained in an interview after his presentation. Dr. Shindo, coauthor of the study, directs the thyroid and parathyroid surgery department at the university.
“Before the initiative, standard postoperative pain control consisted of opioids. However, it was common for patients to mention that they did not need them at all,” said Dr. Lim. “Our prescribing practices today reflect the ability to maintain patient comfort without having to resort to opioids. We are able to keep more than 90% of our patients comfortable with a multimodal approach to pain,” he said.
Dr. Lim and colleagues used a retrospective record review to tally how many opioids were initially prescribed at discharge after lateral neck dissections for thyroid cancer, along with the number and quantity of refills for opioids after discharge. Opioid doses were converted to morphine milligram equivalents (MME), and dosing patterns were compared for the periods before and after Feb. 1, 2017, when operating surgeons changed opioid prescribing patterns. These two subgroups were termed group 1 and group 2, respectively.
In all, 143 of the total 243 patients included in the study were women, and the mean age at the time of surgery was 47 years. Patients in group 1 had 170 surgeries, and those in group 2 had 103 surgeries.
Group 1 patients received a mean 295.4 MME after surgery, and group 2 patients received a mean 85.89 MME, though there was wide variation in discharge prescribing within each group. The absolute difference between the pre- and postinitiative groups was 209.51 MME (95% confidence interval, 157.8-261.2), for an effect size of 1.08. The MME figures for each group reflected both discharge medication and any refills or rescue prescriptions that were required.
“Decreasing the volume of opioids prescribed at discharge will decrease waste and reduce potential for addiction,” the authors noted.
As far as is known, “this is the first study that seeks to identify the extent of opioid needs after an extensive neck dissection for thyroid cancer operation,” said Dr. Lim, who added that he has been surprised at how well patients do after surgery. He said he and other surgeons had expected patients to have more pain from lateral neck dissections than they seem to experience.
“There have been studies, including from our own institution, that reported the relatively small need for opioids after a central neck procedure, such as a total thyroidectomy,” Dr. Lim said. “Our study showed that those requirements remain low even with more extensive lateral neck dissections. In the last 8 months of the study, more than 70% of patients with lateral neck dissections did not require opioids on discharge.”
Dr. Lim said that he and the rest of the care team advise patients to ramp up nonpharmacologic options, including ibuprofen, acetaminophen, ice packs, and throat lozenges – all of which can make a big difference in postoperative comfort.
Paying attention to how patients fare during an inpatient stay or even same-day procedures can help physicians estimate postdischarge needs, said Dr. Lim: “For our lateral neck dissections, patients usually stay overnight, and we can get a pretty good estimate of how their pain is being managed off opioids. For same-day procedures, it requires evaluating the patient before discharge and reassessing the pain needs at that time.”
Helping patients and their families understand the postoperative course and what level of discomfort they can expect has helped in the effort to minimize opioid use, Dr. Lim said. Overall, patients, family, and staff have received the changes “very well,” he added.
Practices that are considering a move toward opioid-free or opioid-sparing regimens after surgery should know that “it does require buy-in from all members of the medical team as well as the patients,” Dr. Lim emphasized.
“It starts at the initial surgical consultation, with surgeons educating patients on what to expect in terms of postoperative discomfort and pain. Patients are informed that they will have some discomfort and mild pain that is generally controlled with nonopioid, over-the-counter medications and cold therapy to the surgical site,” he explained.
“It requires education of the nurses and residents to encourage moving away from using opioids as a first-line therapy,” but it’s worth the hard work to get to a point where patients are going home with few, or no, opioids, said Dr. Lim. “Ultimately, patients are happier and are often relieved that their pain can be controlled without opioids,” he said.
Dr. Shindo is the senior author of a related study examining opioid reduction in neck dissection for a variety of head and neck cancers. In that study, she and her coauthors found that opioid requirements vary by cancer type. In an upcoming manuscript, the researchers are aiming to characterize typical opioid requirements for commonly performed procedures, to provide surgeons with evidence-based baselines for appropriate, but not excessive, opioid prescribing.
Dr. Lim reported no outside sources of funding. He, Dr. Shindo, and a third author reported that they had no conflicts of interest.
SOURCE: Lim J et al. ATA 2019, Poster 401.
REPORTING FROM ATA 2019