Rheumatology News

A quarter of children receiving treatment with rituximab developed hypogammaglobulinemia within 18 months of starting the drug, according to preliminary research shared at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance. The findings lend support to previous research identifying a risk of hypogammaglobulinemia in children and adolescents taking rituximab and the need for monitoring immunoglobulin levels in those prescribed it.

Marija Stepanovic/Getty Images Marija Stepanovic

“Our study highlights a role for heightened vigilance of rituximab-associated hypogammaglobulinemia and infections in pediatric patients with rheumatic conditions,” Mei-Sing Ong, PhD, of Harvard Medical School and the Harvard Pilgrim Health Care Institute, both in Boston, and colleagues concluded. “Increased risks appeared to be mediated, at least in part, by exposure to glucocorticoids (hypogammaglobulinemia and serious infections) or cyclophosphamide (hypogammaglobulinemia) administered prior to rituximab.”

The observational study involved a cohort of 93 patients, aged 2-25 years, treated at Boston Children’s Hospital during 2009-2019. The patients received rituximab for a wide range of rheumatic diseases, including systemic lupus erythematosus, vasculitis, juvenile idiopathic arthritis, and juvenile dermatomyositis or other polymyositis. The researchers excluded patients who had previously had hypogammaglobulinemia before using rituximab.

In this cohort, 26.9% of patients developed hypogammaglobulinemia, and 20.4% of patients developed an infectious complication within 18 months of beginning rituximab treatment. The infection was serious enough to require inpatient treatment in more than half of those who developed infections (57.9%).

Risk of new-onset hypogammaglobulinemia increased with decreasing age (P = .004), and males were more than four times more likely to develop the condition (odds ratio, 4.55; P = .012). Risk of an infection was also more likely among younger patients (OR, 0.87; P = .039).

Patients with vasculitis were fivefold more likely to develop the hypogammaglobulinemia than were those with other rheumatic diseases after the researchers accounted for age, sex, underlying disease, and medication use (OR, 5.04; P = .017). Risk was also greater in patients with exposure to cyclophosphamide in the year before starting rituximab (OR, 3.76; P = .032), although the finding narrowly reached statistical significance after adjustment for those covariates (OR, 4.41; P = .048).

Glucocorticoid treatment in the month before rituximab was associated with an elevated risk of hypogammaglobulinemia before adjustment (OR, 4.53; P = .007) but lost significance after adjustment. Those taking glucocorticoids had a greater than eightfold increase in infection risk (OR, 8.5; P = .006) before adjustment, which dropped to a fivefold risk after accounting for age, sex, underlying disease, and medication use (OR, 5.4; P = .040).

Monitoring needed for relatively common side effect

The findings are consistent with those seen in a cohort study conducted at Lurie Children’s Hospital of Chicago and published in 2019, said Amer M. Khojah, MD, an attending physician in allergy, immunology, and rheumatology at Lurie and an assistant professor of pediatrics at Northwestern University, also in Chicago. He was not involved in the current study.

“The main takeaway from this study is that we need to be careful about this side effect because it’s relatively common,” Dr. Khojah said in an interview.

At his institution, all patients undergo baseline labs to measure IgG levels prior to initiating rituximab and then have labs drawn again at 3 months and 1 year after starting the drug. Transient hypogammaglobulinemia may not require treatment, he said, but if it persists or the patient develops an infection, treatment with intravenous immunoglobulin is indicated. Yet the drug is so commonly used across a wide range of specialties that there’s a great deal of variability in clinical practice in terms of monitoring and follow-up, Dr. Khojah said.

“The problem is, if you don’t measure it, the patient might be get hypogammaglobulinemia and you don’t know it,” potentially leading to infections that the physician may or may not hear about, he said. “If you are the one who gives them the rituximab, you need to make sure they don’t get the side effects” or that they receive treatment if they do, he said.

“These data are supportive of the necessity to follow patients closely for infection after rituximab, especially considering that many infections may be severe and require hospitalization,” Dr. McAtee said in an interview. “The period of immunosuppression and subsequent infection risk following rituximab, even after single courses, may last well beyond a year following a single course. This is particularly true in patients receiving concurrent immunosuppressive therapy.”

Dr. McAtee similarly published data this year finding frequent infections among young patients receiving rituximab. Hypogammaglobulinemia is already more likely in patients who require rituximab because of other immunosuppressive medication they often take, but the risk “jumped substantially following rituximab,” he said. In addition to patients with low levels of IgG, 41% of patients showed low levels of IgM in that study.

“Nearly a third of patients with normal baseline IgM had persistently low levels more than a year after rituximab, consistent with prolonged B-cell recovery,” Dr. McAtee said. “It is necessary to highlight the importance of IgM in these patients, as common strategies to treat hypogammaglobulinemia, specifically intravenous immunoglobulin, do not replete IgM.”

Neither Dr. Khojah nor Dr. McAtee saw the risk of hypogammaglobulinemia as a reason to avoid rituximab when indicated.

“It is often the best choice for patients whose diseases have not responded to first-line therapies,” Dr. McAtee said. “This and similar studies inform the risk-benefit decision that the medical team must make, as well as the medical surveillance to be considered for patients following a course of rituximab. Going forward, strategies to mitigate infection risk after rituximab, particularly in the first 3 months when they are most common, should be pursued.”

The research was funded by CARRA, which receives funding from the Arthritis Foundation. The authors did not note whether they had any disclosures. Dr. Khojah and Dr. McAtee had no disclosures.

A quarter of children receiving treatment with rituximab developed hypogammaglobulinemia within 18 months of starting the drug, according to preliminary research shared at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance. The findings lend support to previous research identifying a risk of hypogammaglobulinemia in children and adolescents taking rituximab and the need for monitoring immunoglobulin levels in those prescribed it.

Marija Stepanovic/Getty Images Marija Stepanovic

“Our study highlights a role for heightened vigilance of rituximab-associated hypogammaglobulinemia and infections in pediatric patients with rheumatic conditions,” Mei-Sing Ong, PhD, of Harvard Medical School and the Harvard Pilgrim Health Care Institute, both in Boston, and colleagues concluded. “Increased risks appeared to be mediated, at least in part, by exposure to glucocorticoids (hypogammaglobulinemia and serious infections) or cyclophosphamide (hypogammaglobulinemia) administered prior to rituximab.”

The observational study involved a cohort of 93 patients, aged 2-25 years, treated at Boston Children’s Hospital during 2009-2019. The patients received rituximab for a wide range of rheumatic diseases, including systemic lupus erythematosus, vasculitis, juvenile idiopathic arthritis, and juvenile dermatomyositis or other polymyositis. The researchers excluded patients who had previously had hypogammaglobulinemia before using rituximab.

In this cohort, 26.9% of patients developed hypogammaglobulinemia, and 20.4% of patients developed an infectious complication within 18 months of beginning rituximab treatment. The infection was serious enough to require inpatient treatment in more than half of those who developed infections (57.9%).

Risk of new-onset hypogammaglobulinemia increased with decreasing age (P = .004), and males were more than four times more likely to develop the condition (odds ratio, 4.55; P = .012). Risk of an infection was also more likely among younger patients (OR, 0.87; P = .039).

Patients with vasculitis were fivefold more likely to develop the hypogammaglobulinemia than were those with other rheumatic diseases after the researchers accounted for age, sex, underlying disease, and medication use (OR, 5.04; P = .017). Risk was also greater in patients with exposure to cyclophosphamide in the year before starting rituximab (OR, 3.76; P = .032), although the finding narrowly reached statistical significance after adjustment for those covariates (OR, 4.41; P = .048).

Glucocorticoid treatment in the month before rituximab was associated with an elevated risk of hypogammaglobulinemia before adjustment (OR, 4.53; P = .007) but lost significance after adjustment. Those taking glucocorticoids had a greater than eightfold increase in infection risk (OR, 8.5; P = .006) before adjustment, which dropped to a fivefold risk after accounting for age, sex, underlying disease, and medication use (OR, 5.4; P = .040).

Monitoring needed for relatively common side effect

The findings are consistent with those seen in a cohort study conducted at Lurie Children’s Hospital of Chicago and published in 2019, said Amer M. Khojah, MD, an attending physician in allergy, immunology, and rheumatology at Lurie and an assistant professor of pediatrics at Northwestern University, also in Chicago. He was not involved in the current study.

“The main takeaway from this study is that we need to be careful about this side effect because it’s relatively common,” Dr. Khojah said in an interview.

At his institution, all patients undergo baseline labs to measure IgG levels prior to initiating rituximab and then have labs drawn again at 3 months and 1 year after starting the drug. Transient hypogammaglobulinemia may not require treatment, he said, but if it persists or the patient develops an infection, treatment with intravenous immunoglobulin is indicated. Yet the drug is so commonly used across a wide range of specialties that there’s a great deal of variability in clinical practice in terms of monitoring and follow-up, Dr. Khojah said.

“The problem is, if you don’t measure it, the patient might be get hypogammaglobulinemia and you don’t know it,” potentially leading to infections that the physician may or may not hear about, he said. “If you are the one who gives them the rituximab, you need to make sure they don’t get the side effects” or that they receive treatment if they do, he said.

“These data are supportive of the necessity to follow patients closely for infection after rituximab, especially considering that many infections may be severe and require hospitalization,” Dr. McAtee said in an interview. “The period of immunosuppression and subsequent infection risk following rituximab, even after single courses, may last well beyond a year following a single course. This is particularly true in patients receiving concurrent immunosuppressive therapy.”

Dr. McAtee similarly published data this year finding frequent infections among young patients receiving rituximab. Hypogammaglobulinemia is already more likely in patients who require rituximab because of other immunosuppressive medication they often take, but the risk “jumped substantially following rituximab,” he said. In addition to patients with low levels of IgG, 41% of patients showed low levels of IgM in that study.

“Nearly a third of patients with normal baseline IgM had persistently low levels more than a year after rituximab, consistent with prolonged B-cell recovery,” Dr. McAtee said. “It is necessary to highlight the importance of IgM in these patients, as common strategies to treat hypogammaglobulinemia, specifically intravenous immunoglobulin, do not replete IgM.”

Neither Dr. Khojah nor Dr. McAtee saw the risk of hypogammaglobulinemia as a reason to avoid rituximab when indicated.

“It is often the best choice for patients whose diseases have not responded to first-line therapies,” Dr. McAtee said. “This and similar studies inform the risk-benefit decision that the medical team must make, as well as the medical surveillance to be considered for patients following a course of rituximab. Going forward, strategies to mitigate infection risk after rituximab, particularly in the first 3 months when they are most common, should be pursued.”

The research was funded by CARRA, which receives funding from the Arthritis Foundation. The authors did not note whether they had any disclosures. Dr. Khojah and Dr. McAtee had no disclosures.

A quarter of children receiving treatment with rituximab developed hypogammaglobulinemia within 18 months of starting the drug, according to preliminary research shared at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance. The findings lend support to previous research identifying a risk of hypogammaglobulinemia in children and adolescents taking rituximab and the need for monitoring immunoglobulin levels in those prescribed it.

Marija Stepanovic/Getty Images Marija Stepanovic

“Our study highlights a role for heightened vigilance of rituximab-associated hypogammaglobulinemia and infections in pediatric patients with rheumatic conditions,” Mei-Sing Ong, PhD, of Harvard Medical School and the Harvard Pilgrim Health Care Institute, both in Boston, and colleagues concluded. “Increased risks appeared to be mediated, at least in part, by exposure to glucocorticoids (hypogammaglobulinemia and serious infections) or cyclophosphamide (hypogammaglobulinemia) administered prior to rituximab.”

The observational study involved a cohort of 93 patients, aged 2-25 years, treated at Boston Children’s Hospital during 2009-2019. The patients received rituximab for a wide range of rheumatic diseases, including systemic lupus erythematosus, vasculitis, juvenile idiopathic arthritis, and juvenile dermatomyositis or other polymyositis. The researchers excluded patients who had previously had hypogammaglobulinemia before using rituximab.

In this cohort, 26.9% of patients developed hypogammaglobulinemia, and 20.4% of patients developed an infectious complication within 18 months of beginning rituximab treatment. The infection was serious enough to require inpatient treatment in more than half of those who developed infections (57.9%).

Risk of new-onset hypogammaglobulinemia increased with decreasing age (P = .004), and males were more than four times more likely to develop the condition (odds ratio, 4.55; P = .012). Risk of an infection was also more likely among younger patients (OR, 0.87; P = .039).

Patients with vasculitis were fivefold more likely to develop the hypogammaglobulinemia than were those with other rheumatic diseases after the researchers accounted for age, sex, underlying disease, and medication use (OR, 5.04; P = .017). Risk was also greater in patients with exposure to cyclophosphamide in the year before starting rituximab (OR, 3.76; P = .032), although the finding narrowly reached statistical significance after adjustment for those covariates (OR, 4.41; P = .048).

Glucocorticoid treatment in the month before rituximab was associated with an elevated risk of hypogammaglobulinemia before adjustment (OR, 4.53; P = .007) but lost significance after adjustment. Those taking glucocorticoids had a greater than eightfold increase in infection risk (OR, 8.5; P = .006) before adjustment, which dropped to a fivefold risk after accounting for age, sex, underlying disease, and medication use (OR, 5.4; P = .040).

Monitoring needed for relatively common side effect

The findings are consistent with those seen in a cohort study conducted at Lurie Children’s Hospital of Chicago and published in 2019, said Amer M. Khojah, MD, an attending physician in allergy, immunology, and rheumatology at Lurie and an assistant professor of pediatrics at Northwestern University, also in Chicago. He was not involved in the current study.

“The main takeaway from this study is that we need to be careful about this side effect because it’s relatively common,” Dr. Khojah said in an interview.

At his institution, all patients undergo baseline labs to measure IgG levels prior to initiating rituximab and then have labs drawn again at 3 months and 1 year after starting the drug. Transient hypogammaglobulinemia may not require treatment, he said, but if it persists or the patient develops an infection, treatment with intravenous immunoglobulin is indicated. Yet the drug is so commonly used across a wide range of specialties that there’s a great deal of variability in clinical practice in terms of monitoring and follow-up, Dr. Khojah said.

“The problem is, if you don’t measure it, the patient might be get hypogammaglobulinemia and you don’t know it,” potentially leading to infections that the physician may or may not hear about, he said. “If you are the one who gives them the rituximab, you need to make sure they don’t get the side effects” or that they receive treatment if they do, he said.

“These data are supportive of the necessity to follow patients closely for infection after rituximab, especially considering that many infections may be severe and require hospitalization,” Dr. McAtee said in an interview. “The period of immunosuppression and subsequent infection risk following rituximab, even after single courses, may last well beyond a year following a single course. This is particularly true in patients receiving concurrent immunosuppressive therapy.”

Dr. McAtee similarly published data this year finding frequent infections among young patients receiving rituximab. Hypogammaglobulinemia is already more likely in patients who require rituximab because of other immunosuppressive medication they often take, but the risk “jumped substantially following rituximab,” he said. In addition to patients with low levels of IgG, 41% of patients showed low levels of IgM in that study.

“Nearly a third of patients with normal baseline IgM had persistently low levels more than a year after rituximab, consistent with prolonged B-cell recovery,” Dr. McAtee said. “It is necessary to highlight the importance of IgM in these patients, as common strategies to treat hypogammaglobulinemia, specifically intravenous immunoglobulin, do not replete IgM.”

Neither Dr. Khojah nor Dr. McAtee saw the risk of hypogammaglobulinemia as a reason to avoid rituximab when indicated.

“It is often the best choice for patients whose diseases have not responded to first-line therapies,” Dr. McAtee said. “This and similar studies inform the risk-benefit decision that the medical team must make, as well as the medical surveillance to be considered for patients following a course of rituximab. Going forward, strategies to mitigate infection risk after rituximab, particularly in the first 3 months when they are most common, should be pursued.”

The research was funded by CARRA, which receives funding from the Arthritis Foundation. The authors did not note whether they had any disclosures. Dr. Khojah and Dr. McAtee had no disclosures.

Dr. Ben-a-bo?

Nope.

Ben-nabi?

Nope.

Ben-NO-bo?

Also no.

My surname is tricky to pronounce for some people. I sometimes exaggerate to help patients get it right: “Beh-NAAH-bee-oh.” Almost daily someone will reply: “Oh, you’re Italian!” Well, no actually, my friend Enzo who was born in Sicily and lives in Milan, he’s Italian. I’m just a Rhode Islander who knows some Italian words from his grandmother. Most times though, I just answer: ‘Yep, I’m Italian.” It’s faster.

We use names as a shortcut to identify people. In clinic, it can help to find things in common quickly, similar to asking where you’re from. (East Coast patients seem to love that I’m from New England and if they’re Italian and from New York, well then, we’re paisans right from the start.)

However, using names to guess how someone identifies can be risky. In some instances, it could even be seen as microaggressive, particularly if you got it wrong.

Like most of you I’ll bet, I’m pretty good at pronouncing names – we practice thousands of times! Other than accepting a compliment for getting a tricky one right, such as Radivojevic (I think it’s Ra-di-VOI-ye-vich), I hadn’t thought much about names until I heard a great podcast on the topic. I thought I’d share a couple tips.

First, if you’re not particularly good at names or if you struggle with certain types of names, it’s better to ask than to butcher it. Like learning the wrong way to hit a golf ball, you may never be able to do it properly once you’ve done it wrong. (Trust me, I know from both.)

If I’m feeling confident, I’ll give it a try. But if unsure, I ask the patient to pronounce it for me, then I repeat it to confirm I’ve gotten it correct. Then I say it once or twice more during the visit. Lastly, for the knotty tongue-twisting ones, I write it phonetically in their chart.

It is important because mispronouncing names can alienate patients. It might make them feel like we don’t “know” them or that we don’t care about them. Making an effort to pronounce every patients’ name correctly I believe is a simple act we can all do to move us closer to mitigating racial biases and eliminating ethnic disparities in care. Just think how much harder it might be to convince skeptical patients to take their lisinopril if you can’t even get their names right.

Worse perhaps than getting the pronunciation wrong is to turn the name into an issue. Saying: “Oh, that’s hard to pronounce” could be felt as a subtly racist remark – it’s not hard for them to pronounce of course, only for you. Also, guessing a patient’s nationality from the name is risky. Asking “are you Russian?” to someone from Ukraine or “is that Chinese?” to someone from Vietnam can quickly turn a nice office visit down a road named “Awkward.” It can give the impression that they “all look the same” to you, exactly the type of exclusion we’re trying to eliminate in medicine.

Saying a patient’s name perfectly is rewarding and a super-efficient way to connect. It can make salient the truth that you care about the patient and about his or her story, even if the name happens to be Mrs. Xiomara Winyuwongse Khosrowshahi Sundararajan Ngoc. Go ahead, give it a try.

Want more on how properly pronounce names correctly? You might like this episode of NPR’s Life Kit.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com

Dr. Ben-a-bo?

Nope.

Ben-nabi?

Nope.

Ben-NO-bo?

Also no.

My surname is tricky to pronounce for some people. I sometimes exaggerate to help patients get it right: “Beh-NAAH-bee-oh.” Almost daily someone will reply: “Oh, you’re Italian!” Well, no actually, my friend Enzo who was born in Sicily and lives in Milan, he’s Italian. I’m just a Rhode Islander who knows some Italian words from his grandmother. Most times though, I just answer: ‘Yep, I’m Italian.” It’s faster.

We use names as a shortcut to identify people. In clinic, it can help to find things in common quickly, similar to asking where you’re from. (East Coast patients seem to love that I’m from New England and if they’re Italian and from New York, well then, we’re paisans right from the start.)

However, using names to guess how someone identifies can be risky. In some instances, it could even be seen as microaggressive, particularly if you got it wrong.

Like most of you I’ll bet, I’m pretty good at pronouncing names – we practice thousands of times! Other than accepting a compliment for getting a tricky one right, such as Radivojevic (I think it’s Ra-di-VOI-ye-vich), I hadn’t thought much about names until I heard a great podcast on the topic. I thought I’d share a couple tips.

First, if you’re not particularly good at names or if you struggle with certain types of names, it’s better to ask than to butcher it. Like learning the wrong way to hit a golf ball, you may never be able to do it properly once you’ve done it wrong. (Trust me, I know from both.)

If I’m feeling confident, I’ll give it a try. But if unsure, I ask the patient to pronounce it for me, then I repeat it to confirm I’ve gotten it correct. Then I say it once or twice more during the visit. Lastly, for the knotty tongue-twisting ones, I write it phonetically in their chart.

It is important because mispronouncing names can alienate patients. It might make them feel like we don’t “know” them or that we don’t care about them. Making an effort to pronounce every patients’ name correctly I believe is a simple act we can all do to move us closer to mitigating racial biases and eliminating ethnic disparities in care. Just think how much harder it might be to convince skeptical patients to take their lisinopril if you can’t even get their names right.

Worse perhaps than getting the pronunciation wrong is to turn the name into an issue. Saying: “Oh, that’s hard to pronounce” could be felt as a subtly racist remark – it’s not hard for them to pronounce of course, only for you. Also, guessing a patient’s nationality from the name is risky. Asking “are you Russian?” to someone from Ukraine or “is that Chinese?” to someone from Vietnam can quickly turn a nice office visit down a road named “Awkward.” It can give the impression that they “all look the same” to you, exactly the type of exclusion we’re trying to eliminate in medicine.

Saying a patient’s name perfectly is rewarding and a super-efficient way to connect. It can make salient the truth that you care about the patient and about his or her story, even if the name happens to be Mrs. Xiomara Winyuwongse Khosrowshahi Sundararajan Ngoc. Go ahead, give it a try.

Want more on how properly pronounce names correctly? You might like this episode of NPR’s Life Kit.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com

Dr. Ben-a-bo?

Nope.

Ben-nabi?

Nope.

Ben-NO-bo?

Also no.

My surname is tricky to pronounce for some people. I sometimes exaggerate to help patients get it right: “Beh-NAAH-bee-oh.” Almost daily someone will reply: “Oh, you’re Italian!” Well, no actually, my friend Enzo who was born in Sicily and lives in Milan, he’s Italian. I’m just a Rhode Islander who knows some Italian words from his grandmother. Most times though, I just answer: ‘Yep, I’m Italian.” It’s faster.

We use names as a shortcut to identify people. In clinic, it can help to find things in common quickly, similar to asking where you’re from. (East Coast patients seem to love that I’m from New England and if they’re Italian and from New York, well then, we’re paisans right from the start.)

However, using names to guess how someone identifies can be risky. In some instances, it could even be seen as microaggressive, particularly if you got it wrong.

Like most of you I’ll bet, I’m pretty good at pronouncing names – we practice thousands of times! Other than accepting a compliment for getting a tricky one right, such as Radivojevic (I think it’s Ra-di-VOI-ye-vich), I hadn’t thought much about names until I heard a great podcast on the topic. I thought I’d share a couple tips.

First, if you’re not particularly good at names or if you struggle with certain types of names, it’s better to ask than to butcher it. Like learning the wrong way to hit a golf ball, you may never be able to do it properly once you’ve done it wrong. (Trust me, I know from both.)

If I’m feeling confident, I’ll give it a try. But if unsure, I ask the patient to pronounce it for me, then I repeat it to confirm I’ve gotten it correct. Then I say it once or twice more during the visit. Lastly, for the knotty tongue-twisting ones, I write it phonetically in their chart.

It is important because mispronouncing names can alienate patients. It might make them feel like we don’t “know” them or that we don’t care about them. Making an effort to pronounce every patients’ name correctly I believe is a simple act we can all do to move us closer to mitigating racial biases and eliminating ethnic disparities in care. Just think how much harder it might be to convince skeptical patients to take their lisinopril if you can’t even get their names right.

Worse perhaps than getting the pronunciation wrong is to turn the name into an issue. Saying: “Oh, that’s hard to pronounce” could be felt as a subtly racist remark – it’s not hard for them to pronounce of course, only for you. Also, guessing a patient’s nationality from the name is risky. Asking “are you Russian?” to someone from Ukraine or “is that Chinese?” to someone from Vietnam can quickly turn a nice office visit down a road named “Awkward.” It can give the impression that they “all look the same” to you, exactly the type of exclusion we’re trying to eliminate in medicine.

Saying a patient’s name perfectly is rewarding and a super-efficient way to connect. It can make salient the truth that you care about the patient and about his or her story, even if the name happens to be Mrs. Xiomara Winyuwongse Khosrowshahi Sundararajan Ngoc. Go ahead, give it a try.

Want more on how properly pronounce names correctly? You might like this episode of NPR’s Life Kit.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com

An investigational polymerase chain reaction (PCR) test that detects the presence of a viral gene in Lyme disease–causing bacteria can distinguish between early and late infection, according to the results of a study that the authors described as “systematic and comprehensive.”

“The current way of diagnosing Lyme disease is struggling to reflect the ‘true’ incidence of Lyme disease,” study investigator Jinyu Shan, PhD, said in an interview. Although there are tests for Lyme disease approved by the Food and Drug Administration, they are based on the development of antibodies in the blood, and the problem is that antibodies might not develop until several weeks after an infection.

Diagnosis therefore still relies heavily on the clinician’s experience. There are often telltale signs – such as a “bullseye” skin rash or having been to an area known to be infested with ticks that carry Lyme disease – but this might not always be the case.

For the new test, “we’re not targeting bacteria. We’re targeting bacteriophages,” said Dr. Shan, a research fellow in the department of genetics and genome biology at the University of Leicester (England).

Fortunately, there’s high correlation between the presence of the terL gene and the presence of Borrelia burgdorferi, the spirochete that causes Lyme disease. “If you find the bacteriophages, the bacteria are there,” said Dr. Shan.

“Importantly, there are 10 times more bacteriophages, compared with the bacteria, so you have a lot more targets,” he added.

In an evaluation of a total of 312 samples (156 whole blood and 156 serum samples), significantly fewer copies of the terL gene were found in samples from people with early Lyme disease than in those with late Lyme disease, whereas the fewest copies of terL were seen in healthy volunteers.

Most pathogenic bacteria carry viral DNA either as multiple complete or partial prophages, Dr. Shan explained. Knowing the prophage sequences means that quantitative PCR primers and probes can be designed and used to detect the presence of the associated bacteria.

Although the novel test still needs evaluation in a clinical trial, it could represent a “step-change” in the detection of Lyme disease, Dr. Shan and associates suggested in their report published in Frontiers in Microbiology.

CDC/ Dr. Amanda Loftis, Dr. William Nicholson, Dr. Will Reeves, Dr. Chris Paddock

Early treatment is key to the prevention of longer-term consequences of Lyme disease. Clinicians familiar with the treatment of Lyme disease might choose to initiate antibiotic treatment without a positive lab test. However, the lack of a test that can pick out people with Lyme disease in the first few weeks of infection means that many people are not diagnosed or treated early enough.

The new phage-based PCR test Dr. Shan and associates have developed could change all that. With only 0.3 mL of blood being needed, it can potentially be developed as a simple point-of-care test, but that’s a long way off.

At this stage, the research is very much a “proof of concept,” Dr. Shan said. One of the things he plans to try to work out next is whether the test can distinguish between active and dormant disease, which is a “big question” in the diagnosis of Lyme disease.

“Bacteriophages can only be sustained by actively growing bacteria,” explained Dr. Shan, so there is a chance that if they are present in a substantive amount the disease is active, and if they are not – or are in very low numbers – then the disease is dormant. The cutoff value, however, “is not trivial to establish, but we are working toward it,” added Dr. Shan.

Over the past 2 years, Dr. Shan and associates have been working with the Belgian-based diagnostics company, R.E.D Laboratories, to see how the test will fare in a real-world environment. This relationship is providing useful information to add to their bid to perform a clinical trial for which they are now seeking additional sponsorship.

“The lack of an early and effective diagnosis of Lyme disease remains a major cause of misdiagnosis and long-term patient suffering,” commented Rosie Milsom, charity manager for Caudwell LymeCo Charity in the United Kingdom.

It could be a game changer if the test passes the necessary clinical trial testing and validation stages, noted Ms. Milsom, who was not involved in the research.

“Not only would the test help to establish the level or length of infection,” she said, “but it could also act as a way to test after treatment to see if the infection levels are decreasing.” If levels are still high, “you would know more treatment is needed.

The research is being funded by the charity Phelix Research and Development with support from the University of Leicester and the Dutch-based Lyme Fund, Lymefonds. Dr. Shan is named as coinventor of the phage-targeting PCR test, alongside Martha R.J. Clokie, professor of microbiology at the University of Leicester and the senior author of the study. Dr. Shan is chief scientific officer for Phelix Research and Development. Ms. Clokie and other coauthors hold key positions within the medical research charity.

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

An investigational polymerase chain reaction (PCR) test that detects the presence of a viral gene in Lyme disease–causing bacteria can distinguish between early and late infection, according to the results of a study that the authors described as “systematic and comprehensive.”

“The current way of diagnosing Lyme disease is struggling to reflect the ‘true’ incidence of Lyme disease,” study investigator Jinyu Shan, PhD, said in an interview. Although there are tests for Lyme disease approved by the Food and Drug Administration, they are based on the development of antibodies in the blood, and the problem is that antibodies might not develop until several weeks after an infection.

Diagnosis therefore still relies heavily on the clinician’s experience. There are often telltale signs – such as a “bullseye” skin rash or having been to an area known to be infested with ticks that carry Lyme disease – but this might not always be the case.

For the new test, “we’re not targeting bacteria. We’re targeting bacteriophages,” said Dr. Shan, a research fellow in the department of genetics and genome biology at the University of Leicester (England).

Fortunately, there’s high correlation between the presence of the terL gene and the presence of Borrelia burgdorferi, the spirochete that causes Lyme disease. “If you find the bacteriophages, the bacteria are there,” said Dr. Shan.

“Importantly, there are 10 times more bacteriophages, compared with the bacteria, so you have a lot more targets,” he added.

In an evaluation of a total of 312 samples (156 whole blood and 156 serum samples), significantly fewer copies of the terL gene were found in samples from people with early Lyme disease than in those with late Lyme disease, whereas the fewest copies of terL were seen in healthy volunteers.

Most pathogenic bacteria carry viral DNA either as multiple complete or partial prophages, Dr. Shan explained. Knowing the prophage sequences means that quantitative PCR primers and probes can be designed and used to detect the presence of the associated bacteria.

Although the novel test still needs evaluation in a clinical trial, it could represent a “step-change” in the detection of Lyme disease, Dr. Shan and associates suggested in their report published in Frontiers in Microbiology.

CDC/ Dr. Amanda Loftis, Dr. William Nicholson, Dr. Will Reeves, Dr. Chris Paddock

Early treatment is key to the prevention of longer-term consequences of Lyme disease. Clinicians familiar with the treatment of Lyme disease might choose to initiate antibiotic treatment without a positive lab test. However, the lack of a test that can pick out people with Lyme disease in the first few weeks of infection means that many people are not diagnosed or treated early enough.

The new phage-based PCR test Dr. Shan and associates have developed could change all that. With only 0.3 mL of blood being needed, it can potentially be developed as a simple point-of-care test, but that’s a long way off.

At this stage, the research is very much a “proof of concept,” Dr. Shan said. One of the things he plans to try to work out next is whether the test can distinguish between active and dormant disease, which is a “big question” in the diagnosis of Lyme disease.

“Bacteriophages can only be sustained by actively growing bacteria,” explained Dr. Shan, so there is a chance that if they are present in a substantive amount the disease is active, and if they are not – or are in very low numbers – then the disease is dormant. The cutoff value, however, “is not trivial to establish, but we are working toward it,” added Dr. Shan.

Over the past 2 years, Dr. Shan and associates have been working with the Belgian-based diagnostics company, R.E.D Laboratories, to see how the test will fare in a real-world environment. This relationship is providing useful information to add to their bid to perform a clinical trial for which they are now seeking additional sponsorship.

“The lack of an early and effective diagnosis of Lyme disease remains a major cause of misdiagnosis and long-term patient suffering,” commented Rosie Milsom, charity manager for Caudwell LymeCo Charity in the United Kingdom.

It could be a game changer if the test passes the necessary clinical trial testing and validation stages, noted Ms. Milsom, who was not involved in the research.

“Not only would the test help to establish the level or length of infection,” she said, “but it could also act as a way to test after treatment to see if the infection levels are decreasing.” If levels are still high, “you would know more treatment is needed.

The research is being funded by the charity Phelix Research and Development with support from the University of Leicester and the Dutch-based Lyme Fund, Lymefonds. Dr. Shan is named as coinventor of the phage-targeting PCR test, alongside Martha R.J. Clokie, professor of microbiology at the University of Leicester and the senior author of the study. Dr. Shan is chief scientific officer for Phelix Research and Development. Ms. Clokie and other coauthors hold key positions within the medical research charity.

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

An investigational polymerase chain reaction (PCR) test that detects the presence of a viral gene in Lyme disease–causing bacteria can distinguish between early and late infection, according to the results of a study that the authors described as “systematic and comprehensive.”

“The current way of diagnosing Lyme disease is struggling to reflect the ‘true’ incidence of Lyme disease,” study investigator Jinyu Shan, PhD, said in an interview. Although there are tests for Lyme disease approved by the Food and Drug Administration, they are based on the development of antibodies in the blood, and the problem is that antibodies might not develop until several weeks after an infection.

Diagnosis therefore still relies heavily on the clinician’s experience. There are often telltale signs – such as a “bullseye” skin rash or having been to an area known to be infested with ticks that carry Lyme disease – but this might not always be the case.

For the new test, “we’re not targeting bacteria. We’re targeting bacteriophages,” said Dr. Shan, a research fellow in the department of genetics and genome biology at the University of Leicester (England).

Fortunately, there’s high correlation between the presence of the terL gene and the presence of Borrelia burgdorferi, the spirochete that causes Lyme disease. “If you find the bacteriophages, the bacteria are there,” said Dr. Shan.

“Importantly, there are 10 times more bacteriophages, compared with the bacteria, so you have a lot more targets,” he added.

In an evaluation of a total of 312 samples (156 whole blood and 156 serum samples), significantly fewer copies of the terL gene were found in samples from people with early Lyme disease than in those with late Lyme disease, whereas the fewest copies of terL were seen in healthy volunteers.

Most pathogenic bacteria carry viral DNA either as multiple complete or partial prophages, Dr. Shan explained. Knowing the prophage sequences means that quantitative PCR primers and probes can be designed and used to detect the presence of the associated bacteria.

Although the novel test still needs evaluation in a clinical trial, it could represent a “step-change” in the detection of Lyme disease, Dr. Shan and associates suggested in their report published in Frontiers in Microbiology.

CDC/ Dr. Amanda Loftis, Dr. William Nicholson, Dr. Will Reeves, Dr. Chris Paddock

Early treatment is key to the prevention of longer-term consequences of Lyme disease. Clinicians familiar with the treatment of Lyme disease might choose to initiate antibiotic treatment without a positive lab test. However, the lack of a test that can pick out people with Lyme disease in the first few weeks of infection means that many people are not diagnosed or treated early enough.

The new phage-based PCR test Dr. Shan and associates have developed could change all that. With only 0.3 mL of blood being needed, it can potentially be developed as a simple point-of-care test, but that’s a long way off.

At this stage, the research is very much a “proof of concept,” Dr. Shan said. One of the things he plans to try to work out next is whether the test can distinguish between active and dormant disease, which is a “big question” in the diagnosis of Lyme disease.

“Bacteriophages can only be sustained by actively growing bacteria,” explained Dr. Shan, so there is a chance that if they are present in a substantive amount the disease is active, and if they are not – or are in very low numbers – then the disease is dormant. The cutoff value, however, “is not trivial to establish, but we are working toward it,” added Dr. Shan.

Over the past 2 years, Dr. Shan and associates have been working with the Belgian-based diagnostics company, R.E.D Laboratories, to see how the test will fare in a real-world environment. This relationship is providing useful information to add to their bid to perform a clinical trial for which they are now seeking additional sponsorship.

“The lack of an early and effective diagnosis of Lyme disease remains a major cause of misdiagnosis and long-term patient suffering,” commented Rosie Milsom, charity manager for Caudwell LymeCo Charity in the United Kingdom.

It could be a game changer if the test passes the necessary clinical trial testing and validation stages, noted Ms. Milsom, who was not involved in the research.

“Not only would the test help to establish the level or length of infection,” she said, “but it could also act as a way to test after treatment to see if the infection levels are decreasing.” If levels are still high, “you would know more treatment is needed.

The research is being funded by the charity Phelix Research and Development with support from the University of Leicester and the Dutch-based Lyme Fund, Lymefonds. Dr. Shan is named as coinventor of the phage-targeting PCR test, alongside Martha R.J. Clokie, professor of microbiology at the University of Leicester and the senior author of the study. Dr. Shan is chief scientific officer for Phelix Research and Development. Ms. Clokie and other coauthors hold key positions within the medical research charity.

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

A new study on the changing rheumatology workforce found that, although there has been a notable rise in female rheumatologists, they see fewer patients and have lower earnings than their male counterparts.

BSIP/UIG/GettyImages

“In order for future health workforce policy and planning to be effective and equitable, it is essential to consider policies and other solutions to support the sustainability of rheumatology workforces in light of increasing feminization,” wrote Jessica Widdifield, PhD, of the Sunnybrook Research Institute in Toronto and her colleagues. The study was published in the Journal of Rheumatology.

To investigate potential workload and earnings disparities between male and female rheumatologists, the researchers launched a population-based study of rheumatologists practicing in Ontario, Canada, and their patient visits between April 1, 2000, and March 31, 2015. To quantify clinical activity, they calculated full-time equivalents (FTEs) using annual fee-for-service billing claims and defined rheumatologists practicing at least one clinical FTE as those at or above the 40th percentile of total billings each year. Any rheumatologists practicing less than one FTE were not included in the larger analysis.

Overall, they found that the total number of rheumatologists increased from 146 in 2000 to 194 in 2015, with 49% of the latter workforce being women. When assessing only rheumatologists practicing at greater than one FTE, the number increased from 89 in 2000 to 120 in 2015, with women making up 41.7% of the 2015 workforce. Although practice sizes decreased for both genders over the course of the study, in 2015 the median practice size was 1,948.5 patients (interquartile range, 1,433-2,562) for men, compared with 1,468.5 patients (IQR, 1,212-1,984) for women. In every year but 2001, men had larger median practice sizes than women.

Total patient visits remained relatively stable for men throughout the study period but declined for women, with the gap between genders widening over time. The peak gap in visits was 1,486 (95% confidence interval, 628-2,517) in 2008. And while median payments increased over time for all rheumatologists, median renumeration peaked in 2015 at $362,522 (IQR, $309,503-$437,127) for women, compared with $403,903 (IQR, $313,297-$544,703) for men. That said, the median difference that year – $45,556.10 (95% confidence interval, $951.60-$92,470.40; P = .04) – was the smallest for any in the study period. The largest difference was $102,176.10 (95% CI, $58,457.50-$152,821.20; P < .0001) in 2011.

An opportunity for female rheumatologists to reshape the specialty

Of course, gender gaps like these are not limited to rheumatology or even medicine, wrote Grace C. Wright, MD, PhD, president of the Association of Women in Rheumatology, in an accompanying editorial. “This issue exists across industries as well as across boundaries.”

“Particularly for women physicians, we do have additional demands on our time,” agreed April Jorge, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, in an interview. “For example, we know that women who work often have additional caregiving responsibilities at home, for kids and/or elderly relatives. I do think those are real reasons why certain providers, particularly women, might have a lower clinical volume.”

Despite the significant gender gaps that still exist, Dr. Jorge – who authored a previous study on the gaps in academic rheumatology – was heartened by the data that indicated more women finding their way into the specialty.

“I think it’s good news for rheumatology to be so balanced between men and women as providers,” she said. “For young women trainees, it’s really important to see role models in their field. For patients, it’s incredibly important for them to have a doctor who can relate and who can advocate for them. So many rheumatic conditions that we treat disproportionately affect women, often women of childbearing age. So it’s really important to have women involved in leading the specialty of rheumatology, including clinical practice but also research, education, and policy.”

Dr. Wright concurred in her editorial, stating that “this feminization of rheumatology provides an opportunity to assess the needs of working women, the generational shifts in attitudes toward work-life balance, and a change in clinical practice toward value over volume.”

The study’s authors shared its possible limitations, including the lack of a standard definition of a clinical FTE rheumatologist – thus their decision to define one – and a lack of context as to why certain rheumatologists were practicing less than others. In addition, they preemptively acknowledged Dr. Jorge’s concern by noting their inability to access gender-related details like marital status, family size, and childcare roles, all of which “could contribute to the relationship between physician gender and practice-level activity.”

The study was funded by an operating grant from the Canadian Initiative for Outcomes in Rheumatology Care and supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Two of the authors reported receiving support from the Arthritis Society Stars Career Development Award.
 

A new study on the changing rheumatology workforce found that, although there has been a notable rise in female rheumatologists, they see fewer patients and have lower earnings than their male counterparts.

BSIP/UIG/GettyImages

“In order for future health workforce policy and planning to be effective and equitable, it is essential to consider policies and other solutions to support the sustainability of rheumatology workforces in light of increasing feminization,” wrote Jessica Widdifield, PhD, of the Sunnybrook Research Institute in Toronto and her colleagues. The study was published in the Journal of Rheumatology.

To investigate potential workload and earnings disparities between male and female rheumatologists, the researchers launched a population-based study of rheumatologists practicing in Ontario, Canada, and their patient visits between April 1, 2000, and March 31, 2015. To quantify clinical activity, they calculated full-time equivalents (FTEs) using annual fee-for-service billing claims and defined rheumatologists practicing at least one clinical FTE as those at or above the 40th percentile of total billings each year. Any rheumatologists practicing less than one FTE were not included in the larger analysis.

Overall, they found that the total number of rheumatologists increased from 146 in 2000 to 194 in 2015, with 49% of the latter workforce being women. When assessing only rheumatologists practicing at greater than one FTE, the number increased from 89 in 2000 to 120 in 2015, with women making up 41.7% of the 2015 workforce. Although practice sizes decreased for both genders over the course of the study, in 2015 the median practice size was 1,948.5 patients (interquartile range, 1,433-2,562) for men, compared with 1,468.5 patients (IQR, 1,212-1,984) for women. In every year but 2001, men had larger median practice sizes than women.

Total patient visits remained relatively stable for men throughout the study period but declined for women, with the gap between genders widening over time. The peak gap in visits was 1,486 (95% confidence interval, 628-2,517) in 2008. And while median payments increased over time for all rheumatologists, median renumeration peaked in 2015 at $362,522 (IQR, $309,503-$437,127) for women, compared with $403,903 (IQR, $313,297-$544,703) for men. That said, the median difference that year – $45,556.10 (95% confidence interval, $951.60-$92,470.40; P = .04) – was the smallest for any in the study period. The largest difference was $102,176.10 (95% CI, $58,457.50-$152,821.20; P < .0001) in 2011.

An opportunity for female rheumatologists to reshape the specialty

Of course, gender gaps like these are not limited to rheumatology or even medicine, wrote Grace C. Wright, MD, PhD, president of the Association of Women in Rheumatology, in an accompanying editorial. “This issue exists across industries as well as across boundaries.”

“Particularly for women physicians, we do have additional demands on our time,” agreed April Jorge, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, in an interview. “For example, we know that women who work often have additional caregiving responsibilities at home, for kids and/or elderly relatives. I do think those are real reasons why certain providers, particularly women, might have a lower clinical volume.”

Despite the significant gender gaps that still exist, Dr. Jorge – who authored a previous study on the gaps in academic rheumatology – was heartened by the data that indicated more women finding their way into the specialty.

“I think it’s good news for rheumatology to be so balanced between men and women as providers,” she said. “For young women trainees, it’s really important to see role models in their field. For patients, it’s incredibly important for them to have a doctor who can relate and who can advocate for them. So many rheumatic conditions that we treat disproportionately affect women, often women of childbearing age. So it’s really important to have women involved in leading the specialty of rheumatology, including clinical practice but also research, education, and policy.”

Dr. Wright concurred in her editorial, stating that “this feminization of rheumatology provides an opportunity to assess the needs of working women, the generational shifts in attitudes toward work-life balance, and a change in clinical practice toward value over volume.”

The study’s authors shared its possible limitations, including the lack of a standard definition of a clinical FTE rheumatologist – thus their decision to define one – and a lack of context as to why certain rheumatologists were practicing less than others. In addition, they preemptively acknowledged Dr. Jorge’s concern by noting their inability to access gender-related details like marital status, family size, and childcare roles, all of which “could contribute to the relationship between physician gender and practice-level activity.”

The study was funded by an operating grant from the Canadian Initiative for Outcomes in Rheumatology Care and supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Two of the authors reported receiving support from the Arthritis Society Stars Career Development Award.
 

A new study on the changing rheumatology workforce found that, although there has been a notable rise in female rheumatologists, they see fewer patients and have lower earnings than their male counterparts.

BSIP/UIG/GettyImages

“In order for future health workforce policy and planning to be effective and equitable, it is essential to consider policies and other solutions to support the sustainability of rheumatology workforces in light of increasing feminization,” wrote Jessica Widdifield, PhD, of the Sunnybrook Research Institute in Toronto and her colleagues. The study was published in the Journal of Rheumatology.

To investigate potential workload and earnings disparities between male and female rheumatologists, the researchers launched a population-based study of rheumatologists practicing in Ontario, Canada, and their patient visits between April 1, 2000, and March 31, 2015. To quantify clinical activity, they calculated full-time equivalents (FTEs) using annual fee-for-service billing claims and defined rheumatologists practicing at least one clinical FTE as those at or above the 40th percentile of total billings each year. Any rheumatologists practicing less than one FTE were not included in the larger analysis.

Overall, they found that the total number of rheumatologists increased from 146 in 2000 to 194 in 2015, with 49% of the latter workforce being women. When assessing only rheumatologists practicing at greater than one FTE, the number increased from 89 in 2000 to 120 in 2015, with women making up 41.7% of the 2015 workforce. Although practice sizes decreased for both genders over the course of the study, in 2015 the median practice size was 1,948.5 patients (interquartile range, 1,433-2,562) for men, compared with 1,468.5 patients (IQR, 1,212-1,984) for women. In every year but 2001, men had larger median practice sizes than women.

Total patient visits remained relatively stable for men throughout the study period but declined for women, with the gap between genders widening over time. The peak gap in visits was 1,486 (95% confidence interval, 628-2,517) in 2008. And while median payments increased over time for all rheumatologists, median renumeration peaked in 2015 at $362,522 (IQR, $309,503-$437,127) for women, compared with $403,903 (IQR, $313,297-$544,703) for men. That said, the median difference that year – $45,556.10 (95% confidence interval, $951.60-$92,470.40; P = .04) – was the smallest for any in the study period. The largest difference was $102,176.10 (95% CI, $58,457.50-$152,821.20; P < .0001) in 2011.

An opportunity for female rheumatologists to reshape the specialty

Of course, gender gaps like these are not limited to rheumatology or even medicine, wrote Grace C. Wright, MD, PhD, president of the Association of Women in Rheumatology, in an accompanying editorial. “This issue exists across industries as well as across boundaries.”

“Particularly for women physicians, we do have additional demands on our time,” agreed April Jorge, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, in an interview. “For example, we know that women who work often have additional caregiving responsibilities at home, for kids and/or elderly relatives. I do think those are real reasons why certain providers, particularly women, might have a lower clinical volume.”

Despite the significant gender gaps that still exist, Dr. Jorge – who authored a previous study on the gaps in academic rheumatology – was heartened by the data that indicated more women finding their way into the specialty.

“I think it’s good news for rheumatology to be so balanced between men and women as providers,” she said. “For young women trainees, it’s really important to see role models in their field. For patients, it’s incredibly important for them to have a doctor who can relate and who can advocate for them. So many rheumatic conditions that we treat disproportionately affect women, often women of childbearing age. So it’s really important to have women involved in leading the specialty of rheumatology, including clinical practice but also research, education, and policy.”

Dr. Wright concurred in her editorial, stating that “this feminization of rheumatology provides an opportunity to assess the needs of working women, the generational shifts in attitudes toward work-life balance, and a change in clinical practice toward value over volume.”

The study’s authors shared its possible limitations, including the lack of a standard definition of a clinical FTE rheumatologist – thus their decision to define one – and a lack of context as to why certain rheumatologists were practicing less than others. In addition, they preemptively acknowledged Dr. Jorge’s concern by noting their inability to access gender-related details like marital status, family size, and childcare roles, all of which “could contribute to the relationship between physician gender and practice-level activity.”

The study was funded by an operating grant from the Canadian Initiative for Outcomes in Rheumatology Care and supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Two of the authors reported receiving support from the Arthritis Society Stars Career Development Award.
 

Black patients diagnosed by dermatologists with cutaneous sarcoidosis were significantly more likely to have unrecognized systemic organ involvement than were non-Black patients, according to a retrospective chart review of patients seen at Massachusetts General Hospital and Brigham and Women’s Hospital, both in Boston.

Black patients were also significantly more likely to have two or more organs involved and have higher rates of cardiac involvement, the latter of which is associated with worse prognosis. “Our data suggest there may be substantial variations in organ involvement between racial groups of patients presenting with cutaneous sarcoidosis,” said medical student Kylee Kus, a medical student at Oakland University, Auburn Hills, Mich., who presented the findings with Bina Kassamali, a medical student at Harvard University, Boston, at the annual Skin of Color Society scientific symposium.

Sotonye Imadojemu, MD, MBE; Avery LeChance, MD, MPH; and Ruth Anne Vleugels, MD, MPH, MBA; of Brigham and Women’s Hospital, are cosenior authors of the abstract.

The researchers identified 111 patients who were diagnosed with cutaneous sarcoidosis over a 20-year period (January 2000–December 2019), 50 of whom presented without established extracutaneous disease. They examined the charts of these 50 patients for whether subsequent work-up revealed systemic disease.

Of the 50 patients, 9 were Black. Seven of these nine patients (77.8%), were found to have systemic involvement, compared with 14 of 41 (46.3%) non-Black patients – a 31.5% higher probability (P < .05). One-third of the nine Black patients were found to have disease in one organ, and 44.4% in two or more organs. In non-Black patients, these rates were 12.2% and 34.1%, respectively.

Cardiovascular involvement was not found in any of the non-Black patients who had extracutaneous disease, but was found in 29% of the Black patients with extracutaneous disease, a statistically significant difference.

Black patients are known to be at higher risk for sarcoidosis than non-Black patients, and because “there is an association between cardiac sarcoid involvement and poor prognosis largely due to manifestations such as heart block, arrhythmias, and heart failure ... the study helps demonstrate how this organ involvement can disproportionately affect the Black population,” Ms. Kassamali said in an interview after the meeting.

A separate, recently published analysis of data from the same patient population examined the work-ups that patients received after a dermatologist’s diagnosis of sarcoidosis and found that patients with no previous systemic work-up were subsequently assessed for cardiac involvement in only 58.3% of cases. Assessment for pulmonary and ocular disease was completed more than 90% of the time.

“Crucial testing for cardiac involvement fell short,” Dr. Imadojemu, of the department of dermatology, Brigham and Women’s Hospital, and coinvestigators wrote in the research letter.

“Because the cutaneous manifestations of sarcoidosis often present at disease onset, dermatologists may be the first physicians to diagnose a patient with sarcoidosis,” they wrote. “As such, dermatologists are often responsible for initiating the appropriate evaluation of patients with sarcoidosis.”

Pulmonary involvement occurs in nearly all cases of sarcoidosis, while ocular and cardiac disease develop in approximately 25% and 10% of patients, respectively. Cardiac sarcoidosis is usually asymptomatic and accounts for 13%-25% of sarcoidosis-related deaths in the United States, they wrote.

An electrocardiogram is the appropriate initial screening tool and “is warranted in all patients with sarcoidosis,” they advised.

Black patients diagnosed by dermatologists with cutaneous sarcoidosis were significantly more likely to have unrecognized systemic organ involvement than were non-Black patients, according to a retrospective chart review of patients seen at Massachusetts General Hospital and Brigham and Women’s Hospital, both in Boston.

Black patients were also significantly more likely to have two or more organs involved and have higher rates of cardiac involvement, the latter of which is associated with worse prognosis. “Our data suggest there may be substantial variations in organ involvement between racial groups of patients presenting with cutaneous sarcoidosis,” said medical student Kylee Kus, a medical student at Oakland University, Auburn Hills, Mich., who presented the findings with Bina Kassamali, a medical student at Harvard University, Boston, at the annual Skin of Color Society scientific symposium.

Sotonye Imadojemu, MD, MBE; Avery LeChance, MD, MPH; and Ruth Anne Vleugels, MD, MPH, MBA; of Brigham and Women’s Hospital, are cosenior authors of the abstract.

The researchers identified 111 patients who were diagnosed with cutaneous sarcoidosis over a 20-year period (January 2000–December 2019), 50 of whom presented without established extracutaneous disease. They examined the charts of these 50 patients for whether subsequent work-up revealed systemic disease.

Of the 50 patients, 9 were Black. Seven of these nine patients (77.8%), were found to have systemic involvement, compared with 14 of 41 (46.3%) non-Black patients – a 31.5% higher probability (P < .05). One-third of the nine Black patients were found to have disease in one organ, and 44.4% in two or more organs. In non-Black patients, these rates were 12.2% and 34.1%, respectively.

Cardiovascular involvement was not found in any of the non-Black patients who had extracutaneous disease, but was found in 29% of the Black patients with extracutaneous disease, a statistically significant difference.

Black patients are known to be at higher risk for sarcoidosis than non-Black patients, and because “there is an association between cardiac sarcoid involvement and poor prognosis largely due to manifestations such as heart block, arrhythmias, and heart failure ... the study helps demonstrate how this organ involvement can disproportionately affect the Black population,” Ms. Kassamali said in an interview after the meeting.

A separate, recently published analysis of data from the same patient population examined the work-ups that patients received after a dermatologist’s diagnosis of sarcoidosis and found that patients with no previous systemic work-up were subsequently assessed for cardiac involvement in only 58.3% of cases. Assessment for pulmonary and ocular disease was completed more than 90% of the time.

“Crucial testing for cardiac involvement fell short,” Dr. Imadojemu, of the department of dermatology, Brigham and Women’s Hospital, and coinvestigators wrote in the research letter.

“Because the cutaneous manifestations of sarcoidosis often present at disease onset, dermatologists may be the first physicians to diagnose a patient with sarcoidosis,” they wrote. “As such, dermatologists are often responsible for initiating the appropriate evaluation of patients with sarcoidosis.”

Pulmonary involvement occurs in nearly all cases of sarcoidosis, while ocular and cardiac disease develop in approximately 25% and 10% of patients, respectively. Cardiac sarcoidosis is usually asymptomatic and accounts for 13%-25% of sarcoidosis-related deaths in the United States, they wrote.

An electrocardiogram is the appropriate initial screening tool and “is warranted in all patients with sarcoidosis,” they advised.

Black patients diagnosed by dermatologists with cutaneous sarcoidosis were significantly more likely to have unrecognized systemic organ involvement than were non-Black patients, according to a retrospective chart review of patients seen at Massachusetts General Hospital and Brigham and Women’s Hospital, both in Boston.

Black patients were also significantly more likely to have two or more organs involved and have higher rates of cardiac involvement, the latter of which is associated with worse prognosis. “Our data suggest there may be substantial variations in organ involvement between racial groups of patients presenting with cutaneous sarcoidosis,” said medical student Kylee Kus, a medical student at Oakland University, Auburn Hills, Mich., who presented the findings with Bina Kassamali, a medical student at Harvard University, Boston, at the annual Skin of Color Society scientific symposium.

Sotonye Imadojemu, MD, MBE; Avery LeChance, MD, MPH; and Ruth Anne Vleugels, MD, MPH, MBA; of Brigham and Women’s Hospital, are cosenior authors of the abstract.

The researchers identified 111 patients who were diagnosed with cutaneous sarcoidosis over a 20-year period (January 2000–December 2019), 50 of whom presented without established extracutaneous disease. They examined the charts of these 50 patients for whether subsequent work-up revealed systemic disease.

Of the 50 patients, 9 were Black. Seven of these nine patients (77.8%), were found to have systemic involvement, compared with 14 of 41 (46.3%) non-Black patients – a 31.5% higher probability (P < .05). One-third of the nine Black patients were found to have disease in one organ, and 44.4% in two or more organs. In non-Black patients, these rates were 12.2% and 34.1%, respectively.

Cardiovascular involvement was not found in any of the non-Black patients who had extracutaneous disease, but was found in 29% of the Black patients with extracutaneous disease, a statistically significant difference.

Black patients are known to be at higher risk for sarcoidosis than non-Black patients, and because “there is an association between cardiac sarcoid involvement and poor prognosis largely due to manifestations such as heart block, arrhythmias, and heart failure ... the study helps demonstrate how this organ involvement can disproportionately affect the Black population,” Ms. Kassamali said in an interview after the meeting.

A separate, recently published analysis of data from the same patient population examined the work-ups that patients received after a dermatologist’s diagnosis of sarcoidosis and found that patients with no previous systemic work-up were subsequently assessed for cardiac involvement in only 58.3% of cases. Assessment for pulmonary and ocular disease was completed more than 90% of the time.

“Crucial testing for cardiac involvement fell short,” Dr. Imadojemu, of the department of dermatology, Brigham and Women’s Hospital, and coinvestigators wrote in the research letter.

“Because the cutaneous manifestations of sarcoidosis often present at disease onset, dermatologists may be the first physicians to diagnose a patient with sarcoidosis,” they wrote. “As such, dermatologists are often responsible for initiating the appropriate evaluation of patients with sarcoidosis.”

Pulmonary involvement occurs in nearly all cases of sarcoidosis, while ocular and cardiac disease develop in approximately 25% and 10% of patients, respectively. Cardiac sarcoidosis is usually asymptomatic and accounts for 13%-25% of sarcoidosis-related deaths in the United States, they wrote.

An electrocardiogram is the appropriate initial screening tool and “is warranted in all patients with sarcoidosis,” they advised.

Clinicians should be on the lookout for immune-related adverse events (irAEs) even after patients have been receiving anti-PD-1 immunotherapy for a year or longer, according to team of international investigators.

They reported that, among melanoma patients, the incidence of new-onset reactions that occurred 1 year or longer after anti-PD-1 treatment was 5.3%.

In a review of 118 patients, the investigators found that irAEs are often “high grade, difficult to manage, and can lead to death.”

Reactions are more likely to occur in those for whom treatment with an anti-PD-1 checkpoint inhibitor – primarily pembrolizumab and nivolumab – continued for longer than a year, and patients can present “long after stopping” the treatment, the investigators noted.

The findings were published online in Annals of Oncology.

“We do not yet understand why some patients have no side effects for months or years, then develop toxicities so late in their course,” said one of the coauthors, Douglas Johnson, MD, assistant professor of hematology/oncology at Vanderbilt University, Nashville, Tenn.

“Physicians should continue to monitor patients for side effects, even if they have been on anti-PD-1 therapy for some time, since delayed side effects may cause morbidity and even death,” Dr. Johnson said.

Patients and clinicians need “to be aware of these risks when making decisions regarding therapy continuation” and need “to consider irAE as a possible diagnosis in any presentation where there is a history of checkpoint inhibitor treatment, regardless of the time frame, to enable early recognition and appropriate treatment,” Dr. Johnson and colleagues concluded.
 

Largest series to document delayed reactions

Immunotherapies have revolutionized cancer treatment of many types of tumors, but they carry a well known risk for autoimmune toxicity, which typically occurs within the first 4-6 months, the authors wrote.

Delayed reactions have been reported but are not as well described. The new study is the largest to date on this question, and Dr. Johnson said the findings likely apply across indications, not simply in regard to melanoma patients.

An expert not involved in the study agrees.

“We are definitely seeing delayed reactions to immunotherapy in our practice” in several organ systems, including the skin, said Jennifer Choi, MD, chief of oncodermatology at Northwestern University’s Comprehensive Cancer Center, Chicago.

“Some of these side effects can take months to resolve and may require systemic treatment, such as steroids, nonsteroidal immunosuppressants, or biologics. Clinicians must be on high alert of any possible side effect for a patient on immunotherapy throughout their entire course, and even after they have completed treatment,” Dr. Choi said in an interview.

Anti-PD-1 therapy doesn’t “follow the typical drug hypersensitivity laws and rules with respect to timing,” said Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington.
 

Median onset was 16 months

The investigators reported in detail on 118 patients. A total of 140 delayed irAEs that occurred 1 year or longer after treatment were identified in 20 centers around the world.

The median onset of delayed irAE was 16 months after start of treatment. Most occurred in conjunction with stand-alone anti-PD-1 therapy, but in the case of 20 patients, a combination of an anti-PD-1 drug and the anti-CTLA-4 drug ipilimumab was used.

In 39% of patients (n = 55), the adverse reaction was of grade 3 or worse. These included two deaths: one case of fatal encephalitis with concurrent anti-PD-1 use, and a death from immune-related multiple organ failure 11 months after anti-PD-1 discontinuation.

Most of the patients (n = 87; 74%) were receiving anti-PD-1 therapy at the time of onset of the adverse reaction; 15 patients (12%) were within 3 months of their last dose, and 16 (14%) were 3 months past their last dose.

Among the subgroup who developed an irAE after discontinuation of treatment was a patient with grade 4 colitis that required colectomy 26 months afterward, although Dr. Johnson noted it’s difficult to be sure that the colitis was related to the immunotherapy, because it occurred so long after treatment had ended.
 

An early warning system

The most common reactions were colitis, pneumonitis, and rash.

The reactions were often tough to manage, the authors reported. Eighty patients (68%) required steroids, and 27 (23%) required steroids plus additional immunosuppressives, such as tumor necrosis factor blockers, particularly for colitis and renal, rheumatologic, and neurologic complications. Rheumatologic events required a median corticosteroid course of 15 months plus additional immunosuppression in half of cases and often left patients with ongoing morbidity.

“Often, the skin is one of the first and most easily visible immune-related adverse event that develops,” said Bernice Kwong, MD, director of the supportive dermato-oncology program at Stanford (Calif.) University, who was not involved in the study and was approached for comment.

Presentations can range from small itchy plaques to total body dermatitis. It is something to be aware of, because the skin can act as an early warning system to catch internal organ damage earlier, she said.

On a positive note, the investigators found no indication that the effect of immunotherapy was diminished by delayed reactions and their treatment.

Managing events “gets a little complicated” when anti-PD-1 drugs are still being administered, but “we have successfully utilized systemic steroid pulses for several weeks without impeding the efficacy of the therapy. For the lichenoid and psoriasiform dermatitis, topical steroids and oral retinoids have been useful and can be used concurrently with immunotherapy,” Dr. Friedman said.
 

Question on treatment duration

No obvious factors were predictive of delayed events, including previous autoimmune disease or earlier reactions, which usually affected different organs, the authors said.

The findings raise a question about the appropriate duration of anti-PD-1 therapy, at least for melanoma.

The standard duration of adjuvant therapy was empirically determined to be 1 year for melanoma, and trials support anti-PD-1 therapy for up to 2 years for metastatic disease.

However, the authors suggest that “shorter treatment duration may reduce the risk of delayed irAE” and may be sufficient for patients who have a complete response.

“This should be considered when making decisions regarding therapy continuation in responding patients,” they wrote.

Ongoing clinical trials are investigating the optimal duration of therapy, they wrote.

No outside funding was reported. Dr. Johnson has been an adviser for Array Biopharma, BMS, Iovance, Jansen, Merck, and Novartis and has received research funding from BMS and Incyte. Other investigators reported similar ties. Dr. Choi, Dr. Kwong, and Dr. Friedman have disclosed no relevant financial relationships.

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

Clinicians should be on the lookout for immune-related adverse events (irAEs) even after patients have been receiving anti-PD-1 immunotherapy for a year or longer, according to team of international investigators.

They reported that, among melanoma patients, the incidence of new-onset reactions that occurred 1 year or longer after anti-PD-1 treatment was 5.3%.

In a review of 118 patients, the investigators found that irAEs are often “high grade, difficult to manage, and can lead to death.”

Reactions are more likely to occur in those for whom treatment with an anti-PD-1 checkpoint inhibitor – primarily pembrolizumab and nivolumab – continued for longer than a year, and patients can present “long after stopping” the treatment, the investigators noted.

The findings were published online in Annals of Oncology.

“We do not yet understand why some patients have no side effects for months or years, then develop toxicities so late in their course,” said one of the coauthors, Douglas Johnson, MD, assistant professor of hematology/oncology at Vanderbilt University, Nashville, Tenn.

“Physicians should continue to monitor patients for side effects, even if they have been on anti-PD-1 therapy for some time, since delayed side effects may cause morbidity and even death,” Dr. Johnson said.

Patients and clinicians need “to be aware of these risks when making decisions regarding therapy continuation” and need “to consider irAE as a possible diagnosis in any presentation where there is a history of checkpoint inhibitor treatment, regardless of the time frame, to enable early recognition and appropriate treatment,” Dr. Johnson and colleagues concluded.
 

Largest series to document delayed reactions

Immunotherapies have revolutionized cancer treatment of many types of tumors, but they carry a well known risk for autoimmune toxicity, which typically occurs within the first 4-6 months, the authors wrote.

Delayed reactions have been reported but are not as well described. The new study is the largest to date on this question, and Dr. Johnson said the findings likely apply across indications, not simply in regard to melanoma patients.

An expert not involved in the study agrees.

“We are definitely seeing delayed reactions to immunotherapy in our practice” in several organ systems, including the skin, said Jennifer Choi, MD, chief of oncodermatology at Northwestern University’s Comprehensive Cancer Center, Chicago.

“Some of these side effects can take months to resolve and may require systemic treatment, such as steroids, nonsteroidal immunosuppressants, or biologics. Clinicians must be on high alert of any possible side effect for a patient on immunotherapy throughout their entire course, and even after they have completed treatment,” Dr. Choi said in an interview.

Anti-PD-1 therapy doesn’t “follow the typical drug hypersensitivity laws and rules with respect to timing,” said Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington.
 

Median onset was 16 months

The investigators reported in detail on 118 patients. A total of 140 delayed irAEs that occurred 1 year or longer after treatment were identified in 20 centers around the world.

The median onset of delayed irAE was 16 months after start of treatment. Most occurred in conjunction with stand-alone anti-PD-1 therapy, but in the case of 20 patients, a combination of an anti-PD-1 drug and the anti-CTLA-4 drug ipilimumab was used.

In 39% of patients (n = 55), the adverse reaction was of grade 3 or worse. These included two deaths: one case of fatal encephalitis with concurrent anti-PD-1 use, and a death from immune-related multiple organ failure 11 months after anti-PD-1 discontinuation.

Most of the patients (n = 87; 74%) were receiving anti-PD-1 therapy at the time of onset of the adverse reaction; 15 patients (12%) were within 3 months of their last dose, and 16 (14%) were 3 months past their last dose.

Among the subgroup who developed an irAE after discontinuation of treatment was a patient with grade 4 colitis that required colectomy 26 months afterward, although Dr. Johnson noted it’s difficult to be sure that the colitis was related to the immunotherapy, because it occurred so long after treatment had ended.
 

An early warning system

The most common reactions were colitis, pneumonitis, and rash.

The reactions were often tough to manage, the authors reported. Eighty patients (68%) required steroids, and 27 (23%) required steroids plus additional immunosuppressives, such as tumor necrosis factor blockers, particularly for colitis and renal, rheumatologic, and neurologic complications. Rheumatologic events required a median corticosteroid course of 15 months plus additional immunosuppression in half of cases and often left patients with ongoing morbidity.

“Often, the skin is one of the first and most easily visible immune-related adverse event that develops,” said Bernice Kwong, MD, director of the supportive dermato-oncology program at Stanford (Calif.) University, who was not involved in the study and was approached for comment.

Presentations can range from small itchy plaques to total body dermatitis. It is something to be aware of, because the skin can act as an early warning system to catch internal organ damage earlier, she said.

On a positive note, the investigators found no indication that the effect of immunotherapy was diminished by delayed reactions and their treatment.

Managing events “gets a little complicated” when anti-PD-1 drugs are still being administered, but “we have successfully utilized systemic steroid pulses for several weeks without impeding the efficacy of the therapy. For the lichenoid and psoriasiform dermatitis, topical steroids and oral retinoids have been useful and can be used concurrently with immunotherapy,” Dr. Friedman said.
 

Question on treatment duration

No obvious factors were predictive of delayed events, including previous autoimmune disease or earlier reactions, which usually affected different organs, the authors said.

The findings raise a question about the appropriate duration of anti-PD-1 therapy, at least for melanoma.

The standard duration of adjuvant therapy was empirically determined to be 1 year for melanoma, and trials support anti-PD-1 therapy for up to 2 years for metastatic disease.

However, the authors suggest that “shorter treatment duration may reduce the risk of delayed irAE” and may be sufficient for patients who have a complete response.

“This should be considered when making decisions regarding therapy continuation in responding patients,” they wrote.

Ongoing clinical trials are investigating the optimal duration of therapy, they wrote.

No outside funding was reported. Dr. Johnson has been an adviser for Array Biopharma, BMS, Iovance, Jansen, Merck, and Novartis and has received research funding from BMS and Incyte. Other investigators reported similar ties. Dr. Choi, Dr. Kwong, and Dr. Friedman have disclosed no relevant financial relationships.

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

Clinicians should be on the lookout for immune-related adverse events (irAEs) even after patients have been receiving anti-PD-1 immunotherapy for a year or longer, according to team of international investigators.

They reported that, among melanoma patients, the incidence of new-onset reactions that occurred 1 year or longer after anti-PD-1 treatment was 5.3%.

In a review of 118 patients, the investigators found that irAEs are often “high grade, difficult to manage, and can lead to death.”

Reactions are more likely to occur in those for whom treatment with an anti-PD-1 checkpoint inhibitor – primarily pembrolizumab and nivolumab – continued for longer than a year, and patients can present “long after stopping” the treatment, the investigators noted.

The findings were published online in Annals of Oncology.

“We do not yet understand why some patients have no side effects for months or years, then develop toxicities so late in their course,” said one of the coauthors, Douglas Johnson, MD, assistant professor of hematology/oncology at Vanderbilt University, Nashville, Tenn.

“Physicians should continue to monitor patients for side effects, even if they have been on anti-PD-1 therapy for some time, since delayed side effects may cause morbidity and even death,” Dr. Johnson said.

Patients and clinicians need “to be aware of these risks when making decisions regarding therapy continuation” and need “to consider irAE as a possible diagnosis in any presentation where there is a history of checkpoint inhibitor treatment, regardless of the time frame, to enable early recognition and appropriate treatment,” Dr. Johnson and colleagues concluded.
 

Largest series to document delayed reactions

Immunotherapies have revolutionized cancer treatment of many types of tumors, but they carry a well known risk for autoimmune toxicity, which typically occurs within the first 4-6 months, the authors wrote.

Delayed reactions have been reported but are not as well described. The new study is the largest to date on this question, and Dr. Johnson said the findings likely apply across indications, not simply in regard to melanoma patients.

An expert not involved in the study agrees.

“We are definitely seeing delayed reactions to immunotherapy in our practice” in several organ systems, including the skin, said Jennifer Choi, MD, chief of oncodermatology at Northwestern University’s Comprehensive Cancer Center, Chicago.

“Some of these side effects can take months to resolve and may require systemic treatment, such as steroids, nonsteroidal immunosuppressants, or biologics. Clinicians must be on high alert of any possible side effect for a patient on immunotherapy throughout their entire course, and even after they have completed treatment,” Dr. Choi said in an interview.

Anti-PD-1 therapy doesn’t “follow the typical drug hypersensitivity laws and rules with respect to timing,” said Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington.
 

Median onset was 16 months

The investigators reported in detail on 118 patients. A total of 140 delayed irAEs that occurred 1 year or longer after treatment were identified in 20 centers around the world.

The median onset of delayed irAE was 16 months after start of treatment. Most occurred in conjunction with stand-alone anti-PD-1 therapy, but in the case of 20 patients, a combination of an anti-PD-1 drug and the anti-CTLA-4 drug ipilimumab was used.

In 39% of patients (n = 55), the adverse reaction was of grade 3 or worse. These included two deaths: one case of fatal encephalitis with concurrent anti-PD-1 use, and a death from immune-related multiple organ failure 11 months after anti-PD-1 discontinuation.

Most of the patients (n = 87; 74%) were receiving anti-PD-1 therapy at the time of onset of the adverse reaction; 15 patients (12%) were within 3 months of their last dose, and 16 (14%) were 3 months past their last dose.

Among the subgroup who developed an irAE after discontinuation of treatment was a patient with grade 4 colitis that required colectomy 26 months afterward, although Dr. Johnson noted it’s difficult to be sure that the colitis was related to the immunotherapy, because it occurred so long after treatment had ended.
 

An early warning system

The most common reactions were colitis, pneumonitis, and rash.

The reactions were often tough to manage, the authors reported. Eighty patients (68%) required steroids, and 27 (23%) required steroids plus additional immunosuppressives, such as tumor necrosis factor blockers, particularly for colitis and renal, rheumatologic, and neurologic complications. Rheumatologic events required a median corticosteroid course of 15 months plus additional immunosuppression in half of cases and often left patients with ongoing morbidity.

“Often, the skin is one of the first and most easily visible immune-related adverse event that develops,” said Bernice Kwong, MD, director of the supportive dermato-oncology program at Stanford (Calif.) University, who was not involved in the study and was approached for comment.

Presentations can range from small itchy plaques to total body dermatitis. It is something to be aware of, because the skin can act as an early warning system to catch internal organ damage earlier, she said.

On a positive note, the investigators found no indication that the effect of immunotherapy was diminished by delayed reactions and their treatment.

Managing events “gets a little complicated” when anti-PD-1 drugs are still being administered, but “we have successfully utilized systemic steroid pulses for several weeks without impeding the efficacy of the therapy. For the lichenoid and psoriasiform dermatitis, topical steroids and oral retinoids have been useful and can be used concurrently with immunotherapy,” Dr. Friedman said.
 

Question on treatment duration

No obvious factors were predictive of delayed events, including previous autoimmune disease or earlier reactions, which usually affected different organs, the authors said.

The findings raise a question about the appropriate duration of anti-PD-1 therapy, at least for melanoma.

The standard duration of adjuvant therapy was empirically determined to be 1 year for melanoma, and trials support anti-PD-1 therapy for up to 2 years for metastatic disease.

However, the authors suggest that “shorter treatment duration may reduce the risk of delayed irAE” and may be sufficient for patients who have a complete response.

“This should be considered when making decisions regarding therapy continuation in responding patients,” they wrote.

Ongoing clinical trials are investigating the optimal duration of therapy, they wrote.

No outside funding was reported. Dr. Johnson has been an adviser for Array Biopharma, BMS, Iovance, Jansen, Merck, and Novartis and has received research funding from BMS and Incyte. Other investigators reported similar ties. Dr. Choi, Dr. Kwong, and Dr. Friedman have disclosed no relevant financial relationships.

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

Patients with mild to moderate systemic lupus erythematosus (SLE) disease activity without any past history of organ damage may still progress to develop damage, particularly renal and cardiovascular disease, or death, in a relatively short amount of follow-up time, new research suggests.

The study, published in Lupus Science & Medicine, also showed that use of hydroxychloroquine lowered the risk of death and renal damage, whereas use of NSAIDs or any antihypertensives increased risk for cardiovascular damage.

“The impact of irreversible organ system damage in the prognosis of SLE remains a major concern because patients who develop damage are more likely to accrue additional damage and die,” wrote Deanna Hill, PhD, of GlaxoSmithKline, Collegeville, Pa., and coauthors, including Michelle Petri, MD, of Johns Hopkins University, Baltimore.

The researchers followed 1,168 adult patients with SLE from the Johns Hopkins Lupus Cohort, most of whom were women, 55% of whom were White and 39% of whom were Black. They divided the follow-up period into three parts: first year after enrollment into the cohort as background, second year as observation period, and the remainder of follow-up time until damage occurred, death, or end of available data.

At baseline, 55% of patients had mild to moderate disease, defined as an adjusted mean SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment SLE Disease Activity Index) score of less than 3. Patients had a median adjusted mean SELENA-SLEDAI score of 3 in the first year, which dropped to 2 in the observation period and remained there during the rest of follow-up.

Eight percent of patients died during the follow-up period. Each one-unit mean increase in SELENA-SLEDAI score during the 1-year observation period was associated with a significant 22% increase in the subsequent risk of death during the subsequent follow-up period (95% confidence interval, 1.13-1.32; P < .001).

Three-quarters of patients (n = 888) had no history of damage at the start of the follow-up period, but 39% of these patients had developed damage by the end of follow-up. Among patients without prior damage, a single-unit increase in disease activity score was also associated with a 9% increase in the risk of accruing organ damage (95% CI, 1.04-1.15; P < .001) after adjustment for confounding factors.

While only 3% of patients – most of whom were women – developed renal damage during the follow-up period, a one-unit increase in disease activity score was associated with a 24% increase in the risk of renal damage (95% CI, 1.08-1.42, P = .003).

The researchers found that 7% of patients developed cardiovascular damage during the follow-up period, and each one-unit increase in disease activity score was associated with a 17% increase in the risk of cardiovascular damage (95% CI, 1.07-1.29; P < .001).

“The findings in this analysis corroborate the influence of disease activity for renal and cardiovascular damage accrual and death and also extend the findings to patients with SLE and mild to moderate disease activity,” the authors wrote.

Impact of treatment

Researchers also examined the effect of treatments, and found that patients treated with hydroxychloroquine during the 1-year observation period had a 54% lower risk of subsequent death (95% CI, 0.29-0.72; P < .05) and a 70% lower risk of renal damage (95% CI, 0.13-0.68, P < .05). However, patients prescribed NSAIDs had a 66% higher risk of cardiovascular damage, while those who used any antihypertensive had an 81% higher risk of cardiovascular damage.

“This may suggest that the known cardiovascular risk of NSAIDs in the general population is also applicable to patients with SLE and highlights the importance of assessing cardiovascular risk in this patient population,” the authors wrote.

Smoking affected the risk of death: Smokers were 74% more likely to die during the follow-up period than were nonsmokers.

There were no significant differences between different ethnicities in the study. While White patients generally had lower disease activity overall, there was no significant differences in the risk of death or organ damage with ethnicity.

The Hopkins Lupus Cohort is supported by the National Institutes of Health, and the study was funded by GlaxoSmithKline. Three authors were paid employees of GlaxoSmithKline and two were paid consultants or contractors.

Patients with mild to moderate systemic lupus erythematosus (SLE) disease activity without any past history of organ damage may still progress to develop damage, particularly renal and cardiovascular disease, or death, in a relatively short amount of follow-up time, new research suggests.

The study, published in Lupus Science & Medicine, also showed that use of hydroxychloroquine lowered the risk of death and renal damage, whereas use of NSAIDs or any antihypertensives increased risk for cardiovascular damage.

“The impact of irreversible organ system damage in the prognosis of SLE remains a major concern because patients who develop damage are more likely to accrue additional damage and die,” wrote Deanna Hill, PhD, of GlaxoSmithKline, Collegeville, Pa., and coauthors, including Michelle Petri, MD, of Johns Hopkins University, Baltimore.

The researchers followed 1,168 adult patients with SLE from the Johns Hopkins Lupus Cohort, most of whom were women, 55% of whom were White and 39% of whom were Black. They divided the follow-up period into three parts: first year after enrollment into the cohort as background, second year as observation period, and the remainder of follow-up time until damage occurred, death, or end of available data.

At baseline, 55% of patients had mild to moderate disease, defined as an adjusted mean SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment SLE Disease Activity Index) score of less than 3. Patients had a median adjusted mean SELENA-SLEDAI score of 3 in the first year, which dropped to 2 in the observation period and remained there during the rest of follow-up.

Eight percent of patients died during the follow-up period. Each one-unit mean increase in SELENA-SLEDAI score during the 1-year observation period was associated with a significant 22% increase in the subsequent risk of death during the subsequent follow-up period (95% confidence interval, 1.13-1.32; P < .001).

Three-quarters of patients (n = 888) had no history of damage at the start of the follow-up period, but 39% of these patients had developed damage by the end of follow-up. Among patients without prior damage, a single-unit increase in disease activity score was also associated with a 9% increase in the risk of accruing organ damage (95% CI, 1.04-1.15; P < .001) after adjustment for confounding factors.

While only 3% of patients – most of whom were women – developed renal damage during the follow-up period, a one-unit increase in disease activity score was associated with a 24% increase in the risk of renal damage (95% CI, 1.08-1.42, P = .003).

The researchers found that 7% of patients developed cardiovascular damage during the follow-up period, and each one-unit increase in disease activity score was associated with a 17% increase in the risk of cardiovascular damage (95% CI, 1.07-1.29; P < .001).

“The findings in this analysis corroborate the influence of disease activity for renal and cardiovascular damage accrual and death and also extend the findings to patients with SLE and mild to moderate disease activity,” the authors wrote.

Impact of treatment

Researchers also examined the effect of treatments, and found that patients treated with hydroxychloroquine during the 1-year observation period had a 54% lower risk of subsequent death (95% CI, 0.29-0.72; P < .05) and a 70% lower risk of renal damage (95% CI, 0.13-0.68, P < .05). However, patients prescribed NSAIDs had a 66% higher risk of cardiovascular damage, while those who used any antihypertensive had an 81% higher risk of cardiovascular damage.

“This may suggest that the known cardiovascular risk of NSAIDs in the general population is also applicable to patients with SLE and highlights the importance of assessing cardiovascular risk in this patient population,” the authors wrote.

Smoking affected the risk of death: Smokers were 74% more likely to die during the follow-up period than were nonsmokers.

There were no significant differences between different ethnicities in the study. While White patients generally had lower disease activity overall, there was no significant differences in the risk of death or organ damage with ethnicity.

The Hopkins Lupus Cohort is supported by the National Institutes of Health, and the study was funded by GlaxoSmithKline. Three authors were paid employees of GlaxoSmithKline and two were paid consultants or contractors.

Patients with mild to moderate systemic lupus erythematosus (SLE) disease activity without any past history of organ damage may still progress to develop damage, particularly renal and cardiovascular disease, or death, in a relatively short amount of follow-up time, new research suggests.

The study, published in Lupus Science & Medicine, also showed that use of hydroxychloroquine lowered the risk of death and renal damage, whereas use of NSAIDs or any antihypertensives increased risk for cardiovascular damage.

“The impact of irreversible organ system damage in the prognosis of SLE remains a major concern because patients who develop damage are more likely to accrue additional damage and die,” wrote Deanna Hill, PhD, of GlaxoSmithKline, Collegeville, Pa., and coauthors, including Michelle Petri, MD, of Johns Hopkins University, Baltimore.

The researchers followed 1,168 adult patients with SLE from the Johns Hopkins Lupus Cohort, most of whom were women, 55% of whom were White and 39% of whom were Black. They divided the follow-up period into three parts: first year after enrollment into the cohort as background, second year as observation period, and the remainder of follow-up time until damage occurred, death, or end of available data.

At baseline, 55% of patients had mild to moderate disease, defined as an adjusted mean SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment SLE Disease Activity Index) score of less than 3. Patients had a median adjusted mean SELENA-SLEDAI score of 3 in the first year, which dropped to 2 in the observation period and remained there during the rest of follow-up.

Eight percent of patients died during the follow-up period. Each one-unit mean increase in SELENA-SLEDAI score during the 1-year observation period was associated with a significant 22% increase in the subsequent risk of death during the subsequent follow-up period (95% confidence interval, 1.13-1.32; P < .001).

Three-quarters of patients (n = 888) had no history of damage at the start of the follow-up period, but 39% of these patients had developed damage by the end of follow-up. Among patients without prior damage, a single-unit increase in disease activity score was also associated with a 9% increase in the risk of accruing organ damage (95% CI, 1.04-1.15; P < .001) after adjustment for confounding factors.

While only 3% of patients – most of whom were women – developed renal damage during the follow-up period, a one-unit increase in disease activity score was associated with a 24% increase in the risk of renal damage (95% CI, 1.08-1.42, P = .003).

The researchers found that 7% of patients developed cardiovascular damage during the follow-up period, and each one-unit increase in disease activity score was associated with a 17% increase in the risk of cardiovascular damage (95% CI, 1.07-1.29; P < .001).

“The findings in this analysis corroborate the influence of disease activity for renal and cardiovascular damage accrual and death and also extend the findings to patients with SLE and mild to moderate disease activity,” the authors wrote.

Impact of treatment

Researchers also examined the effect of treatments, and found that patients treated with hydroxychloroquine during the 1-year observation period had a 54% lower risk of subsequent death (95% CI, 0.29-0.72; P < .05) and a 70% lower risk of renal damage (95% CI, 0.13-0.68, P < .05). However, patients prescribed NSAIDs had a 66% higher risk of cardiovascular damage, while those who used any antihypertensive had an 81% higher risk of cardiovascular damage.

“This may suggest that the known cardiovascular risk of NSAIDs in the general population is also applicable to patients with SLE and highlights the importance of assessing cardiovascular risk in this patient population,” the authors wrote.

Smoking affected the risk of death: Smokers were 74% more likely to die during the follow-up period than were nonsmokers.

There were no significant differences between different ethnicities in the study. While White patients generally had lower disease activity overall, there was no significant differences in the risk of death or organ damage with ethnicity.

The Hopkins Lupus Cohort is supported by the National Institutes of Health, and the study was funded by GlaxoSmithKline. Three authors were paid employees of GlaxoSmithKline and two were paid consultants or contractors.

The recommended pause in use of the Johnson & Johnson COVID-19 vaccine will last at least another week after a Centers for Disease Control and Prevention advisory committee on April 14 decided not to take action.

Johnson &amp; Johnson

The Advisory Committee on Immunization Practices decided there was not adequate information to change again recommend use of the Johnson & Johnson vaccine.

The committee’s decision comes the day after the CDC and Food and Drug Administration recommended that J&J injections be paused after reports of rare, but serious types of blood clots in six patients among the 6.8 million people who had received the J&J vaccine in the United States.

A member of the committee, Beth Bell, MD, said: “I do not want to be sending a message that there is some huge concern here on a different order of magnitude than any other vaccine safety signals that we evaluate. And I don’t want to send a message that there is something fundamentally wrong with the vaccine because that also I don’t agree with.”

At the end of the 4-hour meeting, ACIP members decided to call a meeting in 1 or 2 weeks and evaluate more safety data, specifically reports of people who have received the J&J vaccine in the past 2 weeks.

Some, however, pointed out that delaying a decision could have substantial consequences as well in terms of unused vaccine doses and public confidence.

Committee member Camiile Kotton, MD, described the pause as “devastating.”

“Putting this vaccine on pause for those of us that are frontline health care workers has really been devastating,” she said. “I agree in general that we don’t have enough data to make a decision at this time but we were planning on using this vaccine in the state of Massachusetts for people who were homebound and otherwise not able to get a vaccine. We were planning on using it for our vulnerable inpatient population often with many comorbidities and at high risk for disease but haven’t been able to get vaccinated otherwise.”

Pausing the one-and-done vaccine that doesn’t have the significant refrigeration requirements of the others “is a significant loss,” she said.
 

What is known, not known

Sara Oliver, MD, who leads the COVID-19 Vaccines ACIP Work Group, summarized what is known and unknown about the blood clots.

Among the six cases of cerebral venous sinus thrombosis reported to the Vaccine Adverse Event Reporting System after the J&J shot, all were women aged 18-48 years and all developed the clots 6-13 days after receiving the vaccine.

No cases of these clots have been reported from either the Pfizer or Moderna shots, she noted.

In the United States, the two mRNA vaccine alternatives – the Moderna and Pfizer vaccines – are available “and based on current projections supply of both vaccines are expected to be relatively stable in the near future,” she said.

She said 14 million doses of Pfizer and Moderna are expected each week in the United States and J&J vaccines makes up less than 5% of vaccines administered in the country.

Approximately 13 million J&J doses are available to order or are already at administration sites, she said.

But much more is unknown, she said.

“There may be more cases identified in the coming days to weeks,” Dr. Oliver said, referring back to the average time from vaccination to symptom onset.

Scott Ratzan, MD, editor-in-chief of the Journal of Health Communication: International Perspectives and executive director of Business Partners to CONVINCE (BP2C), a global network of employers that promotes COVID-19 vaccination among employees, suppliers, and customers, applauded ACIP’s delay on making a decision.

Dr. Ratzan, who watched the deliberations online, said in an interview the decision “shows an admirable abundance of caution in the distribution of COVID-19 vaccines.”

“Unfortunately,” he said, “the pause also worsens the existing and pervasive vaccine hesitancy issue.

“We need a rational strategy regarding who should or should not get the J&J/Janssen vaccine since these rare adverse events appear to affect a particular group of people, females aged 18-48. It is essential that we build vaccine confidence and retain the option of using this vaccine for people who are not in this risk group.”

He pointed out there are safety red flags with the Pfizer and Moderna COVID-19 vaccines.

“We should feel reassured about the process of ensuring vaccine safety as the FDA and CDC have quickly addressed risk and shared the data transparently of the J&J vaccine and taken appropriate action,” he said.

ACIP’s executive secretary, Amanda Cohn, MD, said the date for the next meeting would be set by April 16.

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

The recommended pause in use of the Johnson & Johnson COVID-19 vaccine will last at least another week after a Centers for Disease Control and Prevention advisory committee on April 14 decided not to take action.

Johnson &amp; Johnson

The Advisory Committee on Immunization Practices decided there was not adequate information to change again recommend use of the Johnson & Johnson vaccine.

The committee’s decision comes the day after the CDC and Food and Drug Administration recommended that J&J injections be paused after reports of rare, but serious types of blood clots in six patients among the 6.8 million people who had received the J&J vaccine in the United States.

A member of the committee, Beth Bell, MD, said: “I do not want to be sending a message that there is some huge concern here on a different order of magnitude than any other vaccine safety signals that we evaluate. And I don’t want to send a message that there is something fundamentally wrong with the vaccine because that also I don’t agree with.”

At the end of the 4-hour meeting, ACIP members decided to call a meeting in 1 or 2 weeks and evaluate more safety data, specifically reports of people who have received the J&J vaccine in the past 2 weeks.

Some, however, pointed out that delaying a decision could have substantial consequences as well in terms of unused vaccine doses and public confidence.

Committee member Camiile Kotton, MD, described the pause as “devastating.”

“Putting this vaccine on pause for those of us that are frontline health care workers has really been devastating,” she said. “I agree in general that we don’t have enough data to make a decision at this time but we were planning on using this vaccine in the state of Massachusetts for people who were homebound and otherwise not able to get a vaccine. We were planning on using it for our vulnerable inpatient population often with many comorbidities and at high risk for disease but haven’t been able to get vaccinated otherwise.”

Pausing the one-and-done vaccine that doesn’t have the significant refrigeration requirements of the others “is a significant loss,” she said.
 

What is known, not known

Sara Oliver, MD, who leads the COVID-19 Vaccines ACIP Work Group, summarized what is known and unknown about the blood clots.

Among the six cases of cerebral venous sinus thrombosis reported to the Vaccine Adverse Event Reporting System after the J&J shot, all were women aged 18-48 years and all developed the clots 6-13 days after receiving the vaccine.

No cases of these clots have been reported from either the Pfizer or Moderna shots, she noted.

In the United States, the two mRNA vaccine alternatives – the Moderna and Pfizer vaccines – are available “and based on current projections supply of both vaccines are expected to be relatively stable in the near future,” she said.

She said 14 million doses of Pfizer and Moderna are expected each week in the United States and J&J vaccines makes up less than 5% of vaccines administered in the country.

Approximately 13 million J&J doses are available to order or are already at administration sites, she said.

But much more is unknown, she said.

“There may be more cases identified in the coming days to weeks,” Dr. Oliver said, referring back to the average time from vaccination to symptom onset.

Scott Ratzan, MD, editor-in-chief of the Journal of Health Communication: International Perspectives and executive director of Business Partners to CONVINCE (BP2C), a global network of employers that promotes COVID-19 vaccination among employees, suppliers, and customers, applauded ACIP’s delay on making a decision.

Dr. Ratzan, who watched the deliberations online, said in an interview the decision “shows an admirable abundance of caution in the distribution of COVID-19 vaccines.”

“Unfortunately,” he said, “the pause also worsens the existing and pervasive vaccine hesitancy issue.

“We need a rational strategy regarding who should or should not get the J&J/Janssen vaccine since these rare adverse events appear to affect a particular group of people, females aged 18-48. It is essential that we build vaccine confidence and retain the option of using this vaccine for people who are not in this risk group.”

He pointed out there are safety red flags with the Pfizer and Moderna COVID-19 vaccines.

“We should feel reassured about the process of ensuring vaccine safety as the FDA and CDC have quickly addressed risk and shared the data transparently of the J&J vaccine and taken appropriate action,” he said.

ACIP’s executive secretary, Amanda Cohn, MD, said the date for the next meeting would be set by April 16.

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

The recommended pause in use of the Johnson & Johnson COVID-19 vaccine will last at least another week after a Centers for Disease Control and Prevention advisory committee on April 14 decided not to take action.

Johnson &amp; Johnson

The Advisory Committee on Immunization Practices decided there was not adequate information to change again recommend use of the Johnson & Johnson vaccine.

The committee’s decision comes the day after the CDC and Food and Drug Administration recommended that J&J injections be paused after reports of rare, but serious types of blood clots in six patients among the 6.8 million people who had received the J&J vaccine in the United States.

A member of the committee, Beth Bell, MD, said: “I do not want to be sending a message that there is some huge concern here on a different order of magnitude than any other vaccine safety signals that we evaluate. And I don’t want to send a message that there is something fundamentally wrong with the vaccine because that also I don’t agree with.”

At the end of the 4-hour meeting, ACIP members decided to call a meeting in 1 or 2 weeks and evaluate more safety data, specifically reports of people who have received the J&J vaccine in the past 2 weeks.

Some, however, pointed out that delaying a decision could have substantial consequences as well in terms of unused vaccine doses and public confidence.

Committee member Camiile Kotton, MD, described the pause as “devastating.”

“Putting this vaccine on pause for those of us that are frontline health care workers has really been devastating,” she said. “I agree in general that we don’t have enough data to make a decision at this time but we were planning on using this vaccine in the state of Massachusetts for people who were homebound and otherwise not able to get a vaccine. We were planning on using it for our vulnerable inpatient population often with many comorbidities and at high risk for disease but haven’t been able to get vaccinated otherwise.”

Pausing the one-and-done vaccine that doesn’t have the significant refrigeration requirements of the others “is a significant loss,” she said.
 

What is known, not known

Sara Oliver, MD, who leads the COVID-19 Vaccines ACIP Work Group, summarized what is known and unknown about the blood clots.

Among the six cases of cerebral venous sinus thrombosis reported to the Vaccine Adverse Event Reporting System after the J&J shot, all were women aged 18-48 years and all developed the clots 6-13 days after receiving the vaccine.

No cases of these clots have been reported from either the Pfizer or Moderna shots, she noted.

In the United States, the two mRNA vaccine alternatives – the Moderna and Pfizer vaccines – are available “and based on current projections supply of both vaccines are expected to be relatively stable in the near future,” she said.

She said 14 million doses of Pfizer and Moderna are expected each week in the United States and J&J vaccines makes up less than 5% of vaccines administered in the country.

Approximately 13 million J&J doses are available to order or are already at administration sites, she said.

But much more is unknown, she said.

“There may be more cases identified in the coming days to weeks,” Dr. Oliver said, referring back to the average time from vaccination to symptom onset.

Scott Ratzan, MD, editor-in-chief of the Journal of Health Communication: International Perspectives and executive director of Business Partners to CONVINCE (BP2C), a global network of employers that promotes COVID-19 vaccination among employees, suppliers, and customers, applauded ACIP’s delay on making a decision.

Dr. Ratzan, who watched the deliberations online, said in an interview the decision “shows an admirable abundance of caution in the distribution of COVID-19 vaccines.”

“Unfortunately,” he said, “the pause also worsens the existing and pervasive vaccine hesitancy issue.

“We need a rational strategy regarding who should or should not get the J&J/Janssen vaccine since these rare adverse events appear to affect a particular group of people, females aged 18-48. It is essential that we build vaccine confidence and retain the option of using this vaccine for people who are not in this risk group.”

He pointed out there are safety red flags with the Pfizer and Moderna COVID-19 vaccines.

“We should feel reassured about the process of ensuring vaccine safety as the FDA and CDC have quickly addressed risk and shared the data transparently of the J&J vaccine and taken appropriate action,” he said.

ACIP’s executive secretary, Amanda Cohn, MD, said the date for the next meeting would be set by April 16.

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

An advisory committee to the Centers for Disease Control and Prevention is addressing the safety of the Johnson & Johnson COVID-19 vaccine on April 14, 2021, after the CDC and Food and Drug Administration recommended that states hold off on using it pending a detailed review of six cases of the same kind of rare but serious event – a blood clot in the vessels that drain blood from the brain combined with a large drop in platelets, which increases the risk for bleeding.

This combination can lead to severe strokes that can lead to brain damage or death. Among the six cases reported, which came to light over the past 3 weeks, one person died, according to the CDC. All six were women and ranged in age from 18 to 48 years.

According to a report from the Vaccine Adverse Event Reporting System (VAERS), which is maintained by the Department of Health & Human Services, the woman who died was 45. She developed a gradually worsening headache about a week after receiving the Johnson & Johnson vaccine.

On March 17, the day she came to the hospital, she was dry heaving. Her headache had suddenly gotten much worse, and the left side of her body was weak, which are signs of a stroke. A CT scan revealed both bleeding in her brain and a clot in her cortical vein. She died the following day.

In addition to VAERS, which accepts reports from anyone, the CDC and FDA are monitoring at least eight other safety systems maintained by hospitals, research centers, long-term care facilities, and insurance companies for signs of trouble with the vaccines. VAERS data is searchable and open to the public. Most of these systems are not publicly available to protect patient privacy. It’s unclear which systems detected the six cases cited by federal regulators.

“These are very serious and potentially fatal problems occurring in a healthy young adult. It’s serious and we need to get to the bottom of it,” said Ed Belongia, MD, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wis.) Clinic Research Institute. Dr. Belongia leads a research team that helps the CDC monitor vaccine safety and effectiveness. 

“Safety is always the highest priority, and I think what we’ve seen here in the past 24 hours is our vaccine safety monitoring system is working,” he said.

Others agree. “I think what CDC and FDA have detected is a rare, but likely real adverse event associated with this vaccine,” said Paul Offit, MD, director of vaccine education at Children’s Hospital of Philadelphia.

Although much is still unknown about these events, they follow a similar pattern of blood clots reported with the AstraZeneca vaccine in Europe. That vaccine is now sold under the brand name Vaxzevria. 

This has experts questioning whether all vaccines of this type may cause these rare clots.

“I think it’s likely a class effect,” said Dr. Offit, who was a member of the FDA advisory committee that reviewed clinical trial data on the J&J vaccine before it was authorized for use.
 

Adenovirus vaccines scrutinized

Both the Johnson & Johnson and Vaxzevria vaccines use an adenovirus to ferry genetic instructions for making the coronaviruses spike protein into our cells.

Adenoviruses are common, relatively simple viruses that normally cause mild cold or flu symptoms. The ones used in the vaccine are disabled so they can’t make us sick. They’re more like Trojan horses. 

Once inside our cells, they release the DNA instructions they carry to make the spike protein of the new coronavirus. Those cells then crank out copies of the spike protein, which then get displayed on the outer surface of the cell membrane where they are recognized by the immune system. 

The immune system then makes antibodies and other defenses against the spike so that, when the real coronavirus comes along, our bodies are ready to fight the infection.

There’s no question the vaccine works. In clinical trials, the Johnson & Johnson vaccine was 66% percent effective at preventing against moderate to severe COVID-19 infection, and none of the patients who got COVID-19 after vaccination had to be admitted to the hospital or died.

The idea behind using adenoviruses in vaccines isn’t a new one. In a kind of fight-fire-with-fire approach, the idea is to use a virus, which is good at infecting us, to fight a different kind of virus.

Researchers have been working on the concept for about 10 years, but the COVID-19 vaccines that use this technology are some of the first adenovirus-vector vaccines deployed in humans. 

Only one other adenovirus vaccine, for Ebola, has been approved for use in humans. It was approved in Europe last year. Before the Johnson & Johnson vaccine, no other adenovirus vector has been available for use in humans in the United States.

There are six adenovirus-vector vaccines for COVID-19. In addition to AstraZeneca and Johnson & Johnson, there’s the Russian-developed vaccine Sputnik V, along with CanSino from China, and the Covishield vaccine in India.

Adenovirus vaccines are more stable than the mRNA vaccines. That makes them easier to store and transport. 

But they have a significant downside, too. Because adenoviruses infect humans out in the world, we already make antibodies against them. So there’s always a danger that our immune systems might recognize and react to the vaccine, rendering it ineffective. For that reason, scientists try to carefully select the adenovirus vectors, or carriers, they use.

The two vaccines under investigation for blood clots are slightly different. The Johnson & Johnson vaccine uses the vector AD26, because most of the population lacks preexisting immunity to it. Vaxzevria uses an adenovirus that infects chimpanzees, called ChAdOx1. 

Vaxzevria has been widely used in Europe but has not yet been authorized in the United States.

On April 7, the European Medicines Agency, Europe’s counterpart to the FDA, ruled that unusual blood clots with low blood platelets should be listed as rare side effects on the Vaxzevria vaccine.

The decision came after reviewing 62 cases of cerebral venous sinus thrombosis (CVST) linked to the vaccine and 25 cases of another rare type of clot, called a splanchnic vein thrombosis. Splanchnic veins drain blood from the major organs in the digestive system, including the stomach, liver, and intestines; 18 of those events were fatal.

The reports were culled from reporting in Europe and the United Kingdom, where around 25 million people have received the Vaxzevria vaccine, making these clots exceptionally rare, but serious.

So far, six cases of CVST have been reported in the United States, after more than 7 million doses of the Johnson & Johnson vaccines have been administered.

A key question for U.S. regulators will be the background rate for these types of rare combinations of clots and deplenished platelets. The background rate is the number of events that would be expected to occur naturally in a population of unvaccinated people. On a press call on April 13, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, was asked about the frequency of this dangerous combination. He said the combination of low platelets and clots was so rare that it was hard to pinpoint, but might be somewhere between 2 and 14 cases per million people over the course of a year.

The first Johnson & Johnson doses were given in early March. That means the six cases came to light within the first few weeks of use of the vaccine in the United States, a very short amount of time.

“These were six cases per million people for 2 weeks, which is the same thing as 25 million per year, so it’s clearly above the background rate,” Dr. Offit said.
 

Studies suggest possible mechanism

On April 9, the New England Journal of Medicine published a detailed evaluation of the 11 patients in Germany and Austria who developed the rare clots after their Vaxzevria vaccines.

The study detected rare antibodies to a signaling protein called platelet factor 4, which helps to coordinate clot formation.

These same type of antibodies form in some people given the blood thinning drug heparin. In those reactions, which are also exceptionally rare, the same type of syndrome develops, leading to large, devastating clots that consume circulating platelets.

It’s not yet clear whether people who develop reactions to the vaccines already have some platelet factor 4 antibodies before they are vaccinated, or whether the vaccines somehow spur the body to make these antibodies, which then launch a kind of autoimmune attack.

The researchers on the paper gave the syndrome a name, vaccine-induced thrombotic thrombocytopenia (VITT).

It’s also not clear why more cases seem to be in women than in men. Andrew Eisenberger, MD, an associate professor of hematology and oncology at Columbia University, New York, said the most common causes of cerebral venous sinus thrombosis have to do with conditions that raise estrogen levels, like pregnancy and hormonal contraception.

“Estrogen naturally leads to changes in several clotting proteins in the blood that may predispose to abnormal blood clotting in a few different sites in the body,” he said. “The clotting changes we are encountering with some of COVID-19 vaccines are likely to be synergistic with the effects of estrogen on the blood.”

No matter the cause, the CDC on April 13 alerted doctors to keep a high index of suspicion for VITT in patients who have received the Johnson & Johnson vaccination within the last 2 weeks. In those patients, the usual course of treatment with blood thinning drugs like heparin may be harmful.

Symptoms to watch for include severe headache or backache, new neurologic symptoms, severe abdominal pain, shortness of breath, leg swelling, tiny red spots on the skin, or easy bruising. 
 

Grappling with evidence

The CDC’s Advisory Committee on Immunization Practices will meet today in an emergency session to review the cases and see if any changes are needed to use of the J&J vaccine in the United States.

Last week, for example, the United Kingdom restricted the use of the AstraZeneca vaccine in people aged younger than 30 years, saying the risks and benefits of vaccination are “more finely balanced” for this age group.

With cases of COVID-19 rising again in the United States, and the Johnson & Johnson vaccine currently the most convenient form of protection against the virus, the committee will have to weigh the risks of that infection against the risk of rare clots caused by vaccination.

They will also likely have to rule out whether any of the cases had COVID. At least one study has reported CVST clots in three patients with confirmed COVID infections. In Europe, COVID infection did not seem to play a role in the formation of the clots with low platelets.

Hilda Bastian, PhD, a clinical trials expert who cofounded the Cochrane Collaboration, said it won’t be an easy task. Much will depend on how certain the committee members feel they know about all the events linked to the vaccine.

“That’s the really, really hard issue from my point of view for them right this moment. Have we missed any? Or how many are we likely to have missed?” asked Dr. Bastian, who lives in Australia.

“In a country that size with that fragmented [of] a health care system, how sure can you be that you know them all? That’s going to be a really difficult situation for them to grapple with, the quality of information that they’ve got,” she said.

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