Rare Diseases

ORLANDO – While less frequently seen dermatologic diseases do not get a “ton of attention” in expert talks and discussions, even one to two patients presenting with these conditions a month warrants continuing education, according to Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington.

These semi-forsaken diseases are important not to miss and can “also be quite challenging when we think about their management,” he said at the ODAC Dermatology, Aesthetic & Surgical Conference.

Dr. Friedman, also director of the GW dermatology residency program, reviewed several of these diseases – along with tips for management – during a session at the meeting.

Granuloma annulare (GA). This condition, Dr. Friedman said, can have “a lot of faces” – with a localized, general, perforating, subcutaneous, micropapular, or patchy appearance. It does not always have the classic ring pattern for which it is best known, he said. And in patients with darker skin tones, it is characterized by more of a brown or black color, rather than the pink-red color.

Dr. Friedman said that despite a kind of “Pavlovian response” linking GA with diabetes, this link might not be as strong as the field has come to believe, since the studies on which this belief was based included a patient population with narrow demographics. “Maybe GA and type 1 diabetes aren’t necessarily connected,” he said.

Dyslipidemia, on the other hand, has a strong connection with GA, he said. The disease is also linked to thyroid disease and is linked with malignancy, especially in older patients with generalized or atypical presentations of GA, he said.

Spontaneous resolution of the disease is seen within 2 years for 50% to 75% of patients, so “no treatment may be the best treatment,” but antimalarials can be effective, Dr. Friedman said. “I use antimalarials frequently in my practice,” he said. “The key is, they take time to work (4-5 months),” which should be explained to patients.

Antibiotics, he said, can be “somewhat effective,” but in the case of doxycycline at least, the disease can resolve within weeks but then may return when treatment is stopped.

There is some evidence to support using biologics and more recently, Janus kinase (JAK) inhibitors, off-label, to treat GA. Efficacy has been seen with the tumor necrosis factor (TNF) blocker infliximab and with the JAK inhibitor tofacitinib, he said.

 Lichen planus (LP). This is another common disease that can go off-script with its presentation. The disease is often described with the “six P’s” indicating the following characteristics: pruritic, polygonal, planar or flat-topped, purple papules, and plaques. But LP “didn’t read the textbook,” Dr. Friedman said.

“The clinical presentation of lichen planus can be quite broad,” he said. “The P’s aren’t always followed as there are a variety of colors and configurations which can be witnessed.”

With LP, there is a clear association with dyslipidemia and diabetes, so “asking the right questions is going to be important” when talking to the patient. There is also a higher risk of autoimmune diseases, especially of the thyroid type, associated with LP, he said.

No treatment has been Food and Drug Administration approved for LP, but some are expected in the future, he said.

For now, he emphasized creativity in the management of patients with LP. “I love oral retinoids for this,” he said. Antimalarials and methotrexate are also options.

In one case Dr. Friedman saw, nothing seemed to work: light therapy for a year; metronidazole; isotretinoin; halobetasol/tazarotene lotion; and the TNF-blocker adalimumab either weren’t effective or resulted in complications in the patient.

Knowing the recent implication of the interleukin (IL)-17 pathway in the pathophysiology of LP, he then tried the anti-IL17 antibody secukinumab. “This patient had a pretty robust response to treatment,” Dr. Friedman said. “He was very excited. The problem, as always, is access, especially for off-label therapies.”

Tumid lupus erythematosus. This disease is characterized by erythematous, edematous, nonscarring plaques on sun-exposed sites. For treatment, Dr. Friedman said antimalarials can be up to 90% effective, sometimes with rapid resolution of the lesions.

“You want to dose below that 5 mg per kg of true body weight to limit the small potential for ocular toxicity over time,” he said. And, he emphasized, “always combine treatment with good sun-protective measures.”

Dr. Friedman reported financial relationships with Sanova, Pfizer, Novartis, and other companies.

ORLANDO – While less frequently seen dermatologic diseases do not get a “ton of attention” in expert talks and discussions, even one to two patients presenting with these conditions a month warrants continuing education, according to Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington.

These semi-forsaken diseases are important not to miss and can “also be quite challenging when we think about their management,” he said at the ODAC Dermatology, Aesthetic & Surgical Conference.

Dr. Friedman, also director of the GW dermatology residency program, reviewed several of these diseases – along with tips for management – during a session at the meeting.

Granuloma annulare (GA). This condition, Dr. Friedman said, can have “a lot of faces” – with a localized, general, perforating, subcutaneous, micropapular, or patchy appearance. It does not always have the classic ring pattern for which it is best known, he said. And in patients with darker skin tones, it is characterized by more of a brown or black color, rather than the pink-red color.

Dr. Friedman said that despite a kind of “Pavlovian response” linking GA with diabetes, this link might not be as strong as the field has come to believe, since the studies on which this belief was based included a patient population with narrow demographics. “Maybe GA and type 1 diabetes aren’t necessarily connected,” he said.

Dyslipidemia, on the other hand, has a strong connection with GA, he said. The disease is also linked to thyroid disease and is linked with malignancy, especially in older patients with generalized or atypical presentations of GA, he said.

Spontaneous resolution of the disease is seen within 2 years for 50% to 75% of patients, so “no treatment may be the best treatment,” but antimalarials can be effective, Dr. Friedman said. “I use antimalarials frequently in my practice,” he said. “The key is, they take time to work (4-5 months),” which should be explained to patients.

Antibiotics, he said, can be “somewhat effective,” but in the case of doxycycline at least, the disease can resolve within weeks but then may return when treatment is stopped.

There is some evidence to support using biologics and more recently, Janus kinase (JAK) inhibitors, off-label, to treat GA. Efficacy has been seen with the tumor necrosis factor (TNF) blocker infliximab and with the JAK inhibitor tofacitinib, he said.

 Lichen planus (LP). This is another common disease that can go off-script with its presentation. The disease is often described with the “six P’s” indicating the following characteristics: pruritic, polygonal, planar or flat-topped, purple papules, and plaques. But LP “didn’t read the textbook,” Dr. Friedman said.

“The clinical presentation of lichen planus can be quite broad,” he said. “The P’s aren’t always followed as there are a variety of colors and configurations which can be witnessed.”

With LP, there is a clear association with dyslipidemia and diabetes, so “asking the right questions is going to be important” when talking to the patient. There is also a higher risk of autoimmune diseases, especially of the thyroid type, associated with LP, he said.

No treatment has been Food and Drug Administration approved for LP, but some are expected in the future, he said.

For now, he emphasized creativity in the management of patients with LP. “I love oral retinoids for this,” he said. Antimalarials and methotrexate are also options.

In one case Dr. Friedman saw, nothing seemed to work: light therapy for a year; metronidazole; isotretinoin; halobetasol/tazarotene lotion; and the TNF-blocker adalimumab either weren’t effective or resulted in complications in the patient.

Knowing the recent implication of the interleukin (IL)-17 pathway in the pathophysiology of LP, he then tried the anti-IL17 antibody secukinumab. “This patient had a pretty robust response to treatment,” Dr. Friedman said. “He was very excited. The problem, as always, is access, especially for off-label therapies.”

Tumid lupus erythematosus. This disease is characterized by erythematous, edematous, nonscarring plaques on sun-exposed sites. For treatment, Dr. Friedman said antimalarials can be up to 90% effective, sometimes with rapid resolution of the lesions.

“You want to dose below that 5 mg per kg of true body weight to limit the small potential for ocular toxicity over time,” he said. And, he emphasized, “always combine treatment with good sun-protective measures.”

Dr. Friedman reported financial relationships with Sanova, Pfizer, Novartis, and other companies.

ORLANDO – While less frequently seen dermatologic diseases do not get a “ton of attention” in expert talks and discussions, even one to two patients presenting with these conditions a month warrants continuing education, according to Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington.

These semi-forsaken diseases are important not to miss and can “also be quite challenging when we think about their management,” he said at the ODAC Dermatology, Aesthetic & Surgical Conference.

Dr. Friedman, also director of the GW dermatology residency program, reviewed several of these diseases – along with tips for management – during a session at the meeting.

Granuloma annulare (GA). This condition, Dr. Friedman said, can have “a lot of faces” – with a localized, general, perforating, subcutaneous, micropapular, or patchy appearance. It does not always have the classic ring pattern for which it is best known, he said. And in patients with darker skin tones, it is characterized by more of a brown or black color, rather than the pink-red color.

Dr. Friedman said that despite a kind of “Pavlovian response” linking GA with diabetes, this link might not be as strong as the field has come to believe, since the studies on which this belief was based included a patient population with narrow demographics. “Maybe GA and type 1 diabetes aren’t necessarily connected,” he said.

Dyslipidemia, on the other hand, has a strong connection with GA, he said. The disease is also linked to thyroid disease and is linked with malignancy, especially in older patients with generalized or atypical presentations of GA, he said.

Spontaneous resolution of the disease is seen within 2 years for 50% to 75% of patients, so “no treatment may be the best treatment,” but antimalarials can be effective, Dr. Friedman said. “I use antimalarials frequently in my practice,” he said. “The key is, they take time to work (4-5 months),” which should be explained to patients.

Antibiotics, he said, can be “somewhat effective,” but in the case of doxycycline at least, the disease can resolve within weeks but then may return when treatment is stopped.

There is some evidence to support using biologics and more recently, Janus kinase (JAK) inhibitors, off-label, to treat GA. Efficacy has been seen with the tumor necrosis factor (TNF) blocker infliximab and with the JAK inhibitor tofacitinib, he said.

 Lichen planus (LP). This is another common disease that can go off-script with its presentation. The disease is often described with the “six P’s” indicating the following characteristics: pruritic, polygonal, planar or flat-topped, purple papules, and plaques. But LP “didn’t read the textbook,” Dr. Friedman said.

“The clinical presentation of lichen planus can be quite broad,” he said. “The P’s aren’t always followed as there are a variety of colors and configurations which can be witnessed.”

With LP, there is a clear association with dyslipidemia and diabetes, so “asking the right questions is going to be important” when talking to the patient. There is also a higher risk of autoimmune diseases, especially of the thyroid type, associated with LP, he said.

No treatment has been Food and Drug Administration approved for LP, but some are expected in the future, he said.

For now, he emphasized creativity in the management of patients with LP. “I love oral retinoids for this,” he said. Antimalarials and methotrexate are also options.

In one case Dr. Friedman saw, nothing seemed to work: light therapy for a year; metronidazole; isotretinoin; halobetasol/tazarotene lotion; and the TNF-blocker adalimumab either weren’t effective or resulted in complications in the patient.

Knowing the recent implication of the interleukin (IL)-17 pathway in the pathophysiology of LP, he then tried the anti-IL17 antibody secukinumab. “This patient had a pretty robust response to treatment,” Dr. Friedman said. “He was very excited. The problem, as always, is access, especially for off-label therapies.”

Tumid lupus erythematosus. This disease is characterized by erythematous, edematous, nonscarring plaques on sun-exposed sites. For treatment, Dr. Friedman said antimalarials can be up to 90% effective, sometimes with rapid resolution of the lesions.

“You want to dose below that 5 mg per kg of true body weight to limit the small potential for ocular toxicity over time,” he said. And, he emphasized, “always combine treatment with good sun-protective measures.”

Dr. Friedman reported financial relationships with Sanova, Pfizer, Novartis, and other companies.

A recently discovered inflammatory disease known as VEXAS syndrome is more common, variable, and dangerous than previously understood, according to results of a retrospective observational study of a large health care system database. The findings, published in JAMA, found that it struck 1 in 4,269 men over the age of 50 in a largely White population and caused a wide variety of symptoms.

“The disease is quite severe,” study lead author David Beck, MD, PhD, of the department of medicine at NYU Langone Health, said in an interview. Patients with the condition “have a variety of clinical symptoms affecting different parts of the body and are being managed by different medical specialties.”

Dr. Beck and colleagues first described VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome in 2020. They linked it to mutations in the UBA1 (ubiquitin-like modifier activating enzyme 1) gene. The enzyme initiates a process that identifies misfolded proteins as targets for degradation.

“VEXAS syndrome is characterized by anemia and inflammation in the skin, lungs, cartilage, and joints,” Dr. Beck said. “These symptoms are frequently mistaken for other rheumatic or hematologic diseases. However, this syndrome has a different cause, is treated differently, requires additional monitoring, and can be far more severe.”

According to him, hundreds of people have been diagnosed with the disease in the short time since it was defined. The disease is believed to be fatal in some cases. A previous report found that the median survival was 9 years among patients with a certain variant; that was significantly less than patients with two other variants.

For the new study, researchers searched for UBA1 variants in genetic data from 163,096 subjects (mean age, 52.8 years; 94% White, 61% women) who took part in the Geisinger MyCode Community Health Initiative. The 1996-2022 data comes from patients at 10 Pennsylvania hospitals.

Eleven people (9 males, 2 females) had likely UBA1 variants, and all had anemia. The cases accounted for 1 in 13,591 unrelated people (95% confidence interval, 1:7,775-1:23,758), 1 in 4,269 men older than 50 years (95% CI, 1:2,319-1:7,859), and 1 in 26,238 women older than 50 years (95% CI, 1:7,196-1:147,669).

Other common findings included macrocytosis (91%), skin problems (73%), and pulmonary disease (91%). Ten patients (91%) required transfusions.

Five of the 11 subjects didn’t meet the previously defined criteria for VEXAS syndrome. None had been diagnosed with the condition, which is not surprising considering that it hadn’t been discovered and described until recently.

Just over half of the patients – 55% – had a clinical diagnosis that was previously linked to VEXAS syndrome. “This means that slightly less than half of the patients with VEXAS syndrome had no clear associated clinical diagnosis,” Dr. Beck said. “The lack of associated clinical diagnoses may be due to the variety of nonspecific clinical characteristics that span different subspecialities in VEXAS syndrome. VEXAS syndrome represents an example of a multisystem disease where patients and their symptoms may get lost in the shuffle.”

In the future, “professionals should look out for patients with unexplained inflammation – and some combination of hematologic, rheumatologic, pulmonary, and dermatologic clinical manifestations – that either don’t carry a clinical diagnosis or don’t respond to first-line therapies,” Dr. Beck said. “These patients will also frequently be anemic, have low platelet counts, elevated markers of inflammation in the blood, and be dependent on corticosteroids.”

Diagnosis can be made via genetic testing, but the study authors note that it “is not routinely offered on standard workup for myeloid neoplasms or immune dysregulation diagnostic panels.”

As for treatment, Dr. Beck said the disease “can be partially controlled by multiple different anticytokine therapies or biologics. However, in most cases, patients still need additional steroids and/or disease-modifying antirheumatic agents [DMARDs]. In addition, bone marrow transplantation has shown signs of being a highly effective therapy.”

The study authors say more research is needed to understand the disease’s prevalence in more diverse populations.

In an interview, Matthew J. Koster, MD, a rheumatologist at Mayo Clinic in Rochester, Minn., who’s studied the disease but didn’t take part in this research project, said the findings are valid and “highly important.

“The findings of this study highlight what many academic and quaternary referral centers were wondering: Is VEXAS really more common than we think, with patients hiding in plain sight? The answer is yes,” he said. “Currently, there are less than 400 cases reported in the literature of VEXAS, but large centers are diagnosing this condition with some frequency. For example, at Mayo Clinic in Rochester, we diagnose on average one new patient with VEXAS every 7-14 days and have diagnosed 60 in the past 18 months. A national collaborative group in France has diagnosed approximately 250 patients over that same time frame when pooling patients nationwide.”

The prevalence is high enough, he said, that “clinicians should consider that some of the patients with diseases that are not responding to treatment may in fact have VEXAS rather than ‘refractory’ relapsing polychondritis or ‘recalcitrant’ rheumatoid arthritis, etc.”

The National Institute of Health funded the study. Dr. Beck, the other authors, and Dr. Koster report no disclosures.

A recently discovered inflammatory disease known as VEXAS syndrome is more common, variable, and dangerous than previously understood, according to results of a retrospective observational study of a large health care system database. The findings, published in JAMA, found that it struck 1 in 4,269 men over the age of 50 in a largely White population and caused a wide variety of symptoms.

“The disease is quite severe,” study lead author David Beck, MD, PhD, of the department of medicine at NYU Langone Health, said in an interview. Patients with the condition “have a variety of clinical symptoms affecting different parts of the body and are being managed by different medical specialties.”

Dr. Beck and colleagues first described VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome in 2020. They linked it to mutations in the UBA1 (ubiquitin-like modifier activating enzyme 1) gene. The enzyme initiates a process that identifies misfolded proteins as targets for degradation.

“VEXAS syndrome is characterized by anemia and inflammation in the skin, lungs, cartilage, and joints,” Dr. Beck said. “These symptoms are frequently mistaken for other rheumatic or hematologic diseases. However, this syndrome has a different cause, is treated differently, requires additional monitoring, and can be far more severe.”

According to him, hundreds of people have been diagnosed with the disease in the short time since it was defined. The disease is believed to be fatal in some cases. A previous report found that the median survival was 9 years among patients with a certain variant; that was significantly less than patients with two other variants.

For the new study, researchers searched for UBA1 variants in genetic data from 163,096 subjects (mean age, 52.8 years; 94% White, 61% women) who took part in the Geisinger MyCode Community Health Initiative. The 1996-2022 data comes from patients at 10 Pennsylvania hospitals.

Eleven people (9 males, 2 females) had likely UBA1 variants, and all had anemia. The cases accounted for 1 in 13,591 unrelated people (95% confidence interval, 1:7,775-1:23,758), 1 in 4,269 men older than 50 years (95% CI, 1:2,319-1:7,859), and 1 in 26,238 women older than 50 years (95% CI, 1:7,196-1:147,669).

Other common findings included macrocytosis (91%), skin problems (73%), and pulmonary disease (91%). Ten patients (91%) required transfusions.

Five of the 11 subjects didn’t meet the previously defined criteria for VEXAS syndrome. None had been diagnosed with the condition, which is not surprising considering that it hadn’t been discovered and described until recently.

Just over half of the patients – 55% – had a clinical diagnosis that was previously linked to VEXAS syndrome. “This means that slightly less than half of the patients with VEXAS syndrome had no clear associated clinical diagnosis,” Dr. Beck said. “The lack of associated clinical diagnoses may be due to the variety of nonspecific clinical characteristics that span different subspecialities in VEXAS syndrome. VEXAS syndrome represents an example of a multisystem disease where patients and their symptoms may get lost in the shuffle.”

In the future, “professionals should look out for patients with unexplained inflammation – and some combination of hematologic, rheumatologic, pulmonary, and dermatologic clinical manifestations – that either don’t carry a clinical diagnosis or don’t respond to first-line therapies,” Dr. Beck said. “These patients will also frequently be anemic, have low platelet counts, elevated markers of inflammation in the blood, and be dependent on corticosteroids.”

Diagnosis can be made via genetic testing, but the study authors note that it “is not routinely offered on standard workup for myeloid neoplasms or immune dysregulation diagnostic panels.”

As for treatment, Dr. Beck said the disease “can be partially controlled by multiple different anticytokine therapies or biologics. However, in most cases, patients still need additional steroids and/or disease-modifying antirheumatic agents [DMARDs]. In addition, bone marrow transplantation has shown signs of being a highly effective therapy.”

The study authors say more research is needed to understand the disease’s prevalence in more diverse populations.

In an interview, Matthew J. Koster, MD, a rheumatologist at Mayo Clinic in Rochester, Minn., who’s studied the disease but didn’t take part in this research project, said the findings are valid and “highly important.

“The findings of this study highlight what many academic and quaternary referral centers were wondering: Is VEXAS really more common than we think, with patients hiding in plain sight? The answer is yes,” he said. “Currently, there are less than 400 cases reported in the literature of VEXAS, but large centers are diagnosing this condition with some frequency. For example, at Mayo Clinic in Rochester, we diagnose on average one new patient with VEXAS every 7-14 days and have diagnosed 60 in the past 18 months. A national collaborative group in France has diagnosed approximately 250 patients over that same time frame when pooling patients nationwide.”

The prevalence is high enough, he said, that “clinicians should consider that some of the patients with diseases that are not responding to treatment may in fact have VEXAS rather than ‘refractory’ relapsing polychondritis or ‘recalcitrant’ rheumatoid arthritis, etc.”

The National Institute of Health funded the study. Dr. Beck, the other authors, and Dr. Koster report no disclosures.

A recently discovered inflammatory disease known as VEXAS syndrome is more common, variable, and dangerous than previously understood, according to results of a retrospective observational study of a large health care system database. The findings, published in JAMA, found that it struck 1 in 4,269 men over the age of 50 in a largely White population and caused a wide variety of symptoms.

“The disease is quite severe,” study lead author David Beck, MD, PhD, of the department of medicine at NYU Langone Health, said in an interview. Patients with the condition “have a variety of clinical symptoms affecting different parts of the body and are being managed by different medical specialties.”

Dr. Beck and colleagues first described VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome in 2020. They linked it to mutations in the UBA1 (ubiquitin-like modifier activating enzyme 1) gene. The enzyme initiates a process that identifies misfolded proteins as targets for degradation.

“VEXAS syndrome is characterized by anemia and inflammation in the skin, lungs, cartilage, and joints,” Dr. Beck said. “These symptoms are frequently mistaken for other rheumatic or hematologic diseases. However, this syndrome has a different cause, is treated differently, requires additional monitoring, and can be far more severe.”

According to him, hundreds of people have been diagnosed with the disease in the short time since it was defined. The disease is believed to be fatal in some cases. A previous report found that the median survival was 9 years among patients with a certain variant; that was significantly less than patients with two other variants.

For the new study, researchers searched for UBA1 variants in genetic data from 163,096 subjects (mean age, 52.8 years; 94% White, 61% women) who took part in the Geisinger MyCode Community Health Initiative. The 1996-2022 data comes from patients at 10 Pennsylvania hospitals.

Eleven people (9 males, 2 females) had likely UBA1 variants, and all had anemia. The cases accounted for 1 in 13,591 unrelated people (95% confidence interval, 1:7,775-1:23,758), 1 in 4,269 men older than 50 years (95% CI, 1:2,319-1:7,859), and 1 in 26,238 women older than 50 years (95% CI, 1:7,196-1:147,669).

Other common findings included macrocytosis (91%), skin problems (73%), and pulmonary disease (91%). Ten patients (91%) required transfusions.

Five of the 11 subjects didn’t meet the previously defined criteria for VEXAS syndrome. None had been diagnosed with the condition, which is not surprising considering that it hadn’t been discovered and described until recently.

Just over half of the patients – 55% – had a clinical diagnosis that was previously linked to VEXAS syndrome. “This means that slightly less than half of the patients with VEXAS syndrome had no clear associated clinical diagnosis,” Dr. Beck said. “The lack of associated clinical diagnoses may be due to the variety of nonspecific clinical characteristics that span different subspecialities in VEXAS syndrome. VEXAS syndrome represents an example of a multisystem disease where patients and their symptoms may get lost in the shuffle.”

In the future, “professionals should look out for patients with unexplained inflammation – and some combination of hematologic, rheumatologic, pulmonary, and dermatologic clinical manifestations – that either don’t carry a clinical diagnosis or don’t respond to first-line therapies,” Dr. Beck said. “These patients will also frequently be anemic, have low platelet counts, elevated markers of inflammation in the blood, and be dependent on corticosteroids.”

Diagnosis can be made via genetic testing, but the study authors note that it “is not routinely offered on standard workup for myeloid neoplasms or immune dysregulation diagnostic panels.”

As for treatment, Dr. Beck said the disease “can be partially controlled by multiple different anticytokine therapies or biologics. However, in most cases, patients still need additional steroids and/or disease-modifying antirheumatic agents [DMARDs]. In addition, bone marrow transplantation has shown signs of being a highly effective therapy.”

The study authors say more research is needed to understand the disease’s prevalence in more diverse populations.

In an interview, Matthew J. Koster, MD, a rheumatologist at Mayo Clinic in Rochester, Minn., who’s studied the disease but didn’t take part in this research project, said the findings are valid and “highly important.

“The findings of this study highlight what many academic and quaternary referral centers were wondering: Is VEXAS really more common than we think, with patients hiding in plain sight? The answer is yes,” he said. “Currently, there are less than 400 cases reported in the literature of VEXAS, but large centers are diagnosing this condition with some frequency. For example, at Mayo Clinic in Rochester, we diagnose on average one new patient with VEXAS every 7-14 days and have diagnosed 60 in the past 18 months. A national collaborative group in France has diagnosed approximately 250 patients over that same time frame when pooling patients nationwide.”

The prevalence is high enough, he said, that “clinicians should consider that some of the patients with diseases that are not responding to treatment may in fact have VEXAS rather than ‘refractory’ relapsing polychondritis or ‘recalcitrant’ rheumatoid arthritis, etc.”

The National Institute of Health funded the study. Dr. Beck, the other authors, and Dr. Koster report no disclosures.

Systemic mastocytosis is widely underdiagnosed, and many more hematologic oncologists should be looking for it. This call to action was issued late in 2022 by Stanford (Calif.) Cancer Institute’s Jason Gotlib, MD, speaking at the Lymphoma, Leukemia & Myeloma Congress in New York.

Nationwide, approximately 1,000 adults are diagnosed with systemic mastocytosis annually. This rare disease is a myeloid neoplasm with a highly variable phenotypic expression, in which abnormal mast cells proliferate and infiltrate organs and tissues. It swings widely from a nonadvanced form, composed of indolent or smoldering disease, to advanced disease that progresses to leukemia in 6% of cases.

More than 80% of systemic mastocytosis is driven by the KIT D816V mutation. Along with a host of other rare KIT mutations, KIT D816V activates KIT-receptor tyrosine kinase to trigger mast cell proliferation.

Dr. Gotlib could not be contacted for an interview. However, there are many good reasons to identify patients with systemic mastocytosis, according to Attilio Orazi, MD, professor and chair of the department of pathology at Texas Tech University, El Paso. The chief reason is that the patient may be in grave peril.

“The degree of heterogeneity is amazing. ... There’s very indolent [disease], which is really not a big deal. And then you have a disease in which you’re dead in 3 months,” Dr. Orazi said. “So you run the gamut between an indolent, no-problem cutaneous disease to a very nasty systemic, aggressive leukemia-like neoplasm.”

Since 2001, the diagnosis of mastocytosis has been guided by the World Health Organization Classification of Tumours, or “Blue Book.” In 2022, Dr. Orazi along with 137 other senior experts, most of whom were involved in past editions of the Blue Book, published their own version: The International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (the ICC 2022).

In September 2021, this group of specialists held a virtual/in-person advisory committee meeting at the University of Chicago to create the document. One factor in their decision to go it alone, Dr. Orazi said, was that WHO decided to proceed with the fifth edition of the Blue Book using its own internal editorial group without convening an advisory committee, despite repeated requests to do so.

ICC 2022 divides advanced systemic mastocytosis into three subtypes: aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Median survival is 3.5 years for patients with ASM, 2 years for those with SM-AHN and as low as 2 months for MCL.

The second key reason to increase awareness of mastocytosis among physicians, said Dr. Orazi, is that patients falling through the net are likely to be ambulatory, and their presentation can be “a little confusing.”

Patients with indolent disease are relatively straightforward to recognize, explained Dr. Orazi. Similarly, very sick patients with SM-AHN or MCL are easily recognized by hem-oncs.

“But if you see a patient in an ambulatory setting, in your clinic or whatever, and you’re suspicious, then you need to decide [how] you’re going to investigate that patient further,” he said, Dr. Orazi noted the next step is not always obvious, especially for primary-practice or internal medicine physicians likely to be unfamiliar with such a rare disease.

A practice survey published in 2022 by other researchers backed up Dr. Orazi’s remarks. The study found that community/solo-practice physicians were less likely to have tested systemic mastocytosis patients for KIT816V mutation than academic/specialty physicians (58% vs. 80%; P = .004; n = 111). Clinicians treating these patients estimated that it took an average of 8.5 months for a “typical” patient to receive the diagnosis from the time of symptom onset.

The research was headed by Ruben Mesa, MD, director of University of Texas Health, San Antonio, and funded by Blueprint Medicines, the manufacturer of avapritinib (Ayvakit), a new drug for the disease.

Dr. Orazi urged clinicians to have a high degree of suspicion for mastocytosis in a patient who walks into the clinic with any combination of the following: urticarial-type skin manifestations, especially if persistent into adulthood; history of undue reaction to an insect sting; a big spleen in a patient with a history of cutaneous flushing or rash; chronic diarrhea, especially if a biopsy has shown “too many mast cells” in the lamina propria of the small bowel; and positivity for KIT816V mutation.

Dr. Orazi stressed that the majority of patients will have indolent disease, but for the few patients for whom immediate treatment is essential, “the distinction between indolent and aggressive [disease] is really very, very important.”

Patients with advanced systemic mastocytosis can now be effectively treated, following the arrival of midostaurin (Rydapt, Tauritmo) and avapritinib.

Midostaurin, a multikinase/KIT inhibitor, was approved by the Food and Drug Administration in 2017 for the treatment of advanced systemic mastocytosis (ASM, SM-AHN, and MCL). Avapritinib, a selective kinase inhibitor of KIT816V and platelet-derived growth factor receptor alpha as well as multiple KIT exon 11, 11/17 and 17 mutants, gained the same indication in June 2021.

As with all rare diseases, it is challenging to obtain accurate numbers on how many patients are affected by systemic mastocytosis. The first population-based study of the disorder, presented at the 2018 annual meeting of the American Society of Hematology, used the Surveillance, Epidemiology, and End Results database from 2000 to 2014 to estimate incidence at 0.046 per 10,000, which translates to 1,050 new adult cases per year. The study data have never been published in full.

How many of these cases are advanced disease? There are no U.S. data but extrapolating from a Danish registry study that found 82% of systemic mastocytosis cases to be indolent disease, the incidence of advanced systemic mastocytosis in the United States could be as low as 200 adults a year.

This information, in turn, suggests that identifying more patients with advanced disease would not only benefit those patients but would also benefit clinical trial investigators who are seeking the proverbial needle in the haystack.

Nationwide, five clinical trials are recruiting individuals with advanced systemic mastocytosis, collectively looking for 352 patients in the United States. Two of the studies focus on mast-cell activation (NCT0544944) and cutaneous mastocytoses (NCT04846348). Two trials in a range of hematological malignancies are testing bispecific antibodies flotetuzumab and MGD024 (both from Macrogenics; NCT04681105, NCT05362773).

Apex, a phase 2 study of tyrosine-kinase inhibitor bezuclastinib (a Cogent hopeful), is specifically focusing on advanced disease. Dr. Gotlib and coinvestigators are aiming for 140 participants.

As a pathologist, Dr. Orazi said he find mastocytosis fascinating because he believes he has “a truly useful role,” contrasting with some other hematological diseases in which the molecular profile rules.

“Pathology plays a major role here,” he explained, “because you have to correlate what you see at the microscope with the full clinical picture, selected laboratory tests such as CBC and serum tryptase, and molecular results. You often need integration through a pathologist to put all the pieces together.

“It’s easier to treat once you know exactly what disease you’re dealing with and whether it is an aggressive or indolent subtype,” Dr. Orazi concluded.

Dr. Orazi disclosed no conflicts of interest. Dr. Gotlib has disclosed ties with Blueprint Medicines, Deciphera, Incyte, and Kartos Therapeutics, and has led committees for Blueprint Medicine’s EXPLORER and PATHFINDER studies, Deciphera’s Study Steering Committee for ripretinib in AdvSM, and the Central Response Review Committee for the phase 2 study of bezuclastinib in AdvSM.

Systemic mastocytosis is widely underdiagnosed, and many more hematologic oncologists should be looking for it. This call to action was issued late in 2022 by Stanford (Calif.) Cancer Institute’s Jason Gotlib, MD, speaking at the Lymphoma, Leukemia & Myeloma Congress in New York.

Nationwide, approximately 1,000 adults are diagnosed with systemic mastocytosis annually. This rare disease is a myeloid neoplasm with a highly variable phenotypic expression, in which abnormal mast cells proliferate and infiltrate organs and tissues. It swings widely from a nonadvanced form, composed of indolent or smoldering disease, to advanced disease that progresses to leukemia in 6% of cases.

More than 80% of systemic mastocytosis is driven by the KIT D816V mutation. Along with a host of other rare KIT mutations, KIT D816V activates KIT-receptor tyrosine kinase to trigger mast cell proliferation.

Dr. Gotlib could not be contacted for an interview. However, there are many good reasons to identify patients with systemic mastocytosis, according to Attilio Orazi, MD, professor and chair of the department of pathology at Texas Tech University, El Paso. The chief reason is that the patient may be in grave peril.

“The degree of heterogeneity is amazing. ... There’s very indolent [disease], which is really not a big deal. And then you have a disease in which you’re dead in 3 months,” Dr. Orazi said. “So you run the gamut between an indolent, no-problem cutaneous disease to a very nasty systemic, aggressive leukemia-like neoplasm.”

Since 2001, the diagnosis of mastocytosis has been guided by the World Health Organization Classification of Tumours, or “Blue Book.” In 2022, Dr. Orazi along with 137 other senior experts, most of whom were involved in past editions of the Blue Book, published their own version: The International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (the ICC 2022).

In September 2021, this group of specialists held a virtual/in-person advisory committee meeting at the University of Chicago to create the document. One factor in their decision to go it alone, Dr. Orazi said, was that WHO decided to proceed with the fifth edition of the Blue Book using its own internal editorial group without convening an advisory committee, despite repeated requests to do so.

ICC 2022 divides advanced systemic mastocytosis into three subtypes: aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Median survival is 3.5 years for patients with ASM, 2 years for those with SM-AHN and as low as 2 months for MCL.

The second key reason to increase awareness of mastocytosis among physicians, said Dr. Orazi, is that patients falling through the net are likely to be ambulatory, and their presentation can be “a little confusing.”

Patients with indolent disease are relatively straightforward to recognize, explained Dr. Orazi. Similarly, very sick patients with SM-AHN or MCL are easily recognized by hem-oncs.

“But if you see a patient in an ambulatory setting, in your clinic or whatever, and you’re suspicious, then you need to decide [how] you’re going to investigate that patient further,” he said, Dr. Orazi noted the next step is not always obvious, especially for primary-practice or internal medicine physicians likely to be unfamiliar with such a rare disease.

A practice survey published in 2022 by other researchers backed up Dr. Orazi’s remarks. The study found that community/solo-practice physicians were less likely to have tested systemic mastocytosis patients for KIT816V mutation than academic/specialty physicians (58% vs. 80%; P = .004; n = 111). Clinicians treating these patients estimated that it took an average of 8.5 months for a “typical” patient to receive the diagnosis from the time of symptom onset.

The research was headed by Ruben Mesa, MD, director of University of Texas Health, San Antonio, and funded by Blueprint Medicines, the manufacturer of avapritinib (Ayvakit), a new drug for the disease.

Dr. Orazi urged clinicians to have a high degree of suspicion for mastocytosis in a patient who walks into the clinic with any combination of the following: urticarial-type skin manifestations, especially if persistent into adulthood; history of undue reaction to an insect sting; a big spleen in a patient with a history of cutaneous flushing or rash; chronic diarrhea, especially if a biopsy has shown “too many mast cells” in the lamina propria of the small bowel; and positivity for KIT816V mutation.

Dr. Orazi stressed that the majority of patients will have indolent disease, but for the few patients for whom immediate treatment is essential, “the distinction between indolent and aggressive [disease] is really very, very important.”

Patients with advanced systemic mastocytosis can now be effectively treated, following the arrival of midostaurin (Rydapt, Tauritmo) and avapritinib.

Midostaurin, a multikinase/KIT inhibitor, was approved by the Food and Drug Administration in 2017 for the treatment of advanced systemic mastocytosis (ASM, SM-AHN, and MCL). Avapritinib, a selective kinase inhibitor of KIT816V and platelet-derived growth factor receptor alpha as well as multiple KIT exon 11, 11/17 and 17 mutants, gained the same indication in June 2021.

As with all rare diseases, it is challenging to obtain accurate numbers on how many patients are affected by systemic mastocytosis. The first population-based study of the disorder, presented at the 2018 annual meeting of the American Society of Hematology, used the Surveillance, Epidemiology, and End Results database from 2000 to 2014 to estimate incidence at 0.046 per 10,000, which translates to 1,050 new adult cases per year. The study data have never been published in full.

How many of these cases are advanced disease? There are no U.S. data but extrapolating from a Danish registry study that found 82% of systemic mastocytosis cases to be indolent disease, the incidence of advanced systemic mastocytosis in the United States could be as low as 200 adults a year.

This information, in turn, suggests that identifying more patients with advanced disease would not only benefit those patients but would also benefit clinical trial investigators who are seeking the proverbial needle in the haystack.

Nationwide, five clinical trials are recruiting individuals with advanced systemic mastocytosis, collectively looking for 352 patients in the United States. Two of the studies focus on mast-cell activation (NCT0544944) and cutaneous mastocytoses (NCT04846348). Two trials in a range of hematological malignancies are testing bispecific antibodies flotetuzumab and MGD024 (both from Macrogenics; NCT04681105, NCT05362773).

Apex, a phase 2 study of tyrosine-kinase inhibitor bezuclastinib (a Cogent hopeful), is specifically focusing on advanced disease. Dr. Gotlib and coinvestigators are aiming for 140 participants.

As a pathologist, Dr. Orazi said he find mastocytosis fascinating because he believes he has “a truly useful role,” contrasting with some other hematological diseases in which the molecular profile rules.

“Pathology plays a major role here,” he explained, “because you have to correlate what you see at the microscope with the full clinical picture, selected laboratory tests such as CBC and serum tryptase, and molecular results. You often need integration through a pathologist to put all the pieces together.

“It’s easier to treat once you know exactly what disease you’re dealing with and whether it is an aggressive or indolent subtype,” Dr. Orazi concluded.

Dr. Orazi disclosed no conflicts of interest. Dr. Gotlib has disclosed ties with Blueprint Medicines, Deciphera, Incyte, and Kartos Therapeutics, and has led committees for Blueprint Medicine’s EXPLORER and PATHFINDER studies, Deciphera’s Study Steering Committee for ripretinib in AdvSM, and the Central Response Review Committee for the phase 2 study of bezuclastinib in AdvSM.

Systemic mastocytosis is widely underdiagnosed, and many more hematologic oncologists should be looking for it. This call to action was issued late in 2022 by Stanford (Calif.) Cancer Institute’s Jason Gotlib, MD, speaking at the Lymphoma, Leukemia & Myeloma Congress in New York.

Nationwide, approximately 1,000 adults are diagnosed with systemic mastocytosis annually. This rare disease is a myeloid neoplasm with a highly variable phenotypic expression, in which abnormal mast cells proliferate and infiltrate organs and tissues. It swings widely from a nonadvanced form, composed of indolent or smoldering disease, to advanced disease that progresses to leukemia in 6% of cases.

More than 80% of systemic mastocytosis is driven by the KIT D816V mutation. Along with a host of other rare KIT mutations, KIT D816V activates KIT-receptor tyrosine kinase to trigger mast cell proliferation.

Dr. Gotlib could not be contacted for an interview. However, there are many good reasons to identify patients with systemic mastocytosis, according to Attilio Orazi, MD, professor and chair of the department of pathology at Texas Tech University, El Paso. The chief reason is that the patient may be in grave peril.

“The degree of heterogeneity is amazing. ... There’s very indolent [disease], which is really not a big deal. And then you have a disease in which you’re dead in 3 months,” Dr. Orazi said. “So you run the gamut between an indolent, no-problem cutaneous disease to a very nasty systemic, aggressive leukemia-like neoplasm.”

Since 2001, the diagnosis of mastocytosis has been guided by the World Health Organization Classification of Tumours, or “Blue Book.” In 2022, Dr. Orazi along with 137 other senior experts, most of whom were involved in past editions of the Blue Book, published their own version: The International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (the ICC 2022).

In September 2021, this group of specialists held a virtual/in-person advisory committee meeting at the University of Chicago to create the document. One factor in their decision to go it alone, Dr. Orazi said, was that WHO decided to proceed with the fifth edition of the Blue Book using its own internal editorial group without convening an advisory committee, despite repeated requests to do so.

ICC 2022 divides advanced systemic mastocytosis into three subtypes: aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Median survival is 3.5 years for patients with ASM, 2 years for those with SM-AHN and as low as 2 months for MCL.

The second key reason to increase awareness of mastocytosis among physicians, said Dr. Orazi, is that patients falling through the net are likely to be ambulatory, and their presentation can be “a little confusing.”

Patients with indolent disease are relatively straightforward to recognize, explained Dr. Orazi. Similarly, very sick patients with SM-AHN or MCL are easily recognized by hem-oncs.

“But if you see a patient in an ambulatory setting, in your clinic or whatever, and you’re suspicious, then you need to decide [how] you’re going to investigate that patient further,” he said, Dr. Orazi noted the next step is not always obvious, especially for primary-practice or internal medicine physicians likely to be unfamiliar with such a rare disease.

A practice survey published in 2022 by other researchers backed up Dr. Orazi’s remarks. The study found that community/solo-practice physicians were less likely to have tested systemic mastocytosis patients for KIT816V mutation than academic/specialty physicians (58% vs. 80%; P = .004; n = 111). Clinicians treating these patients estimated that it took an average of 8.5 months for a “typical” patient to receive the diagnosis from the time of symptom onset.

The research was headed by Ruben Mesa, MD, director of University of Texas Health, San Antonio, and funded by Blueprint Medicines, the manufacturer of avapritinib (Ayvakit), a new drug for the disease.

Dr. Orazi urged clinicians to have a high degree of suspicion for mastocytosis in a patient who walks into the clinic with any combination of the following: urticarial-type skin manifestations, especially if persistent into adulthood; history of undue reaction to an insect sting; a big spleen in a patient with a history of cutaneous flushing or rash; chronic diarrhea, especially if a biopsy has shown “too many mast cells” in the lamina propria of the small bowel; and positivity for KIT816V mutation.

Dr. Orazi stressed that the majority of patients will have indolent disease, but for the few patients for whom immediate treatment is essential, “the distinction between indolent and aggressive [disease] is really very, very important.”

Patients with advanced systemic mastocytosis can now be effectively treated, following the arrival of midostaurin (Rydapt, Tauritmo) and avapritinib.

Midostaurin, a multikinase/KIT inhibitor, was approved by the Food and Drug Administration in 2017 for the treatment of advanced systemic mastocytosis (ASM, SM-AHN, and MCL). Avapritinib, a selective kinase inhibitor of KIT816V and platelet-derived growth factor receptor alpha as well as multiple KIT exon 11, 11/17 and 17 mutants, gained the same indication in June 2021.

As with all rare diseases, it is challenging to obtain accurate numbers on how many patients are affected by systemic mastocytosis. The first population-based study of the disorder, presented at the 2018 annual meeting of the American Society of Hematology, used the Surveillance, Epidemiology, and End Results database from 2000 to 2014 to estimate incidence at 0.046 per 10,000, which translates to 1,050 new adult cases per year. The study data have never been published in full.

How many of these cases are advanced disease? There are no U.S. data but extrapolating from a Danish registry study that found 82% of systemic mastocytosis cases to be indolent disease, the incidence of advanced systemic mastocytosis in the United States could be as low as 200 adults a year.

This information, in turn, suggests that identifying more patients with advanced disease would not only benefit those patients but would also benefit clinical trial investigators who are seeking the proverbial needle in the haystack.

Nationwide, five clinical trials are recruiting individuals with advanced systemic mastocytosis, collectively looking for 352 patients in the United States. Two of the studies focus on mast-cell activation (NCT0544944) and cutaneous mastocytoses (NCT04846348). Two trials in a range of hematological malignancies are testing bispecific antibodies flotetuzumab and MGD024 (both from Macrogenics; NCT04681105, NCT05362773).

Apex, a phase 2 study of tyrosine-kinase inhibitor bezuclastinib (a Cogent hopeful), is specifically focusing on advanced disease. Dr. Gotlib and coinvestigators are aiming for 140 participants.

As a pathologist, Dr. Orazi said he find mastocytosis fascinating because he believes he has “a truly useful role,” contrasting with some other hematological diseases in which the molecular profile rules.

“Pathology plays a major role here,” he explained, “because you have to correlate what you see at the microscope with the full clinical picture, selected laboratory tests such as CBC and serum tryptase, and molecular results. You often need integration through a pathologist to put all the pieces together.

“It’s easier to treat once you know exactly what disease you’re dealing with and whether it is an aggressive or indolent subtype,” Dr. Orazi concluded.

Dr. Orazi disclosed no conflicts of interest. Dr. Gotlib has disclosed ties with Blueprint Medicines, Deciphera, Incyte, and Kartos Therapeutics, and has led committees for Blueprint Medicine’s EXPLORER and PATHFINDER studies, Deciphera’s Study Steering Committee for ripretinib in AdvSM, and the Central Response Review Committee for the phase 2 study of bezuclastinib in AdvSM.

When I was a resident (back in the Cretaceous era), the idea of autoimmune encephalitis was just beginning to take hold. It was kind of like Bigfoot. A few reports, vague articles, the occasional sighting of what may or may not be a case. …

Unlike Bigfoot, however, the evidence quickly added up until there was no question that such a disorder existed. Then disorder became disorders, and now it seems a few more types are added to the list each year.

This doesn’t change the fact that they’re still, in the grand scheme of general neurology, relatively rare, though no one questions that they exist.

Today people still wishfully take pictures of Bigfoot, but they turn out to be images of bears or other animals, or tricks of light and shadow.

This is an issue with human thought. Many times we see what we want to see, especially if it’s more interesting than a mundane alternative.

An autoimmune encephalitis article in the January 2023 issue of JAMA Neurology looked into this. On reviewing 393 patients diagnosed with the disorder, the researchers found that 27% of them actually didn’t have it at all. Such things as functional disorders, neurodegenerative diseases, and primary psychiatric diagnoses were, instead, the culprits.

I’m not criticizing those who made an incorrect diagnosis. We all do. That’s the nature of medicine.

Which is worse? Missing the diagnosis entirely and not treating, or diagnosing a patient with something else and treating incorrectly? I guess it depends on the disease and nature of treatment.

Certainly, finding a case of autoimmune encephalitis is more interesting than, say toxic-metabolic encephalopathy from a bladder infection, just as getting a picture of Bigfoot is way more cool than one of a bear with mange.

But we need to be careful when faced with equivocal labs and data lest we read too much into them. There are too many gray zones in medicine to lead you astray. Not to say we won’t be. Even well-intentioned physicians (which I assume is pretty much all of us) are going to make mistakes.

But it’s not just rare diseases. In the early 1990s two different studies found that 24% of patients diagnosed with Parkinson’s disease were found to have something else on autopsy.

That was 30 years ago. Now we have DaT scans to help. Maybe our abilities as neurologists have also gotten better (though I don’t think the neurological exam has changed much since Charcot).

Our gadgets, labs, and treatments get better every year. We have tools available to us now that were unthinkable a generation ago. For that matter, they were unthinkable when I began my career.

But they don’t change the fact that human error never goes away. All of us are susceptible to it, and all of us make mistakes.

Such is the way of medicine now, and likely always. All we can do is our best and keep moving forward.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

When I was a resident (back in the Cretaceous era), the idea of autoimmune encephalitis was just beginning to take hold. It was kind of like Bigfoot. A few reports, vague articles, the occasional sighting of what may or may not be a case. …

Unlike Bigfoot, however, the evidence quickly added up until there was no question that such a disorder existed. Then disorder became disorders, and now it seems a few more types are added to the list each year.

This doesn’t change the fact that they’re still, in the grand scheme of general neurology, relatively rare, though no one questions that they exist.

Today people still wishfully take pictures of Bigfoot, but they turn out to be images of bears or other animals, or tricks of light and shadow.

This is an issue with human thought. Many times we see what we want to see, especially if it’s more interesting than a mundane alternative.

An autoimmune encephalitis article in the January 2023 issue of JAMA Neurology looked into this. On reviewing 393 patients diagnosed with the disorder, the researchers found that 27% of them actually didn’t have it at all. Such things as functional disorders, neurodegenerative diseases, and primary psychiatric diagnoses were, instead, the culprits.

I’m not criticizing those who made an incorrect diagnosis. We all do. That’s the nature of medicine.

Which is worse? Missing the diagnosis entirely and not treating, or diagnosing a patient with something else and treating incorrectly? I guess it depends on the disease and nature of treatment.

Certainly, finding a case of autoimmune encephalitis is more interesting than, say toxic-metabolic encephalopathy from a bladder infection, just as getting a picture of Bigfoot is way more cool than one of a bear with mange.

But we need to be careful when faced with equivocal labs and data lest we read too much into them. There are too many gray zones in medicine to lead you astray. Not to say we won’t be. Even well-intentioned physicians (which I assume is pretty much all of us) are going to make mistakes.

But it’s not just rare diseases. In the early 1990s two different studies found that 24% of patients diagnosed with Parkinson’s disease were found to have something else on autopsy.

That was 30 years ago. Now we have DaT scans to help. Maybe our abilities as neurologists have also gotten better (though I don’t think the neurological exam has changed much since Charcot).

Our gadgets, labs, and treatments get better every year. We have tools available to us now that were unthinkable a generation ago. For that matter, they were unthinkable when I began my career.

But they don’t change the fact that human error never goes away. All of us are susceptible to it, and all of us make mistakes.

Such is the way of medicine now, and likely always. All we can do is our best and keep moving forward.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

When I was a resident (back in the Cretaceous era), the idea of autoimmune encephalitis was just beginning to take hold. It was kind of like Bigfoot. A few reports, vague articles, the occasional sighting of what may or may not be a case. …

Unlike Bigfoot, however, the evidence quickly added up until there was no question that such a disorder existed. Then disorder became disorders, and now it seems a few more types are added to the list each year.

This doesn’t change the fact that they’re still, in the grand scheme of general neurology, relatively rare, though no one questions that they exist.

Today people still wishfully take pictures of Bigfoot, but they turn out to be images of bears or other animals, or tricks of light and shadow.

This is an issue with human thought. Many times we see what we want to see, especially if it’s more interesting than a mundane alternative.

An autoimmune encephalitis article in the January 2023 issue of JAMA Neurology looked into this. On reviewing 393 patients diagnosed with the disorder, the researchers found that 27% of them actually didn’t have it at all. Such things as functional disorders, neurodegenerative diseases, and primary psychiatric diagnoses were, instead, the culprits.

I’m not criticizing those who made an incorrect diagnosis. We all do. That’s the nature of medicine.

Which is worse? Missing the diagnosis entirely and not treating, or diagnosing a patient with something else and treating incorrectly? I guess it depends on the disease and nature of treatment.

Certainly, finding a case of autoimmune encephalitis is more interesting than, say toxic-metabolic encephalopathy from a bladder infection, just as getting a picture of Bigfoot is way more cool than one of a bear with mange.

But we need to be careful when faced with equivocal labs and data lest we read too much into them. There are too many gray zones in medicine to lead you astray. Not to say we won’t be. Even well-intentioned physicians (which I assume is pretty much all of us) are going to make mistakes.

But it’s not just rare diseases. In the early 1990s two different studies found that 24% of patients diagnosed with Parkinson’s disease were found to have something else on autopsy.

That was 30 years ago. Now we have DaT scans to help. Maybe our abilities as neurologists have also gotten better (though I don’t think the neurological exam has changed much since Charcot).

Our gadgets, labs, and treatments get better every year. We have tools available to us now that were unthinkable a generation ago. For that matter, they were unthinkable when I began my career.

But they don’t change the fact that human error never goes away. All of us are susceptible to it, and all of us make mistakes.

Such is the way of medicine now, and likely always. All we can do is our best and keep moving forward.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Doug Flora, MD, knows the value of early cancer detection because it helped him survive kidney cancer 5 years ago. But as a medical oncologist and hematologist, and the executive medical director of oncology services at St. Elizabeth Healthcare in Edgewood, Ky., he also knows that a new era of early cancer detection testing poses big challenges for his network of six hospitals and 169 specialty and primary care offices throughout Kentucky, Ohio, and Indiana.

Multicancer early detection (MCED) tests are finally a reality and could be a potential game changer because they can screen for the possibility of up to 50 different cancers in asymptomatic individuals with one blood draw. They represent one of the fastest growing segments in medical diagnostics with a projected value of $2.77 billion by 2030, according to the market research firm Grand View Research.

These tests are different from traditional liquid biopsies, which are designed to identify actionable gene mutations to help inform treatment decisions of patients already diagnosed with cancer. Instead, MCED tests work to detect fragments of circulating free DNA that have been shed by tumors and released into the bloodstream. Detecting these cancer signals could indicate that an individual has cancer well before they ever develop symptoms.

For some cancer types, particularly those commonly diagnosed at advanced stages or those without general population screening tests, MCED testing could have a significant impact.

In its new report, Grand View Research highlights nine “prominent players” active in the MCED market; of these, two have been granted breakthrough device designation by the Food and Drug Administration: OverC MCDBT by Burning Rock on Jan. 3, 2023, and Galleri by Grail in 2019. Galleri was launched in June 2021 and can be obtained with a prescription at a cost of $949.

Yet, while patients are asking for these tests and primary care physicians are prescribing them, oncologists are grappling with how to manage the first patients whose tests tell them they may have cancer.

Ordering the tests may seem straightforward, but in reality, it is not. In fact, they are so new that most health systems have no internal guidelines for physicians. Guidelines would address when the tests should be prescribed, and whether a patient should undergo more testing or be referred to an oncologist.
 

Clinical trials underway

There are currently at least 17 clinical trials underway to investigate the performance and clinical utility of MCED tests. Six of these involve Grail, including NHS-Galleri, the largest study to date of 140,000 participants in the United Kingdom where participants will be followed for 3 years with annual visits at 12 and 24 months. And, the National Cancer Institute is spearheading a clinical trial of its own, according to a search of ClinicalTrials.gov.

In September 2022, Grail presented findings from its pivotal PATHFINDER study at the annual meeting of the European Society of Medical Oncology. Researchers reported that cancer signals were detected in 1.4% (92) of 6,621 participants enrolled in the study. Of the 92, 35 people were diagnosed with 36 cancers: 19 were solid tumors (2 oropharyngeal, 5 breast, l liver, 1 intrahepatic bile duct, 2 colon/rectum, 2 prostate, 1 lung, 1 pancreas, 1 small intestine, 1 uterus, 1 ovary and 1 bone) and 17 hematologic cancers (1 plasma cell myeloma/disorders, 2 lymphoid leukemia, 2 Waldenström’s macroglobulinemia, and 12 lymphoma).

Almost half of newly diagnosed cases were cancers in stage 1 or 2. Of stage 1 cancers, three were solid tumors and four were hematologic cancers. Of stage 2 cancers, three were solid tumors and four were hematologic cancers. All other cancers were in stage 3 and 4 or were listed as recurrent or no stage. Deb Schrag, MD, MPH, chair of the department of medicine at Memorial Sloan Kettering Cancer Center in New York, who presented the results from PATHFINDER at ESMO, reported that, of all diagnosed cancers, only breast, colon/rectum, prostate, and lung have established screening protocols.

The findings were so striking that the meeting scientific co-chair, Fabrice André, MD, PhD, told ESMO the oncology field must prepare for an onslaught of new patients.

“Within the next 5 years, we will need more doctors, surgeons and nurses with more diagnostic and treatment infrastructures to care for the rising number of people who will be identified by multicancer early detection tests,” said Dr. André, who is director of research at Gustave Roussy Cancer Center, Villejuif, France, and future president of ESMO (2025-2026). “We need to involve all stakeholders in deciding new pathways of care. We need to agree who will be tested and when and where tests will be carried out, and to anticipate the changes that will happen as a result of these tests.”

But first, he urged, the need for comparative trials “across all types of cancer to find out if having an early detection test affects morbidity and mortality. We also need to know how the tests benefit patients, and how to discuss the results with them,” Dr. André said.
 

Demand may burden health systems

Dr. Flora suggested that companies like Grail are rushing their product to market without conducting long-term sizable clinical trials.

“These diagnostic companies are a billion dollar publicly traded or venture capital-funded companies that are losing millions of dollars a quarter as they’re scaling up these tests. So, there is some pressure on the sales forces ... to start moving product long before the science has met our lowest areas for entry,” Dr. Flora said. “They are aggressively marketing to a primary care audience that knows nothing about MCEDs. It’s a sales-driven development solving a problem we all believe is real, but we don’t know if it actually solves the problem.”

There are many unanswered questions, he said. Among these include whether the tests do indeed extend survival. “What they’re suggesting – that is if the blood test detects it – that we’re going to save your life. That’s not yet been proven. This is where the providers are pushing back against these industry types to say: ‘This is the wild west right now.’ It’s very irresponsible to go out there and try to sell hundreds of millions of dollars of product to doctors who have never studied genetics,” Dr. Flora said.

Grail’s chief medical officer Jeff Venstrom, MD, however, said physicians don’t need a background in genetic testing to order or interpret Galleri because it’s not a genetic test. Genetic tests look for genetic variants associated with cancer risk, which Galleri does not. MCED tests rely on genomic profiling to identify alterations in tumors.

“Maybe there’s still confusion in the market, which is common for new technologies when they’re initially launched. This is not a 23andMe test. We do not report germline mutations that have implications for cancer risk. We’re using this blood sample to test for the presence or absence of a cancer signal. The test result is very clear and simple: One area of the report says ‘yes’ or ‘no.’ It is a binary result that says if a signal is detected or not. The second provides additional information around where that signal could be coming from,” he said.

Galleri could fill a huge unmet need in cancer prevention, Dr. Venstrom said. Not only could it detect cancer at an earlier stage, but it could serve as a screening tool for cancers like pancreatic cancer in which screening is not available.

The test is not intended to replace standard of care screening, he said. The ordering provider should have a conversation with the patient about overall cancer risk. “Are you smoking? What’s your risk of obesity-associated cancers? Do you have a family history of cancer? I think this should all be in the context of a good conversation around preventative care,” he said.
 

Planning and prep in Boston

In Boston, Aparna Parikh, MD, an oncologist who specializes in gastrointestinal cancers, agreed that MCED testing has forced her team at the Mass General Cancer Center global cancer care program to think outside of the box.

“We’re a major academic center and it’s not easy [because] this is all uncharted territory,” she said. “We all recognize there are more tests coming, and they are here to stay. As a health system, we have to be ready to manage not only the tests, but patient anxieties, and all the complexities that come with it. We just don’t know yet how to best navigate.”

Although Dr. Parikh’s center has set up a working group tasked with organizing an outpatient clinic for patients with positive MCED tests, the current system is haphazard.

“Right now, it gets bounced around between people,” she explained. “Sometimes, patients are getting referred to the oncology team rather than the primary care team to try to sort out where the cancer signal is coming from, that is, if it’s not immediately obvious. No one really knows who should be the right person to own it,” Dr. Parikh said. While the test is supposed to give tissue-specific results, “it’s not perfect” and sometimes imaging and other work-ups are needed to locate the source of the signa.

“A group of four or five oncologists get looped in and then we’re trying to sort it out on a case-by-case basis, but understanding that with more and more tests coming, that kind of ad hoc approach isn’t going to be sufficient. We need a happy medium between the primary care and the disease specific oncologist, someone who can kind of help think through the diagnostic workup until they have a cancer diagnosis to get them to the right place,” Dr. Parikh said.

Dr. Venstrom said Grail is committed to providing support to clinicians in these situations. “We’re doing everything we can with our medical education forums. We have this pretty intense and extensive postpositive suite of resources,” he explained. “Some of our doctors on staff call the ordering provider within 24 hours just to clarify if there are any questions or confusion from the report. For example, if it suggests the signal is coming from the lung, we provide additional support around additional workups.”
 

Out-of-pocket test may widen disparities in care

With the exception of a few health insurance companies that have committed to covering some of the cost for the test, Galleri is an out-of-pocket expense.

Dr. Venstrom acknowledged that broad insurance coverage for the Galleri test remains a hurdle, although “we’ve secured coverage for a handful of companies of self-insured employers and forward-thinking insurers.” This includes partnerships with Point32Health, and Alignment Health, among others, he said.

There is also growing support among more than 400 cancer organizations for the Multi-Cancer Early Detection Screening Coverage Act to accelerate coverage for Medicare beneficiaries. “We are constantly trying to understand the evidence that’s needed for payors to make sure that we get the broadest access possible for this test,” he said.
 

The first positive test result

Back at St. Elizabeth Healthcare where they’ve only seen one positive MCED test result thus far, Dr. Flora is more concerned about patients giving informed consent before they even get the test. “When the reps started hammering our primary care doctors, we sent communiques throughout the system saying that we would very much like to regulate this to make sure that before our patients receive accidental harm, that they at least have a conversation with somebody who understands the test,” he explained.

All 15 patients who requested the test at the hospital were first required to discuss the implications with a genetic counselor who is part of the system. “We are really pro–cancer screening,” he said, but added his hospital is “not pumped” about the Galleri test. “We’re being very cautious about overstatements made by sales guys to our primary care doctors, so we’re letting our own precision medicine people handle it.”

There’s a similar system in place at Community Health Network, a nonprofit health system with nine hospitals and 1,300 employee providers throughout Central Indiana. Patrick McGill, MD, a primary care physician and chief analytics officer for the network says they have streamlined patients with positive tests through their high-risk oncology clinic. “They don’t go straight to a medical oncologist which I know some systems are struggling with,” he said. “They get additional testing, whether it’s imaging they might need or other lab testing. We’ve had a few lung positives, and a few leukemia positives which might go straight to medical oncology. I think we had one breast that was positive so she got additional breast imaging.”

Through its foundation, CHN will offer 2,000 tests free of charge. “We decided to take cost off the table with this funding,” Dr. McGill said. “A lot of health systems I talk to are always concerned that insurance doesn’t cover it and it’s cost prohibitive. Is it creating additional disparities because only people who can afford it can get the test?”

Dr. Schrag serves as an uncompensated advisor for Grail. Previously, while with the Dana-Farber Cancer Institute, she received research funding from Grail.

Doug Flora, MD, knows the value of early cancer detection because it helped him survive kidney cancer 5 years ago. But as a medical oncologist and hematologist, and the executive medical director of oncology services at St. Elizabeth Healthcare in Edgewood, Ky., he also knows that a new era of early cancer detection testing poses big challenges for his network of six hospitals and 169 specialty and primary care offices throughout Kentucky, Ohio, and Indiana.

Multicancer early detection (MCED) tests are finally a reality and could be a potential game changer because they can screen for the possibility of up to 50 different cancers in asymptomatic individuals with one blood draw. They represent one of the fastest growing segments in medical diagnostics with a projected value of $2.77 billion by 2030, according to the market research firm Grand View Research.

These tests are different from traditional liquid biopsies, which are designed to identify actionable gene mutations to help inform treatment decisions of patients already diagnosed with cancer. Instead, MCED tests work to detect fragments of circulating free DNA that have been shed by tumors and released into the bloodstream. Detecting these cancer signals could indicate that an individual has cancer well before they ever develop symptoms.

For some cancer types, particularly those commonly diagnosed at advanced stages or those without general population screening tests, MCED testing could have a significant impact.

In its new report, Grand View Research highlights nine “prominent players” active in the MCED market; of these, two have been granted breakthrough device designation by the Food and Drug Administration: OverC MCDBT by Burning Rock on Jan. 3, 2023, and Galleri by Grail in 2019. Galleri was launched in June 2021 and can be obtained with a prescription at a cost of $949.

Yet, while patients are asking for these tests and primary care physicians are prescribing them, oncologists are grappling with how to manage the first patients whose tests tell them they may have cancer.

Ordering the tests may seem straightforward, but in reality, it is not. In fact, they are so new that most health systems have no internal guidelines for physicians. Guidelines would address when the tests should be prescribed, and whether a patient should undergo more testing or be referred to an oncologist.
 

Clinical trials underway

There are currently at least 17 clinical trials underway to investigate the performance and clinical utility of MCED tests. Six of these involve Grail, including NHS-Galleri, the largest study to date of 140,000 participants in the United Kingdom where participants will be followed for 3 years with annual visits at 12 and 24 months. And, the National Cancer Institute is spearheading a clinical trial of its own, according to a search of ClinicalTrials.gov.

In September 2022, Grail presented findings from its pivotal PATHFINDER study at the annual meeting of the European Society of Medical Oncology. Researchers reported that cancer signals were detected in 1.4% (92) of 6,621 participants enrolled in the study. Of the 92, 35 people were diagnosed with 36 cancers: 19 were solid tumors (2 oropharyngeal, 5 breast, l liver, 1 intrahepatic bile duct, 2 colon/rectum, 2 prostate, 1 lung, 1 pancreas, 1 small intestine, 1 uterus, 1 ovary and 1 bone) and 17 hematologic cancers (1 plasma cell myeloma/disorders, 2 lymphoid leukemia, 2 Waldenström’s macroglobulinemia, and 12 lymphoma).

Almost half of newly diagnosed cases were cancers in stage 1 or 2. Of stage 1 cancers, three were solid tumors and four were hematologic cancers. Of stage 2 cancers, three were solid tumors and four were hematologic cancers. All other cancers were in stage 3 and 4 or were listed as recurrent or no stage. Deb Schrag, MD, MPH, chair of the department of medicine at Memorial Sloan Kettering Cancer Center in New York, who presented the results from PATHFINDER at ESMO, reported that, of all diagnosed cancers, only breast, colon/rectum, prostate, and lung have established screening protocols.

The findings were so striking that the meeting scientific co-chair, Fabrice André, MD, PhD, told ESMO the oncology field must prepare for an onslaught of new patients.

“Within the next 5 years, we will need more doctors, surgeons and nurses with more diagnostic and treatment infrastructures to care for the rising number of people who will be identified by multicancer early detection tests,” said Dr. André, who is director of research at Gustave Roussy Cancer Center, Villejuif, France, and future president of ESMO (2025-2026). “We need to involve all stakeholders in deciding new pathways of care. We need to agree who will be tested and when and where tests will be carried out, and to anticipate the changes that will happen as a result of these tests.”

But first, he urged, the need for comparative trials “across all types of cancer to find out if having an early detection test affects morbidity and mortality. We also need to know how the tests benefit patients, and how to discuss the results with them,” Dr. André said.
 

Demand may burden health systems

Dr. Flora suggested that companies like Grail are rushing their product to market without conducting long-term sizable clinical trials.

“These diagnostic companies are a billion dollar publicly traded or venture capital-funded companies that are losing millions of dollars a quarter as they’re scaling up these tests. So, there is some pressure on the sales forces ... to start moving product long before the science has met our lowest areas for entry,” Dr. Flora said. “They are aggressively marketing to a primary care audience that knows nothing about MCEDs. It’s a sales-driven development solving a problem we all believe is real, but we don’t know if it actually solves the problem.”

There are many unanswered questions, he said. Among these include whether the tests do indeed extend survival. “What they’re suggesting – that is if the blood test detects it – that we’re going to save your life. That’s not yet been proven. This is where the providers are pushing back against these industry types to say: ‘This is the wild west right now.’ It’s very irresponsible to go out there and try to sell hundreds of millions of dollars of product to doctors who have never studied genetics,” Dr. Flora said.

Grail’s chief medical officer Jeff Venstrom, MD, however, said physicians don’t need a background in genetic testing to order or interpret Galleri because it’s not a genetic test. Genetic tests look for genetic variants associated with cancer risk, which Galleri does not. MCED tests rely on genomic profiling to identify alterations in tumors.

“Maybe there’s still confusion in the market, which is common for new technologies when they’re initially launched. This is not a 23andMe test. We do not report germline mutations that have implications for cancer risk. We’re using this blood sample to test for the presence or absence of a cancer signal. The test result is very clear and simple: One area of the report says ‘yes’ or ‘no.’ It is a binary result that says if a signal is detected or not. The second provides additional information around where that signal could be coming from,” he said.

Galleri could fill a huge unmet need in cancer prevention, Dr. Venstrom said. Not only could it detect cancer at an earlier stage, but it could serve as a screening tool for cancers like pancreatic cancer in which screening is not available.

The test is not intended to replace standard of care screening, he said. The ordering provider should have a conversation with the patient about overall cancer risk. “Are you smoking? What’s your risk of obesity-associated cancers? Do you have a family history of cancer? I think this should all be in the context of a good conversation around preventative care,” he said.
 

Planning and prep in Boston

In Boston, Aparna Parikh, MD, an oncologist who specializes in gastrointestinal cancers, agreed that MCED testing has forced her team at the Mass General Cancer Center global cancer care program to think outside of the box.

“We’re a major academic center and it’s not easy [because] this is all uncharted territory,” she said. “We all recognize there are more tests coming, and they are here to stay. As a health system, we have to be ready to manage not only the tests, but patient anxieties, and all the complexities that come with it. We just don’t know yet how to best navigate.”

Although Dr. Parikh’s center has set up a working group tasked with organizing an outpatient clinic for patients with positive MCED tests, the current system is haphazard.

“Right now, it gets bounced around between people,” she explained. “Sometimes, patients are getting referred to the oncology team rather than the primary care team to try to sort out where the cancer signal is coming from, that is, if it’s not immediately obvious. No one really knows who should be the right person to own it,” Dr. Parikh said. While the test is supposed to give tissue-specific results, “it’s not perfect” and sometimes imaging and other work-ups are needed to locate the source of the signa.

“A group of four or five oncologists get looped in and then we’re trying to sort it out on a case-by-case basis, but understanding that with more and more tests coming, that kind of ad hoc approach isn’t going to be sufficient. We need a happy medium between the primary care and the disease specific oncologist, someone who can kind of help think through the diagnostic workup until they have a cancer diagnosis to get them to the right place,” Dr. Parikh said.

Dr. Venstrom said Grail is committed to providing support to clinicians in these situations. “We’re doing everything we can with our medical education forums. We have this pretty intense and extensive postpositive suite of resources,” he explained. “Some of our doctors on staff call the ordering provider within 24 hours just to clarify if there are any questions or confusion from the report. For example, if it suggests the signal is coming from the lung, we provide additional support around additional workups.”
 

Out-of-pocket test may widen disparities in care

With the exception of a few health insurance companies that have committed to covering some of the cost for the test, Galleri is an out-of-pocket expense.

Dr. Venstrom acknowledged that broad insurance coverage for the Galleri test remains a hurdle, although “we’ve secured coverage for a handful of companies of self-insured employers and forward-thinking insurers.” This includes partnerships with Point32Health, and Alignment Health, among others, he said.

There is also growing support among more than 400 cancer organizations for the Multi-Cancer Early Detection Screening Coverage Act to accelerate coverage for Medicare beneficiaries. “We are constantly trying to understand the evidence that’s needed for payors to make sure that we get the broadest access possible for this test,” he said.
 

The first positive test result

Back at St. Elizabeth Healthcare where they’ve only seen one positive MCED test result thus far, Dr. Flora is more concerned about patients giving informed consent before they even get the test. “When the reps started hammering our primary care doctors, we sent communiques throughout the system saying that we would very much like to regulate this to make sure that before our patients receive accidental harm, that they at least have a conversation with somebody who understands the test,” he explained.

All 15 patients who requested the test at the hospital were first required to discuss the implications with a genetic counselor who is part of the system. “We are really pro–cancer screening,” he said, but added his hospital is “not pumped” about the Galleri test. “We’re being very cautious about overstatements made by sales guys to our primary care doctors, so we’re letting our own precision medicine people handle it.”

There’s a similar system in place at Community Health Network, a nonprofit health system with nine hospitals and 1,300 employee providers throughout Central Indiana. Patrick McGill, MD, a primary care physician and chief analytics officer for the network says they have streamlined patients with positive tests through their high-risk oncology clinic. “They don’t go straight to a medical oncologist which I know some systems are struggling with,” he said. “They get additional testing, whether it’s imaging they might need or other lab testing. We’ve had a few lung positives, and a few leukemia positives which might go straight to medical oncology. I think we had one breast that was positive so she got additional breast imaging.”

Through its foundation, CHN will offer 2,000 tests free of charge. “We decided to take cost off the table with this funding,” Dr. McGill said. “A lot of health systems I talk to are always concerned that insurance doesn’t cover it and it’s cost prohibitive. Is it creating additional disparities because only people who can afford it can get the test?”

Dr. Schrag serves as an uncompensated advisor for Grail. Previously, while with the Dana-Farber Cancer Institute, she received research funding from Grail.

Doug Flora, MD, knows the value of early cancer detection because it helped him survive kidney cancer 5 years ago. But as a medical oncologist and hematologist, and the executive medical director of oncology services at St. Elizabeth Healthcare in Edgewood, Ky., he also knows that a new era of early cancer detection testing poses big challenges for his network of six hospitals and 169 specialty and primary care offices throughout Kentucky, Ohio, and Indiana.

Multicancer early detection (MCED) tests are finally a reality and could be a potential game changer because they can screen for the possibility of up to 50 different cancers in asymptomatic individuals with one blood draw. They represent one of the fastest growing segments in medical diagnostics with a projected value of $2.77 billion by 2030, according to the market research firm Grand View Research.

These tests are different from traditional liquid biopsies, which are designed to identify actionable gene mutations to help inform treatment decisions of patients already diagnosed with cancer. Instead, MCED tests work to detect fragments of circulating free DNA that have been shed by tumors and released into the bloodstream. Detecting these cancer signals could indicate that an individual has cancer well before they ever develop symptoms.

For some cancer types, particularly those commonly diagnosed at advanced stages or those without general population screening tests, MCED testing could have a significant impact.

In its new report, Grand View Research highlights nine “prominent players” active in the MCED market; of these, two have been granted breakthrough device designation by the Food and Drug Administration: OverC MCDBT by Burning Rock on Jan. 3, 2023, and Galleri by Grail in 2019. Galleri was launched in June 2021 and can be obtained with a prescription at a cost of $949.

Yet, while patients are asking for these tests and primary care physicians are prescribing them, oncologists are grappling with how to manage the first patients whose tests tell them they may have cancer.

Ordering the tests may seem straightforward, but in reality, it is not. In fact, they are so new that most health systems have no internal guidelines for physicians. Guidelines would address when the tests should be prescribed, and whether a patient should undergo more testing or be referred to an oncologist.
 

Clinical trials underway

There are currently at least 17 clinical trials underway to investigate the performance and clinical utility of MCED tests. Six of these involve Grail, including NHS-Galleri, the largest study to date of 140,000 participants in the United Kingdom where participants will be followed for 3 years with annual visits at 12 and 24 months. And, the National Cancer Institute is spearheading a clinical trial of its own, according to a search of ClinicalTrials.gov.

In September 2022, Grail presented findings from its pivotal PATHFINDER study at the annual meeting of the European Society of Medical Oncology. Researchers reported that cancer signals were detected in 1.4% (92) of 6,621 participants enrolled in the study. Of the 92, 35 people were diagnosed with 36 cancers: 19 were solid tumors (2 oropharyngeal, 5 breast, l liver, 1 intrahepatic bile duct, 2 colon/rectum, 2 prostate, 1 lung, 1 pancreas, 1 small intestine, 1 uterus, 1 ovary and 1 bone) and 17 hematologic cancers (1 plasma cell myeloma/disorders, 2 lymphoid leukemia, 2 Waldenström’s macroglobulinemia, and 12 lymphoma).

Almost half of newly diagnosed cases were cancers in stage 1 or 2. Of stage 1 cancers, three were solid tumors and four were hematologic cancers. Of stage 2 cancers, three were solid tumors and four were hematologic cancers. All other cancers were in stage 3 and 4 or were listed as recurrent or no stage. Deb Schrag, MD, MPH, chair of the department of medicine at Memorial Sloan Kettering Cancer Center in New York, who presented the results from PATHFINDER at ESMO, reported that, of all diagnosed cancers, only breast, colon/rectum, prostate, and lung have established screening protocols.

The findings were so striking that the meeting scientific co-chair, Fabrice André, MD, PhD, told ESMO the oncology field must prepare for an onslaught of new patients.

“Within the next 5 years, we will need more doctors, surgeons and nurses with more diagnostic and treatment infrastructures to care for the rising number of people who will be identified by multicancer early detection tests,” said Dr. André, who is director of research at Gustave Roussy Cancer Center, Villejuif, France, and future president of ESMO (2025-2026). “We need to involve all stakeholders in deciding new pathways of care. We need to agree who will be tested and when and where tests will be carried out, and to anticipate the changes that will happen as a result of these tests.”

But first, he urged, the need for comparative trials “across all types of cancer to find out if having an early detection test affects morbidity and mortality. We also need to know how the tests benefit patients, and how to discuss the results with them,” Dr. André said.
 

Demand may burden health systems

Dr. Flora suggested that companies like Grail are rushing their product to market without conducting long-term sizable clinical trials.

“These diagnostic companies are a billion dollar publicly traded or venture capital-funded companies that are losing millions of dollars a quarter as they’re scaling up these tests. So, there is some pressure on the sales forces ... to start moving product long before the science has met our lowest areas for entry,” Dr. Flora said. “They are aggressively marketing to a primary care audience that knows nothing about MCEDs. It’s a sales-driven development solving a problem we all believe is real, but we don’t know if it actually solves the problem.”

There are many unanswered questions, he said. Among these include whether the tests do indeed extend survival. “What they’re suggesting – that is if the blood test detects it – that we’re going to save your life. That’s not yet been proven. This is where the providers are pushing back against these industry types to say: ‘This is the wild west right now.’ It’s very irresponsible to go out there and try to sell hundreds of millions of dollars of product to doctors who have never studied genetics,” Dr. Flora said.

Grail’s chief medical officer Jeff Venstrom, MD, however, said physicians don’t need a background in genetic testing to order or interpret Galleri because it’s not a genetic test. Genetic tests look for genetic variants associated with cancer risk, which Galleri does not. MCED tests rely on genomic profiling to identify alterations in tumors.

“Maybe there’s still confusion in the market, which is common for new technologies when they’re initially launched. This is not a 23andMe test. We do not report germline mutations that have implications for cancer risk. We’re using this blood sample to test for the presence or absence of a cancer signal. The test result is very clear and simple: One area of the report says ‘yes’ or ‘no.’ It is a binary result that says if a signal is detected or not. The second provides additional information around where that signal could be coming from,” he said.

Galleri could fill a huge unmet need in cancer prevention, Dr. Venstrom said. Not only could it detect cancer at an earlier stage, but it could serve as a screening tool for cancers like pancreatic cancer in which screening is not available.

The test is not intended to replace standard of care screening, he said. The ordering provider should have a conversation with the patient about overall cancer risk. “Are you smoking? What’s your risk of obesity-associated cancers? Do you have a family history of cancer? I think this should all be in the context of a good conversation around preventative care,” he said.
 

Planning and prep in Boston

In Boston, Aparna Parikh, MD, an oncologist who specializes in gastrointestinal cancers, agreed that MCED testing has forced her team at the Mass General Cancer Center global cancer care program to think outside of the box.

“We’re a major academic center and it’s not easy [because] this is all uncharted territory,” she said. “We all recognize there are more tests coming, and they are here to stay. As a health system, we have to be ready to manage not only the tests, but patient anxieties, and all the complexities that come with it. We just don’t know yet how to best navigate.”

Although Dr. Parikh’s center has set up a working group tasked with organizing an outpatient clinic for patients with positive MCED tests, the current system is haphazard.

“Right now, it gets bounced around between people,” she explained. “Sometimes, patients are getting referred to the oncology team rather than the primary care team to try to sort out where the cancer signal is coming from, that is, if it’s not immediately obvious. No one really knows who should be the right person to own it,” Dr. Parikh said. While the test is supposed to give tissue-specific results, “it’s not perfect” and sometimes imaging and other work-ups are needed to locate the source of the signa.

“A group of four or five oncologists get looped in and then we’re trying to sort it out on a case-by-case basis, but understanding that with more and more tests coming, that kind of ad hoc approach isn’t going to be sufficient. We need a happy medium between the primary care and the disease specific oncologist, someone who can kind of help think through the diagnostic workup until they have a cancer diagnosis to get them to the right place,” Dr. Parikh said.

Dr. Venstrom said Grail is committed to providing support to clinicians in these situations. “We’re doing everything we can with our medical education forums. We have this pretty intense and extensive postpositive suite of resources,” he explained. “Some of our doctors on staff call the ordering provider within 24 hours just to clarify if there are any questions or confusion from the report. For example, if it suggests the signal is coming from the lung, we provide additional support around additional workups.”
 

Out-of-pocket test may widen disparities in care

With the exception of a few health insurance companies that have committed to covering some of the cost for the test, Galleri is an out-of-pocket expense.

Dr. Venstrom acknowledged that broad insurance coverage for the Galleri test remains a hurdle, although “we’ve secured coverage for a handful of companies of self-insured employers and forward-thinking insurers.” This includes partnerships with Point32Health, and Alignment Health, among others, he said.

There is also growing support among more than 400 cancer organizations for the Multi-Cancer Early Detection Screening Coverage Act to accelerate coverage for Medicare beneficiaries. “We are constantly trying to understand the evidence that’s needed for payors to make sure that we get the broadest access possible for this test,” he said.
 

The first positive test result

Back at St. Elizabeth Healthcare where they’ve only seen one positive MCED test result thus far, Dr. Flora is more concerned about patients giving informed consent before they even get the test. “When the reps started hammering our primary care doctors, we sent communiques throughout the system saying that we would very much like to regulate this to make sure that before our patients receive accidental harm, that they at least have a conversation with somebody who understands the test,” he explained.

All 15 patients who requested the test at the hospital were first required to discuss the implications with a genetic counselor who is part of the system. “We are really pro–cancer screening,” he said, but added his hospital is “not pumped” about the Galleri test. “We’re being very cautious about overstatements made by sales guys to our primary care doctors, so we’re letting our own precision medicine people handle it.”

There’s a similar system in place at Community Health Network, a nonprofit health system with nine hospitals and 1,300 employee providers throughout Central Indiana. Patrick McGill, MD, a primary care physician and chief analytics officer for the network says they have streamlined patients with positive tests through their high-risk oncology clinic. “They don’t go straight to a medical oncologist which I know some systems are struggling with,” he said. “They get additional testing, whether it’s imaging they might need or other lab testing. We’ve had a few lung positives, and a few leukemia positives which might go straight to medical oncology. I think we had one breast that was positive so she got additional breast imaging.”

Through its foundation, CHN will offer 2,000 tests free of charge. “We decided to take cost off the table with this funding,” Dr. McGill said. “A lot of health systems I talk to are always concerned that insurance doesn’t cover it and it’s cost prohibitive. Is it creating additional disparities because only people who can afford it can get the test?”

Dr. Schrag serves as an uncompensated advisor for Grail. Previously, while with the Dana-Farber Cancer Institute, she received research funding from Grail.

A new drug application for a first-in-class photodynamic (PDT) therapy for treating early-stage cutaneous T-cell lymphoma (CTCL) has been submitted to the Food and Drug Administration based on phase 3 findings published in JAMA Dermatology.

The treatment employs an ointment formulation of synthetic hypericin (HyBryte), a photosensitizer, that is preferentially absorbed into malignant cells and activated with visible light – rather than ultraviolet light – approximately 24 hours later. Investigators saw significant clinical responses in both patch and plaque type lesions and across races during the 24-week placebo-controlled, double-blinded, phase 3, randomized clinical trial.

“Traditional phototherapy, ultraviolet B phototherapy, has a limited depth of penetration, so patients with thicker plaque lesions don’t respond as well ... and UVB phototherapy typically is less effective in penetrating pigmented skin,” Ellen J. Kim, MD, lead author of the FLASH phase 3 trial, said in an interview.

Visible light in the yellow-red spectrum (500-650 nm) “penetrates deeper into the skin” and is nonmutagenic in vitro, so “theoretically it should have a much more favorable long-term safety profile,” said Dr. Kim, a dermatologist at the University of Pennsylvania, Philadelphia.

Currently, she said, the risk of secondary malignancies inherent with UV PDT, including melanoma, is a deterrent for some patients, especially “patients with really fair skin and a history of skin cancer.”

Hypericin PDT also seems well suited for use with an at-home light unit. “In our field, it’s not about which therapy is [universally] better or best, but a matter of what works best for each patient at that moment in time, depending on the side-effect profile and other issues such as access,” Dr. Kim said. “It will be great to have another option for an incurable disease that requires chronic management.”

Mycosis fungoides (MF)/CTCL is considered an orphan disease, and the treatment has received orphan drug and fast track designations from the FDA, and orphan designation from the European Medicines Agency, according to a press release from its developer, Soligenix. The company is anticipating potential approval in the second half of 2023 and is targeting early 2024 for a U.S. launch, the statement said.

Phase 3 results

The pivotal trial involved 169 patients at 39 academic and community-based U.S. medical centers and consisted of several 6-week cycles of twice-weekly treatment punctuated by 2-week breaks. In cycle 1, patients were randomized 2:1 to receive hypericin or placebo treatment of three index lesions. Cycle 2 involved the crossover of placebo patients to active treatment of index lesions, and cycle 3 (optional) involved open-label treatment of all desired lesions (index and nonindex).

The trial defined the primary endpoint in phase 1 as 50% or greater improvement in the modified Composite Assessment of Index Lesion Severity score – a tool that’s endorsed by U.S. and international MF/CTCL specialty group consensus guidelines. For cycles 2 and 3, open-label response rates were secondary endpoints. Responses were assessed after 2-week rest periods to allow for treatment-induced skin reactions to subside.

After one cycle of treatment, topical hypericin PDT was more effective than placebo (an index lesion response rate of 16% vs. 4%; P =.04). The index lesion response rate with treatment increased to 40% after two cycles and 49% after three cycles. All were statistically significant changes.

Response rates were similar in patch and plaque-type lesions and regardless of age, sex, race, stage IA versus IB, time since diagnosis, and number of prior therapies. Adverse events were primarily mild application-site skin reactions. No serious drug-related adverse events occurred, Dr. Kim said, and “we had a low drop-out rate overall.”
 

Into the real world

The 24-week phase 3 trial duration is short, considering that “typically, phototherapy takes between 4 to 24 months [to achieve] full responses in CTCL,” Dr. Kim said in the interview.

So with real-world application, she said, “we’ll want to see where the overall response peaks with longer treatment, what the effects are of continuous treatment without any built-in breaks, and whether we will indeed see less skin cancer development in patients who are at higher risk of developing skin cancers from light treatment.”

Such questions will be explored as part of a new 4-year, 50-patient, open-label, multicenter study with the primary aim of investigating home-based hypericin PDT therapy in a supervised setting, said Dr. Kim, principal investigator of this study. Patients who are doing well after 6 weeks of twice-weekly therapy will be given at-home light units to continue therapy and achieve 1 year of treatment with no breaks. They will be monitored with video-based telemedicine.

“Long term, having a home unit should really improve patient access and compliance and hopefully effectiveness,” Dr. Kim said. Based on the phase 3 experience, “we think that continuous treatment will be well tolerated and that we may see greater responses.”

On Dec. 19, Soligenix announced that enrollment had begun in a phase 2a study of synthetic hypericin for treating patients with mild to moderate psoriasis.

Dr. Kim reported to JAMA Dermatology grants from Innate Pharma and Galderma; consulting/advisory fees from Almirall, Galderma, and Helsinn; and honoraria from Ology and UptoDate.

A new drug application for a first-in-class photodynamic (PDT) therapy for treating early-stage cutaneous T-cell lymphoma (CTCL) has been submitted to the Food and Drug Administration based on phase 3 findings published in JAMA Dermatology.

The treatment employs an ointment formulation of synthetic hypericin (HyBryte), a photosensitizer, that is preferentially absorbed into malignant cells and activated with visible light – rather than ultraviolet light – approximately 24 hours later. Investigators saw significant clinical responses in both patch and plaque type lesions and across races during the 24-week placebo-controlled, double-blinded, phase 3, randomized clinical trial.

“Traditional phototherapy, ultraviolet B phototherapy, has a limited depth of penetration, so patients with thicker plaque lesions don’t respond as well ... and UVB phototherapy typically is less effective in penetrating pigmented skin,” Ellen J. Kim, MD, lead author of the FLASH phase 3 trial, said in an interview.

Visible light in the yellow-red spectrum (500-650 nm) “penetrates deeper into the skin” and is nonmutagenic in vitro, so “theoretically it should have a much more favorable long-term safety profile,” said Dr. Kim, a dermatologist at the University of Pennsylvania, Philadelphia.

Currently, she said, the risk of secondary malignancies inherent with UV PDT, including melanoma, is a deterrent for some patients, especially “patients with really fair skin and a history of skin cancer.”

Hypericin PDT also seems well suited for use with an at-home light unit. “In our field, it’s not about which therapy is [universally] better or best, but a matter of what works best for each patient at that moment in time, depending on the side-effect profile and other issues such as access,” Dr. Kim said. “It will be great to have another option for an incurable disease that requires chronic management.”

Mycosis fungoides (MF)/CTCL is considered an orphan disease, and the treatment has received orphan drug and fast track designations from the FDA, and orphan designation from the European Medicines Agency, according to a press release from its developer, Soligenix. The company is anticipating potential approval in the second half of 2023 and is targeting early 2024 for a U.S. launch, the statement said.

Phase 3 results

The pivotal trial involved 169 patients at 39 academic and community-based U.S. medical centers and consisted of several 6-week cycles of twice-weekly treatment punctuated by 2-week breaks. In cycle 1, patients were randomized 2:1 to receive hypericin or placebo treatment of three index lesions. Cycle 2 involved the crossover of placebo patients to active treatment of index lesions, and cycle 3 (optional) involved open-label treatment of all desired lesions (index and nonindex).

The trial defined the primary endpoint in phase 1 as 50% or greater improvement in the modified Composite Assessment of Index Lesion Severity score – a tool that’s endorsed by U.S. and international MF/CTCL specialty group consensus guidelines. For cycles 2 and 3, open-label response rates were secondary endpoints. Responses were assessed after 2-week rest periods to allow for treatment-induced skin reactions to subside.

After one cycle of treatment, topical hypericin PDT was more effective than placebo (an index lesion response rate of 16% vs. 4%; P =.04). The index lesion response rate with treatment increased to 40% after two cycles and 49% after three cycles. All were statistically significant changes.

Response rates were similar in patch and plaque-type lesions and regardless of age, sex, race, stage IA versus IB, time since diagnosis, and number of prior therapies. Adverse events were primarily mild application-site skin reactions. No serious drug-related adverse events occurred, Dr. Kim said, and “we had a low drop-out rate overall.”
 

Into the real world

The 24-week phase 3 trial duration is short, considering that “typically, phototherapy takes between 4 to 24 months [to achieve] full responses in CTCL,” Dr. Kim said in the interview.

So with real-world application, she said, “we’ll want to see where the overall response peaks with longer treatment, what the effects are of continuous treatment without any built-in breaks, and whether we will indeed see less skin cancer development in patients who are at higher risk of developing skin cancers from light treatment.”

Such questions will be explored as part of a new 4-year, 50-patient, open-label, multicenter study with the primary aim of investigating home-based hypericin PDT therapy in a supervised setting, said Dr. Kim, principal investigator of this study. Patients who are doing well after 6 weeks of twice-weekly therapy will be given at-home light units to continue therapy and achieve 1 year of treatment with no breaks. They will be monitored with video-based telemedicine.

“Long term, having a home unit should really improve patient access and compliance and hopefully effectiveness,” Dr. Kim said. Based on the phase 3 experience, “we think that continuous treatment will be well tolerated and that we may see greater responses.”

On Dec. 19, Soligenix announced that enrollment had begun in a phase 2a study of synthetic hypericin for treating patients with mild to moderate psoriasis.

Dr. Kim reported to JAMA Dermatology grants from Innate Pharma and Galderma; consulting/advisory fees from Almirall, Galderma, and Helsinn; and honoraria from Ology and UptoDate.

A new drug application for a first-in-class photodynamic (PDT) therapy for treating early-stage cutaneous T-cell lymphoma (CTCL) has been submitted to the Food and Drug Administration based on phase 3 findings published in JAMA Dermatology.

The treatment employs an ointment formulation of synthetic hypericin (HyBryte), a photosensitizer, that is preferentially absorbed into malignant cells and activated with visible light – rather than ultraviolet light – approximately 24 hours later. Investigators saw significant clinical responses in both patch and plaque type lesions and across races during the 24-week placebo-controlled, double-blinded, phase 3, randomized clinical trial.

“Traditional phototherapy, ultraviolet B phototherapy, has a limited depth of penetration, so patients with thicker plaque lesions don’t respond as well ... and UVB phototherapy typically is less effective in penetrating pigmented skin,” Ellen J. Kim, MD, lead author of the FLASH phase 3 trial, said in an interview.

Visible light in the yellow-red spectrum (500-650 nm) “penetrates deeper into the skin” and is nonmutagenic in vitro, so “theoretically it should have a much more favorable long-term safety profile,” said Dr. Kim, a dermatologist at the University of Pennsylvania, Philadelphia.

Currently, she said, the risk of secondary malignancies inherent with UV PDT, including melanoma, is a deterrent for some patients, especially “patients with really fair skin and a history of skin cancer.”

Hypericin PDT also seems well suited for use with an at-home light unit. “In our field, it’s not about which therapy is [universally] better or best, but a matter of what works best for each patient at that moment in time, depending on the side-effect profile and other issues such as access,” Dr. Kim said. “It will be great to have another option for an incurable disease that requires chronic management.”

Mycosis fungoides (MF)/CTCL is considered an orphan disease, and the treatment has received orphan drug and fast track designations from the FDA, and orphan designation from the European Medicines Agency, according to a press release from its developer, Soligenix. The company is anticipating potential approval in the second half of 2023 and is targeting early 2024 for a U.S. launch, the statement said.

Phase 3 results

The pivotal trial involved 169 patients at 39 academic and community-based U.S. medical centers and consisted of several 6-week cycles of twice-weekly treatment punctuated by 2-week breaks. In cycle 1, patients were randomized 2:1 to receive hypericin or placebo treatment of three index lesions. Cycle 2 involved the crossover of placebo patients to active treatment of index lesions, and cycle 3 (optional) involved open-label treatment of all desired lesions (index and nonindex).

The trial defined the primary endpoint in phase 1 as 50% or greater improvement in the modified Composite Assessment of Index Lesion Severity score – a tool that’s endorsed by U.S. and international MF/CTCL specialty group consensus guidelines. For cycles 2 and 3, open-label response rates were secondary endpoints. Responses were assessed after 2-week rest periods to allow for treatment-induced skin reactions to subside.

After one cycle of treatment, topical hypericin PDT was more effective than placebo (an index lesion response rate of 16% vs. 4%; P =.04). The index lesion response rate with treatment increased to 40% after two cycles and 49% after three cycles. All were statistically significant changes.

Response rates were similar in patch and plaque-type lesions and regardless of age, sex, race, stage IA versus IB, time since diagnosis, and number of prior therapies. Adverse events were primarily mild application-site skin reactions. No serious drug-related adverse events occurred, Dr. Kim said, and “we had a low drop-out rate overall.”
 

Into the real world

The 24-week phase 3 trial duration is short, considering that “typically, phototherapy takes between 4 to 24 months [to achieve] full responses in CTCL,” Dr. Kim said in the interview.

So with real-world application, she said, “we’ll want to see where the overall response peaks with longer treatment, what the effects are of continuous treatment without any built-in breaks, and whether we will indeed see less skin cancer development in patients who are at higher risk of developing skin cancers from light treatment.”

Such questions will be explored as part of a new 4-year, 50-patient, open-label, multicenter study with the primary aim of investigating home-based hypericin PDT therapy in a supervised setting, said Dr. Kim, principal investigator of this study. Patients who are doing well after 6 weeks of twice-weekly therapy will be given at-home light units to continue therapy and achieve 1 year of treatment with no breaks. They will be monitored with video-based telemedicine.

“Long term, having a home unit should really improve patient access and compliance and hopefully effectiveness,” Dr. Kim said. Based on the phase 3 experience, “we think that continuous treatment will be well tolerated and that we may see greater responses.”

On Dec. 19, Soligenix announced that enrollment had begun in a phase 2a study of synthetic hypericin for treating patients with mild to moderate psoriasis.

Dr. Kim reported to JAMA Dermatology grants from Innate Pharma and Galderma; consulting/advisory fees from Almirall, Galderma, and Helsinn; and honoraria from Ology and UptoDate.

First described in 2020 by researchers from the U.S. National Institutes of Health, VEXAS syndrome is a systemic autoinflammatory disease of undefined origin. Its name is an acronym: Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic. The prevalence of this syndrome is unknown, but it is not so rare. As it is an X-linked disease, men are predominantly affected.

First identification

The NIH team screened the exomes and genomes of 2,560 individuals. Of this group, 1,477 had been referred because of undiagnosed recurrent fevers, systemic inflammation, or both, and 1,083 were affected by atypical, unclassified disorders. The researchers identified 25 men with a somatic mutation in the ubiquitin-like modifier activating enzyme 1 (UBA1) gene, which is involved in the protein ubiquitylation system. This posttranslational modification has a pleiotropic function that likely explains the clinical heterogeneity seen in VEXAS patients: regulation of protein turnover, especially those involved in the cell cycle, cell death, and signal transduction. Ubiquitylation is also involved in nonproteolytic functions, such as assembly of multiprotein complexes, intracellular signaling, inflammatory signaling, and DNA repair.

Clinical presentation

The clinicobiological presentation of VEXAS syndrome is very heterogeneous. Typically, patients present with a systemic inflammatory disease with unexplained episodes of fever, involvement of the lungs, skin, blood vessels, and joints. Molecular diagnosis is made by the sequencing of UBA1.

Most patients present with the characteristic clinical signs of other inflammatory diseases, such as polyarteritis nodosa and recurrent polychondritis. But VEXAS patients are at high risk of developing hematologic conditions. Indeed, the following were seen among the 25 participants in the NIH study: macrocytic anemia (96%), venous thromboembolism (44%), myelodysplastic syndrome (24%), and multiple myeloma or monoclonal gammopathy of undetermined significance (20%).

In VEXAS patients, levels of serum inflammatory markers are increased. These markers include tumor necrosis factor, interleukin-8, interleukin-6, interferon-inducible protein-10, interferon-gamma, C-reactive protein. In addition, there is aberrant activation of innate immune-signaling pathways.

In a large-scale analysis of a multicenter case series of 116 French patients, researchers found that VEXAS syndrome primarily affected men. The disease was progressive, and onset occurred after age 50 years. These patients can be divided into three phenotypically distinct clusters on the basis of integration of clinical and biological data. In the 58 cases in which myelodysplastic syndrome was present, the mortality rates were higher. The researchers also reported that the UBA1 p.Met41L mutation was associated with a better prognosis.
 

Treatment data

VEXAS syndrome resists the classical therapeutic arsenal. Patients require high-dose glucocorticoids, and prognosis appears to be poor. The available treatment data are retrospective. Of the 25 participants in the NIH study, 40% died within 5 years from disease-related causes or complications related to treatment. Among the promising therapeutic avenues is the use of inhibitors of the Janus kinase pathway.

This article was translated from Univadis France. A version of this article appeared on Medscape.com.

First described in 2020 by researchers from the U.S. National Institutes of Health, VEXAS syndrome is a systemic autoinflammatory disease of undefined origin. Its name is an acronym: Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic. The prevalence of this syndrome is unknown, but it is not so rare. As it is an X-linked disease, men are predominantly affected.

First identification

The NIH team screened the exomes and genomes of 2,560 individuals. Of this group, 1,477 had been referred because of undiagnosed recurrent fevers, systemic inflammation, or both, and 1,083 were affected by atypical, unclassified disorders. The researchers identified 25 men with a somatic mutation in the ubiquitin-like modifier activating enzyme 1 (UBA1) gene, which is involved in the protein ubiquitylation system. This posttranslational modification has a pleiotropic function that likely explains the clinical heterogeneity seen in VEXAS patients: regulation of protein turnover, especially those involved in the cell cycle, cell death, and signal transduction. Ubiquitylation is also involved in nonproteolytic functions, such as assembly of multiprotein complexes, intracellular signaling, inflammatory signaling, and DNA repair.

Clinical presentation

The clinicobiological presentation of VEXAS syndrome is very heterogeneous. Typically, patients present with a systemic inflammatory disease with unexplained episodes of fever, involvement of the lungs, skin, blood vessels, and joints. Molecular diagnosis is made by the sequencing of UBA1.

Most patients present with the characteristic clinical signs of other inflammatory diseases, such as polyarteritis nodosa and recurrent polychondritis. But VEXAS patients are at high risk of developing hematologic conditions. Indeed, the following were seen among the 25 participants in the NIH study: macrocytic anemia (96%), venous thromboembolism (44%), myelodysplastic syndrome (24%), and multiple myeloma or monoclonal gammopathy of undetermined significance (20%).

In VEXAS patients, levels of serum inflammatory markers are increased. These markers include tumor necrosis factor, interleukin-8, interleukin-6, interferon-inducible protein-10, interferon-gamma, C-reactive protein. In addition, there is aberrant activation of innate immune-signaling pathways.

In a large-scale analysis of a multicenter case series of 116 French patients, researchers found that VEXAS syndrome primarily affected men. The disease was progressive, and onset occurred after age 50 years. These patients can be divided into three phenotypically distinct clusters on the basis of integration of clinical and biological data. In the 58 cases in which myelodysplastic syndrome was present, the mortality rates were higher. The researchers also reported that the UBA1 p.Met41L mutation was associated with a better prognosis.
 

Treatment data

VEXAS syndrome resists the classical therapeutic arsenal. Patients require high-dose glucocorticoids, and prognosis appears to be poor. The available treatment data are retrospective. Of the 25 participants in the NIH study, 40% died within 5 years from disease-related causes or complications related to treatment. Among the promising therapeutic avenues is the use of inhibitors of the Janus kinase pathway.

This article was translated from Univadis France. A version of this article appeared on Medscape.com.

First described in 2020 by researchers from the U.S. National Institutes of Health, VEXAS syndrome is a systemic autoinflammatory disease of undefined origin. Its name is an acronym: Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic. The prevalence of this syndrome is unknown, but it is not so rare. As it is an X-linked disease, men are predominantly affected.

First identification

The NIH team screened the exomes and genomes of 2,560 individuals. Of this group, 1,477 had been referred because of undiagnosed recurrent fevers, systemic inflammation, or both, and 1,083 were affected by atypical, unclassified disorders. The researchers identified 25 men with a somatic mutation in the ubiquitin-like modifier activating enzyme 1 (UBA1) gene, which is involved in the protein ubiquitylation system. This posttranslational modification has a pleiotropic function that likely explains the clinical heterogeneity seen in VEXAS patients: regulation of protein turnover, especially those involved in the cell cycle, cell death, and signal transduction. Ubiquitylation is also involved in nonproteolytic functions, such as assembly of multiprotein complexes, intracellular signaling, inflammatory signaling, and DNA repair.

Clinical presentation

The clinicobiological presentation of VEXAS syndrome is very heterogeneous. Typically, patients present with a systemic inflammatory disease with unexplained episodes of fever, involvement of the lungs, skin, blood vessels, and joints. Molecular diagnosis is made by the sequencing of UBA1.

Most patients present with the characteristic clinical signs of other inflammatory diseases, such as polyarteritis nodosa and recurrent polychondritis. But VEXAS patients are at high risk of developing hematologic conditions. Indeed, the following were seen among the 25 participants in the NIH study: macrocytic anemia (96%), venous thromboembolism (44%), myelodysplastic syndrome (24%), and multiple myeloma or monoclonal gammopathy of undetermined significance (20%).

In VEXAS patients, levels of serum inflammatory markers are increased. These markers include tumor necrosis factor, interleukin-8, interleukin-6, interferon-inducible protein-10, interferon-gamma, C-reactive protein. In addition, there is aberrant activation of innate immune-signaling pathways.

In a large-scale analysis of a multicenter case series of 116 French patients, researchers found that VEXAS syndrome primarily affected men. The disease was progressive, and onset occurred after age 50 years. These patients can be divided into three phenotypically distinct clusters on the basis of integration of clinical and biological data. In the 58 cases in which myelodysplastic syndrome was present, the mortality rates were higher. The researchers also reported that the UBA1 p.Met41L mutation was associated with a better prognosis.
 

Treatment data

VEXAS syndrome resists the classical therapeutic arsenal. Patients require high-dose glucocorticoids, and prognosis appears to be poor. The available treatment data are retrospective. Of the 25 participants in the NIH study, 40% died within 5 years from disease-related causes or complications related to treatment. Among the promising therapeutic avenues is the use of inhibitors of the Janus kinase pathway.

This article was translated from Univadis France. A version of this article appeared on Medscape.com.

Because of the high out-of-pocket costs of new-to-market neurologic drugs that are of similar benefit as older agents, only a small percentage of patients with neurologic disorders have access to these cutting-edge medications, new research shows.

“Our study of people with neurologic conditions found that fewer than 20% were being treated with new medications,” study author Brian C. Callaghan, MD, with University of Michigan Health in Ann Arbor, said in a statement.

“For new, high-cost medications that have similar effectiveness to older drugs, limited use is likely appropriate. However, future studies are needed to look into whether the high costs are barriers to those new medications that can really make a difference for people living with neurologic disease,” Dr. Callaghan said.

The study was published online in Neurology.
 

Most expensive drugs

Using insurance claims data, the investigators compared the utilization and costs of new-to-market drugs from 2014 to 2018 with those for existing guideline-supported medications for treating 11 neurologic conditions.

The new drugs included:

• erenumab, fremanezumab, and galcanezumab for migraine.
• ocrelizumab and peginterferon beta-1a for multiple sclerosis (MS).
• pimavanserin and safinamide for Parkinson’s disease.
• droxidopa for orthostatic hypertension.
• eculizumab for myasthenia gravis (MG).
• edaravone for amyotrophic lateral sclerosis (ALS).
• deutetrabenazine and valbenazine for Huntington’s disease and tardive dyskinesia.
• patisiran and inotersen for transthyretin amyloidosis (ATTR).
• eteplirsen and deflazacort for Duchenne disease.
• nusinersen for spinal muscular atrophy (SMA).

Utilization of new drugs was modest – they accounted for one in five prescriptions for every condition except tardive dyskinesia (32% for valbenazine), the researchers noted.

Mean out-of-pocket costs were significantly higher for the new medications, although there was large variability among individual drugs.

The two most expensive drugs were edaravone, for ALS, with a mean out-of-pocket cost of $713 for a 30-day supply, and eculizumab, for MG, which costs $91 per month.

“For new-to-market medications, the distribution of out-of-pocket costs were highly variable and the trends over time were unpredictable compared with existing guideline-supported medications,” the authors reported.

They noted that potential reasons for low utilization of newer agents include delay in provider uptake and prescriber and/or patient avoidance because of high cost.

Given that most of the new neurologic agents offer little advantage compared with existing treatments – exceptions being new drugs for SMA and ATTR – drug costs should be a key consideration in prescribing decisions, Dr. Callaghan and colleagues concluded.

One limitation of the study is that follow-up time was short for some of the recently approved medications. Another limitation is that the number of people in the study who had rare diseases was small.
 

Revolution in neurotherapeutics

“We are living in a time when new treatments bring hope to people with neurologic diseases and disorders,” Orly Avitzur, MD, president of the American Academy of Neurology, said in a statement.

“However, even existing prescription medication can be expensive and drug prices continue to rise. In order for neurologists to provide people with the highest quality care, it is imperative that new drugs are accessible and affordable to the people who need them,” Dr. Avitzur added.

Writing in a linked editorial, A. Gordon Smith, MD, professor and chair, department of neurology, Virginia Commonwealth University, Richmond, said there is a revolution in neurotherapeutics, with particularly robust growth in new drug approvals for orphan diseases (those affecting < 200,000 Americans).

“This study adds to a growing literature indicating rising drug prices are a threat to the health care system. No matter how effective a disease-modifying therapy may be, if a patient cannot afford the cost, it doesn’t work,” Dr. Smith wrote.

He added that neurologists must be “diligent in assessing for financial toxicity and appropriately tailor individual treatment recommendations. We must insist on development of point-of-care tools to accurately estimate each patient’s potential financial toxicity including RTBT [real-time benefit tools].

“Neurologists’ primary obligation is to the individual patient, but we are also compelled to support access to high-quality care for all people, which requires advocacy for appropriate policy reforms to ensure value based and fair drug pricing and treatment success,” Dr. Smith added.

The study was funded by the American Academy of Neurology Health Services Research Subcommittee. Dr. Callaghan consults for a PCORI grant, DynaMed, receives research support from the American Academy of Neurology, and performs medical/legal consultations, including consultations for the Vaccine Injury Compensation Program. Dr. Smith has disclosed no relevant financial relationships.

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

Because of the high out-of-pocket costs of new-to-market neurologic drugs that are of similar benefit as older agents, only a small percentage of patients with neurologic disorders have access to these cutting-edge medications, new research shows.

“Our study of people with neurologic conditions found that fewer than 20% were being treated with new medications,” study author Brian C. Callaghan, MD, with University of Michigan Health in Ann Arbor, said in a statement.

“For new, high-cost medications that have similar effectiveness to older drugs, limited use is likely appropriate. However, future studies are needed to look into whether the high costs are barriers to those new medications that can really make a difference for people living with neurologic disease,” Dr. Callaghan said.

The study was published online in Neurology.
 

Most expensive drugs

Using insurance claims data, the investigators compared the utilization and costs of new-to-market drugs from 2014 to 2018 with those for existing guideline-supported medications for treating 11 neurologic conditions.

The new drugs included:

• erenumab, fremanezumab, and galcanezumab for migraine.
• ocrelizumab and peginterferon beta-1a for multiple sclerosis (MS).
• pimavanserin and safinamide for Parkinson’s disease.
• droxidopa for orthostatic hypertension.
• eculizumab for myasthenia gravis (MG).
• edaravone for amyotrophic lateral sclerosis (ALS).
• deutetrabenazine and valbenazine for Huntington’s disease and tardive dyskinesia.
• patisiran and inotersen for transthyretin amyloidosis (ATTR).
• eteplirsen and deflazacort for Duchenne disease.
• nusinersen for spinal muscular atrophy (SMA).

Utilization of new drugs was modest – they accounted for one in five prescriptions for every condition except tardive dyskinesia (32% for valbenazine), the researchers noted.

Mean out-of-pocket costs were significantly higher for the new medications, although there was large variability among individual drugs.

The two most expensive drugs were edaravone, for ALS, with a mean out-of-pocket cost of $713 for a 30-day supply, and eculizumab, for MG, which costs $91 per month.

“For new-to-market medications, the distribution of out-of-pocket costs were highly variable and the trends over time were unpredictable compared with existing guideline-supported medications,” the authors reported.

They noted that potential reasons for low utilization of newer agents include delay in provider uptake and prescriber and/or patient avoidance because of high cost.

Given that most of the new neurologic agents offer little advantage compared with existing treatments – exceptions being new drugs for SMA and ATTR – drug costs should be a key consideration in prescribing decisions, Dr. Callaghan and colleagues concluded.

One limitation of the study is that follow-up time was short for some of the recently approved medications. Another limitation is that the number of people in the study who had rare diseases was small.
 

Revolution in neurotherapeutics

“We are living in a time when new treatments bring hope to people with neurologic diseases and disorders,” Orly Avitzur, MD, president of the American Academy of Neurology, said in a statement.

“However, even existing prescription medication can be expensive and drug prices continue to rise. In order for neurologists to provide people with the highest quality care, it is imperative that new drugs are accessible and affordable to the people who need them,” Dr. Avitzur added.

Writing in a linked editorial, A. Gordon Smith, MD, professor and chair, department of neurology, Virginia Commonwealth University, Richmond, said there is a revolution in neurotherapeutics, with particularly robust growth in new drug approvals for orphan diseases (those affecting < 200,000 Americans).

“This study adds to a growing literature indicating rising drug prices are a threat to the health care system. No matter how effective a disease-modifying therapy may be, if a patient cannot afford the cost, it doesn’t work,” Dr. Smith wrote.

He added that neurologists must be “diligent in assessing for financial toxicity and appropriately tailor individual treatment recommendations. We must insist on development of point-of-care tools to accurately estimate each patient’s potential financial toxicity including RTBT [real-time benefit tools].

“Neurologists’ primary obligation is to the individual patient, but we are also compelled to support access to high-quality care for all people, which requires advocacy for appropriate policy reforms to ensure value based and fair drug pricing and treatment success,” Dr. Smith added.

The study was funded by the American Academy of Neurology Health Services Research Subcommittee. Dr. Callaghan consults for a PCORI grant, DynaMed, receives research support from the American Academy of Neurology, and performs medical/legal consultations, including consultations for the Vaccine Injury Compensation Program. Dr. Smith has disclosed no relevant financial relationships.

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

Because of the high out-of-pocket costs of new-to-market neurologic drugs that are of similar benefit as older agents, only a small percentage of patients with neurologic disorders have access to these cutting-edge medications, new research shows.

“Our study of people with neurologic conditions found that fewer than 20% were being treated with new medications,” study author Brian C. Callaghan, MD, with University of Michigan Health in Ann Arbor, said in a statement.

“For new, high-cost medications that have similar effectiveness to older drugs, limited use is likely appropriate. However, future studies are needed to look into whether the high costs are barriers to those new medications that can really make a difference for people living with neurologic disease,” Dr. Callaghan said.

The study was published online in Neurology.
 

Most expensive drugs

Using insurance claims data, the investigators compared the utilization and costs of new-to-market drugs from 2014 to 2018 with those for existing guideline-supported medications for treating 11 neurologic conditions.

The new drugs included:

• erenumab, fremanezumab, and galcanezumab for migraine.
• ocrelizumab and peginterferon beta-1a for multiple sclerosis (MS).
• pimavanserin and safinamide for Parkinson’s disease.
• droxidopa for orthostatic hypertension.
• eculizumab for myasthenia gravis (MG).
• edaravone for amyotrophic lateral sclerosis (ALS).
• deutetrabenazine and valbenazine for Huntington’s disease and tardive dyskinesia.
• patisiran and inotersen for transthyretin amyloidosis (ATTR).
• eteplirsen and deflazacort for Duchenne disease.
• nusinersen for spinal muscular atrophy (SMA).

Utilization of new drugs was modest – they accounted for one in five prescriptions for every condition except tardive dyskinesia (32% for valbenazine), the researchers noted.

Mean out-of-pocket costs were significantly higher for the new medications, although there was large variability among individual drugs.

The two most expensive drugs were edaravone, for ALS, with a mean out-of-pocket cost of $713 for a 30-day supply, and eculizumab, for MG, which costs $91 per month.

“For new-to-market medications, the distribution of out-of-pocket costs were highly variable and the trends over time were unpredictable compared with existing guideline-supported medications,” the authors reported.

They noted that potential reasons for low utilization of newer agents include delay in provider uptake and prescriber and/or patient avoidance because of high cost.

Given that most of the new neurologic agents offer little advantage compared with existing treatments – exceptions being new drugs for SMA and ATTR – drug costs should be a key consideration in prescribing decisions, Dr. Callaghan and colleagues concluded.

One limitation of the study is that follow-up time was short for some of the recently approved medications. Another limitation is that the number of people in the study who had rare diseases was small.
 

Revolution in neurotherapeutics

“We are living in a time when new treatments bring hope to people with neurologic diseases and disorders,” Orly Avitzur, MD, president of the American Academy of Neurology, said in a statement.

“However, even existing prescription medication can be expensive and drug prices continue to rise. In order for neurologists to provide people with the highest quality care, it is imperative that new drugs are accessible and affordable to the people who need them,” Dr. Avitzur added.

Writing in a linked editorial, A. Gordon Smith, MD, professor and chair, department of neurology, Virginia Commonwealth University, Richmond, said there is a revolution in neurotherapeutics, with particularly robust growth in new drug approvals for orphan diseases (those affecting < 200,000 Americans).

“This study adds to a growing literature indicating rising drug prices are a threat to the health care system. No matter how effective a disease-modifying therapy may be, if a patient cannot afford the cost, it doesn’t work,” Dr. Smith wrote.

He added that neurologists must be “diligent in assessing for financial toxicity and appropriately tailor individual treatment recommendations. We must insist on development of point-of-care tools to accurately estimate each patient’s potential financial toxicity including RTBT [real-time benefit tools].

“Neurologists’ primary obligation is to the individual patient, but we are also compelled to support access to high-quality care for all people, which requires advocacy for appropriate policy reforms to ensure value based and fair drug pricing and treatment success,” Dr. Smith added.

The study was funded by the American Academy of Neurology Health Services Research Subcommittee. Dr. Callaghan consults for a PCORI grant, DynaMed, receives research support from the American Academy of Neurology, and performs medical/legal consultations, including consultations for the Vaccine Injury Compensation Program. Dr. Smith has disclosed no relevant financial relationships.

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

PHILADELPHIA – An international group of researchers has proposed the first classification criteria for chronic nonbacterial osteomyelitis (CNO) and a severe form of it, chronic recurrent multifocal osteomyelitis (CRMO).

CNO/CRMO most frequently affect children and adolescents and can significantly affect quality of life.

Yongdong (Dan) Zhao, MD, PhD, a pediatric rheumatologist at Seattle Children’s Hospital, Seattle, Washington, and Seza Ozen, MD, MSc, medical faculty head at Hacettepe University in Ankara, Turkey – members of the expert panel for criteria development – explained the proposed criteria, developed over 6 years, at the American College of Rheumatology 2022 Annual Meeting.

They gave examples of the point system that will help researchers correctly classify CNO/CRMO if the criteria are approved by ACR and the European Alliance of Associations for Rheumatology (EULAR).

Melissa S. Oliver, MD, a pediatric rheumatologist at Riley Children’s Hospital and Indiana University, Indianapolis, told this news organization: “This proposal is important because CNO/CRMO has primarily been a diagnosis of exclusion. There are no specific tests or biomarkers for this disease. It can mimic malignancy and infectious osteomyelitis in its presentation, and these must be ruled out thoroughly first.”

However, she noted, this can be challenging and can delay diagnosis and treatment.

The classification criteria are novel, she said, because an international collaborative group used a consensus process involving physicians managing CNO and patients or caregivers of children with CNO.
 

Findings for and against CNO

Dr. Ozen summarized some examples of findings for and against a CNO/CRMO classification.

Statistically significant findings in favor of CNO/CRMO, she said, include intermittent bone pain; bone pain in upper torso; swelling of upper torso; presence of symmetric lesions; and presence of adaptive immune cell and/or fibrosis in biopsy.

Conversely, findings against CNO/CRMO include fever; signs of infection by labs; signs of cancer by biopsy; specific abnormal x-ray/CT scan; specific abnormal MRI; or pain resolved with antibiotics alone.

Dr. Zhao described a point system with a threshold of 55 points for classification of CNO/CRMO.

He gave actual examples from the registry to demonstrate high and low probability of CNO/CRMO.
 

Pro-CNO example

The first was a boy, aged 7 years 10 months, who had a year and a half of pain in his back and legs, but no fever. Pain was constant, waxing and waning. He had a personal and family history of psoriasis and was tender to palpation at multiple sites. Labs were normal and bone biopsy and vitamin C tests were not done; imaging findings showed multiple bones were affected. There was no antibiotic treatment.

That patient was scored 81, much higher than the threshold of 55, and would be classified as having CNO.
 

Non-CNO example

Conversely, the following example of a patient would score 47 – under the threshold – and would not be classified as having CNO.

That patient was an 11-year-old boy who had 2 months of pain in his right thigh with no fever. The pain was constantly waxing and waning. He was tender to palpation at only his right thigh without swelling. Labs were normal. He had no coexisting conditions. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were not measured, and no vitamin C test was performed. Imaging showed one right femur lesion on a PET-CT scan. There was no antibiotic treatment, and a bone biopsy culture showed malignancy but no inflammation or fibrosis.

Dr. Zhao said the mimickers most likely to be misclassified are vitamin C deficiency; hypophosphatasia; benign bone tumor, such as osteogenic osteoma; and a malignancy with normal labs and multifocal pattern of bone lesions.

The classification criteria will be “extremely helpful to diagnose patients with CNO/CRMO earlier,” said Dr. Oliver, who helped develop the criteria.

“The goal is that the proposed classification criteria will be used by all physicians to diagnose suspected CNO patients earlier and refer to a rheumatologist earlier so that appropriate therapies will not be delayed.”

The group will seek ACR and EULAR endorsement, and if granted, work toward widespread implementation. The criteria will allow researchers to have a more homogeneous study population for future clinical trials, Dr. Zhao said.

Dr. Zhao, Dr. Ozen, and Dr. Oliver declared no relevant financial relationships. Dr. Oliver helped develop the proposed guidelines.

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

PHILADELPHIA – An international group of researchers has proposed the first classification criteria for chronic nonbacterial osteomyelitis (CNO) and a severe form of it, chronic recurrent multifocal osteomyelitis (CRMO).

CNO/CRMO most frequently affect children and adolescents and can significantly affect quality of life.

Yongdong (Dan) Zhao, MD, PhD, a pediatric rheumatologist at Seattle Children’s Hospital, Seattle, Washington, and Seza Ozen, MD, MSc, medical faculty head at Hacettepe University in Ankara, Turkey – members of the expert panel for criteria development – explained the proposed criteria, developed over 6 years, at the American College of Rheumatology 2022 Annual Meeting.

They gave examples of the point system that will help researchers correctly classify CNO/CRMO if the criteria are approved by ACR and the European Alliance of Associations for Rheumatology (EULAR).

Melissa S. Oliver, MD, a pediatric rheumatologist at Riley Children’s Hospital and Indiana University, Indianapolis, told this news organization: “This proposal is important because CNO/CRMO has primarily been a diagnosis of exclusion. There are no specific tests or biomarkers for this disease. It can mimic malignancy and infectious osteomyelitis in its presentation, and these must be ruled out thoroughly first.”

However, she noted, this can be challenging and can delay diagnosis and treatment.

The classification criteria are novel, she said, because an international collaborative group used a consensus process involving physicians managing CNO and patients or caregivers of children with CNO.
 

Findings for and against CNO

Dr. Ozen summarized some examples of findings for and against a CNO/CRMO classification.

Statistically significant findings in favor of CNO/CRMO, she said, include intermittent bone pain; bone pain in upper torso; swelling of upper torso; presence of symmetric lesions; and presence of adaptive immune cell and/or fibrosis in biopsy.

Conversely, findings against CNO/CRMO include fever; signs of infection by labs; signs of cancer by biopsy; specific abnormal x-ray/CT scan; specific abnormal MRI; or pain resolved with antibiotics alone.

Dr. Zhao described a point system with a threshold of 55 points for classification of CNO/CRMO.

He gave actual examples from the registry to demonstrate high and low probability of CNO/CRMO.
 

Pro-CNO example

The first was a boy, aged 7 years 10 months, who had a year and a half of pain in his back and legs, but no fever. Pain was constant, waxing and waning. He had a personal and family history of psoriasis and was tender to palpation at multiple sites. Labs were normal and bone biopsy and vitamin C tests were not done; imaging findings showed multiple bones were affected. There was no antibiotic treatment.

That patient was scored 81, much higher than the threshold of 55, and would be classified as having CNO.
 

Non-CNO example

Conversely, the following example of a patient would score 47 – under the threshold – and would not be classified as having CNO.

That patient was an 11-year-old boy who had 2 months of pain in his right thigh with no fever. The pain was constantly waxing and waning. He was tender to palpation at only his right thigh without swelling. Labs were normal. He had no coexisting conditions. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were not measured, and no vitamin C test was performed. Imaging showed one right femur lesion on a PET-CT scan. There was no antibiotic treatment, and a bone biopsy culture showed malignancy but no inflammation or fibrosis.

Dr. Zhao said the mimickers most likely to be misclassified are vitamin C deficiency; hypophosphatasia; benign bone tumor, such as osteogenic osteoma; and a malignancy with normal labs and multifocal pattern of bone lesions.

The classification criteria will be “extremely helpful to diagnose patients with CNO/CRMO earlier,” said Dr. Oliver, who helped develop the criteria.

“The goal is that the proposed classification criteria will be used by all physicians to diagnose suspected CNO patients earlier and refer to a rheumatologist earlier so that appropriate therapies will not be delayed.”

The group will seek ACR and EULAR endorsement, and if granted, work toward widespread implementation. The criteria will allow researchers to have a more homogeneous study population for future clinical trials, Dr. Zhao said.

Dr. Zhao, Dr. Ozen, and Dr. Oliver declared no relevant financial relationships. Dr. Oliver helped develop the proposed guidelines.

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

PHILADELPHIA – An international group of researchers has proposed the first classification criteria for chronic nonbacterial osteomyelitis (CNO) and a severe form of it, chronic recurrent multifocal osteomyelitis (CRMO).

CNO/CRMO most frequently affect children and adolescents and can significantly affect quality of life.

Yongdong (Dan) Zhao, MD, PhD, a pediatric rheumatologist at Seattle Children’s Hospital, Seattle, Washington, and Seza Ozen, MD, MSc, medical faculty head at Hacettepe University in Ankara, Turkey – members of the expert panel for criteria development – explained the proposed criteria, developed over 6 years, at the American College of Rheumatology 2022 Annual Meeting.

They gave examples of the point system that will help researchers correctly classify CNO/CRMO if the criteria are approved by ACR and the European Alliance of Associations for Rheumatology (EULAR).

Melissa S. Oliver, MD, a pediatric rheumatologist at Riley Children’s Hospital and Indiana University, Indianapolis, told this news organization: “This proposal is important because CNO/CRMO has primarily been a diagnosis of exclusion. There are no specific tests or biomarkers for this disease. It can mimic malignancy and infectious osteomyelitis in its presentation, and these must be ruled out thoroughly first.”

However, she noted, this can be challenging and can delay diagnosis and treatment.

The classification criteria are novel, she said, because an international collaborative group used a consensus process involving physicians managing CNO and patients or caregivers of children with CNO.
 

Findings for and against CNO

Dr. Ozen summarized some examples of findings for and against a CNO/CRMO classification.

Statistically significant findings in favor of CNO/CRMO, she said, include intermittent bone pain; bone pain in upper torso; swelling of upper torso; presence of symmetric lesions; and presence of adaptive immune cell and/or fibrosis in biopsy.

Conversely, findings against CNO/CRMO include fever; signs of infection by labs; signs of cancer by biopsy; specific abnormal x-ray/CT scan; specific abnormal MRI; or pain resolved with antibiotics alone.

Dr. Zhao described a point system with a threshold of 55 points for classification of CNO/CRMO.

He gave actual examples from the registry to demonstrate high and low probability of CNO/CRMO.
 

Pro-CNO example

The first was a boy, aged 7 years 10 months, who had a year and a half of pain in his back and legs, but no fever. Pain was constant, waxing and waning. He had a personal and family history of psoriasis and was tender to palpation at multiple sites. Labs were normal and bone biopsy and vitamin C tests were not done; imaging findings showed multiple bones were affected. There was no antibiotic treatment.

That patient was scored 81, much higher than the threshold of 55, and would be classified as having CNO.
 

Non-CNO example

Conversely, the following example of a patient would score 47 – under the threshold – and would not be classified as having CNO.

That patient was an 11-year-old boy who had 2 months of pain in his right thigh with no fever. The pain was constantly waxing and waning. He was tender to palpation at only his right thigh without swelling. Labs were normal. He had no coexisting conditions. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were not measured, and no vitamin C test was performed. Imaging showed one right femur lesion on a PET-CT scan. There was no antibiotic treatment, and a bone biopsy culture showed malignancy but no inflammation or fibrosis.

Dr. Zhao said the mimickers most likely to be misclassified are vitamin C deficiency; hypophosphatasia; benign bone tumor, such as osteogenic osteoma; and a malignancy with normal labs and multifocal pattern of bone lesions.

The classification criteria will be “extremely helpful to diagnose patients with CNO/CRMO earlier,” said Dr. Oliver, who helped develop the criteria.

“The goal is that the proposed classification criteria will be used by all physicians to diagnose suspected CNO patients earlier and refer to a rheumatologist earlier so that appropriate therapies will not be delayed.”

The group will seek ACR and EULAR endorsement, and if granted, work toward widespread implementation. The criteria will allow researchers to have a more homogeneous study population for future clinical trials, Dr. Zhao said.

Dr. Zhao, Dr. Ozen, and Dr. Oliver declared no relevant financial relationships. Dr. Oliver helped develop the proposed guidelines.

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

Boston dietitian Katarina Mollo, MEd, RDN, LDN, has virtually no memory of life without celiac disease (CD). Diagnosed at age 4, Dr. Mollo has been on a gluten-free diet for 41 years, which she says has kept her healthy and may also be why she hasn’t developed other autoimmune diseases. It’s also played a part in her thinking about screening patients with CD.

“I think [physicians] should definitely be screening people with celiac disease for autoimmune disorders, especially if they see things like anemia or if a child has dropped on the growth chart and has nutrient deficiencies,” said Dr. Mollo, whose daughter also has the disease. “I would recommend that they see someone who specializes in celiac disease so they can get monitored and have regular follow-up checks for nutrient deficiencies and other autoimmune disorders.”

Dr. Mollo’s views on screening are echoed by many CD specialists and physicians, who cite multiple studies that have found that people with the disease face higher risks for diabetes, thyroid conditions, arthritis, and other autoimmune disorders.

Gastroenterologist Alessio Fasano, MD, with Massachusetts General Hospital, Boston, said there has been a “shift in the paradigm in thinking” about cross-screening for CD and autoimmune disorders. As result, he believes the answer to the question of whether to routinely do so is a no-brainer.

“The bottom line is, if you have CD, it [should be] routine that during your annual follow-ups you check for the possibility of the onset of other autoimmune disease. And people with other autoimmune diseases, like type 1 diabetes, should also be screened for CD because of the comorbidity,” said Dr. Fasano, professor of pediatrics and gastroenterology at Harvard Medical School and professor of nutrition at the Harvard School of Public Health, both in Boston. “This is what we call good clinical practice.”
 

Screening, despite lack of consensus guidelines

Other CD specialists differ on the need for universal cross-screening but agree that, at least in some cases, people with one autoimmune disorder should be tested for others.

Jolanda Denham, MD, a pediatric gastroenterologist affiliated with Nemours Children’s Hospital in Orlando, routinely recommends that her patients with CD be screened for certain autoimmune disorders – such as type 1 diabetes and autoimmune thyroid and liver diseases – even though medical organizations have not developed clear consensus or standard guidelines on cross-screening.

“There currently is no evidence to support the screening of celiac patients for all autoimmune and rheumatologic disorders,” she said. “It is true that celiac disease is an autoimmune disorder, and as such, there is a definite increased risk of these disorders in patients with celiac disease and vice versa.”

Echoing Dr. Denham, New York–based gastroenterologist Benjamin Lebwohl, MD, president of the Society for the Study of Celiac Disease, urges physicians to look beyond consensus guidelines and to err on the side of caution and make the best decisions for their patients on a case-by-case basis.

“Given the increased risk of certain autoimmune conditions in people with celiac disease, it behooves physicians to have a low threshold to evaluate for these conditions if any suggestive symptoms are present,” said Dr. Lebwohl, director of clinical research at the Celiac Disease Center at Columbia University, New York.

“Whether to screen for these conditions among people who are entirely without symptoms is less certain, and there is no consensus on that. But it is reasonable and common to include some basic tests with annual blood work, such as thyroid function and a liver profile, since both autoimmune thyroid disease and autoimmune liver disease can be silent early on and the patient would potentially benefit from identification and treatment of these conditions,” he said.

The American Diabetes Association and the International Society of Pediatric and Adolescent Diabetes do recommend that people with diabetes be screened for CD years after diagnosis, noted Robert Rapaport, MD, a pediatric endocrinologist, with Kravis Children’s Hospital, New York. But in a study published in 2021, he and colleagues found that this wasn’t occurring, which prompted them to recommend yearly screening.

“There is a consensus that in children with type 1 diabetes, we screen them for other autoimmune disorders, specifically for thyroid disease and celiac disease,” said Dr. Rapaport, who is also Emma Elizabeth Sullivan Professor of Pediatric Endocrinology and Diabetes at Icahn School of Medicine at Mount Sinai, New York. “But there is no consensus going the other way – for patients with celiac disease, what other autoimmune conditions they should be screened for.”

This hasn’t kept some doctors from extending cross-screening efforts to their patients.

“At our center, we screen ... for thyroid disease and autoimmune liver disease as part of routine healthcare maintenance for our celiac disease patients. We discuss symptoms of diabetes and send screening with [hemoglobin] A1c for anyone who has symptoms,” said Lui Edwin, MD, a pediatric gastroenterologist with Children’s Hospital Colorado, Aurora, and director of the Colorado Center for Celiac Disease, who delivered a lecture on CD-autoimmune screening at the International Celiac Disease Symposium in October.

“It is definitely worth screening for celiac disease in [those with] other autoimmune disorders,” Dr. Edwin added.

“The symptoms can be very heterogeneous. Diagnosing and treating celiac disease can make a huge impact with respect to symptoms, quality of life, and preventing disease-related complications,” he said.
 

Mounting evidence linking CD to autoimmune disorders

Many studies have linked CD to a variety of other autoimmune disorders. The association could be due to common genetic factors or because CD might lead to such conditions. Researchers have found that people diagnosed with CD later in life are more likely to develop other autoimmune disorders.

Going gluten free has preventive advantages

In a landmark 2012 study, researchers with the Celiac Disease Center at Columbia University stopped short of recommending routine screening for the general public or asymptomatic individuals in high-prevalence groups. But they concluded that more screening of symptomatic individuals – and close relatives – would speed treatment for those with more than one autoimmune disorder.

They also noted that some studies have found that a gluten-free diet might help prevent the development of other autoimmune disorders.

Marisa Gallant Stahl, MD, a gastroenterologist with Children’s Hospital Colorado, agreed that it is important that physicians keep gluten-free diets in mind when determining which patients to cross-screen.

“The literature is mixed, but some studies suggest that treating celiac disease with a gluten-free diet actually augments the treatment and control of other autoimmune disorders [and] adherence to a gluten-free diet does reduce the risk of cancer associated with celiac disease,” she said.

Dr. Denham agreed. “Strict adherence to a gluten-free diet definitely protects against the development of enteropathy-associated T-cell lymphoma but may be protective against non-Hodgkin’s lymphoma and adenocarcinoma of the small intestine as well. All three are associated with long-term nonadherence to a gluten-free diet.”

She also noted that a gluten-free diet may help people with CD manage other autoimmune disorders, which can be complicated by CD.

“Good control of celiac disease will help prevent complications that can worsen symptoms and outcomes of concomitant autoimmune and rheumatologic disorders,” she said.
 

Other factors to consider

Dr. Fasano added that autoimmune disorders can be complicated by CD in cases in which oral medications or healthful foods are not properly absorbed in the intestines.

“For example, with Hashimoto’s disease, if you have hormone replacement with oral treatments and your intestines are not 100% functional because you have inflammation, then you may have a problem [with] the absorption of medications like levothyroxine,” he said.

“It’s the same story with diabetes. You don’t take insulin by mouth, but glucose [control] strongly depends on several factors, mostly what comes from the diet, and if it’s erratic, that can be a problem. ... So, the treatment of autoimmune diseases can be influenced by celiac disease,” he said.

In addition, Dr. Fasano and others believe that people with CD and other autoimmune disorders should be managed by a team of experts who can personalize the care on the basis of specific needs of the individual patient. These should include specialists, dietitians, mental health counselors, and family social workers.

“It has to be a multidisciplinary approach to maintain the good health of an individual,” Dr. Fasano said. “Celiac disease is the quintessential example in which the primary care physician needs to be the quarterback of the team, the patient is active in his or her health, and [specialists] not only deliver personalized care but also preventive intervention, particularly the prevention of comorbidities.”

Financial disclosures for those quoted in this article were not available at the time of publication.

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

Boston dietitian Katarina Mollo, MEd, RDN, LDN, has virtually no memory of life without celiac disease (CD). Diagnosed at age 4, Dr. Mollo has been on a gluten-free diet for 41 years, which she says has kept her healthy and may also be why she hasn’t developed other autoimmune diseases. It’s also played a part in her thinking about screening patients with CD.

“I think [physicians] should definitely be screening people with celiac disease for autoimmune disorders, especially if they see things like anemia or if a child has dropped on the growth chart and has nutrient deficiencies,” said Dr. Mollo, whose daughter also has the disease. “I would recommend that they see someone who specializes in celiac disease so they can get monitored and have regular follow-up checks for nutrient deficiencies and other autoimmune disorders.”

Dr. Mollo’s views on screening are echoed by many CD specialists and physicians, who cite multiple studies that have found that people with the disease face higher risks for diabetes, thyroid conditions, arthritis, and other autoimmune disorders.

Gastroenterologist Alessio Fasano, MD, with Massachusetts General Hospital, Boston, said there has been a “shift in the paradigm in thinking” about cross-screening for CD and autoimmune disorders. As result, he believes the answer to the question of whether to routinely do so is a no-brainer.

“The bottom line is, if you have CD, it [should be] routine that during your annual follow-ups you check for the possibility of the onset of other autoimmune disease. And people with other autoimmune diseases, like type 1 diabetes, should also be screened for CD because of the comorbidity,” said Dr. Fasano, professor of pediatrics and gastroenterology at Harvard Medical School and professor of nutrition at the Harvard School of Public Health, both in Boston. “This is what we call good clinical practice.”
 

Screening, despite lack of consensus guidelines

Other CD specialists differ on the need for universal cross-screening but agree that, at least in some cases, people with one autoimmune disorder should be tested for others.

Jolanda Denham, MD, a pediatric gastroenterologist affiliated with Nemours Children’s Hospital in Orlando, routinely recommends that her patients with CD be screened for certain autoimmune disorders – such as type 1 diabetes and autoimmune thyroid and liver diseases – even though medical organizations have not developed clear consensus or standard guidelines on cross-screening.

“There currently is no evidence to support the screening of celiac patients for all autoimmune and rheumatologic disorders,” she said. “It is true that celiac disease is an autoimmune disorder, and as such, there is a definite increased risk of these disorders in patients with celiac disease and vice versa.”

Echoing Dr. Denham, New York–based gastroenterologist Benjamin Lebwohl, MD, president of the Society for the Study of Celiac Disease, urges physicians to look beyond consensus guidelines and to err on the side of caution and make the best decisions for their patients on a case-by-case basis.

“Given the increased risk of certain autoimmune conditions in people with celiac disease, it behooves physicians to have a low threshold to evaluate for these conditions if any suggestive symptoms are present,” said Dr. Lebwohl, director of clinical research at the Celiac Disease Center at Columbia University, New York.

“Whether to screen for these conditions among people who are entirely without symptoms is less certain, and there is no consensus on that. But it is reasonable and common to include some basic tests with annual blood work, such as thyroid function and a liver profile, since both autoimmune thyroid disease and autoimmune liver disease can be silent early on and the patient would potentially benefit from identification and treatment of these conditions,” he said.

The American Diabetes Association and the International Society of Pediatric and Adolescent Diabetes do recommend that people with diabetes be screened for CD years after diagnosis, noted Robert Rapaport, MD, a pediatric endocrinologist, with Kravis Children’s Hospital, New York. But in a study published in 2021, he and colleagues found that this wasn’t occurring, which prompted them to recommend yearly screening.

“There is a consensus that in children with type 1 diabetes, we screen them for other autoimmune disorders, specifically for thyroid disease and celiac disease,” said Dr. Rapaport, who is also Emma Elizabeth Sullivan Professor of Pediatric Endocrinology and Diabetes at Icahn School of Medicine at Mount Sinai, New York. “But there is no consensus going the other way – for patients with celiac disease, what other autoimmune conditions they should be screened for.”

This hasn’t kept some doctors from extending cross-screening efforts to their patients.

“At our center, we screen ... for thyroid disease and autoimmune liver disease as part of routine healthcare maintenance for our celiac disease patients. We discuss symptoms of diabetes and send screening with [hemoglobin] A1c for anyone who has symptoms,” said Lui Edwin, MD, a pediatric gastroenterologist with Children’s Hospital Colorado, Aurora, and director of the Colorado Center for Celiac Disease, who delivered a lecture on CD-autoimmune screening at the International Celiac Disease Symposium in October.

“It is definitely worth screening for celiac disease in [those with] other autoimmune disorders,” Dr. Edwin added.

“The symptoms can be very heterogeneous. Diagnosing and treating celiac disease can make a huge impact with respect to symptoms, quality of life, and preventing disease-related complications,” he said.
 

Mounting evidence linking CD to autoimmune disorders

Many studies have linked CD to a variety of other autoimmune disorders. The association could be due to common genetic factors or because CD might lead to such conditions. Researchers have found that people diagnosed with CD later in life are more likely to develop other autoimmune disorders.

Going gluten free has preventive advantages

In a landmark 2012 study, researchers with the Celiac Disease Center at Columbia University stopped short of recommending routine screening for the general public or asymptomatic individuals in high-prevalence groups. But they concluded that more screening of symptomatic individuals – and close relatives – would speed treatment for those with more than one autoimmune disorder.

They also noted that some studies have found that a gluten-free diet might help prevent the development of other autoimmune disorders.

Marisa Gallant Stahl, MD, a gastroenterologist with Children’s Hospital Colorado, agreed that it is important that physicians keep gluten-free diets in mind when determining which patients to cross-screen.

“The literature is mixed, but some studies suggest that treating celiac disease with a gluten-free diet actually augments the treatment and control of other autoimmune disorders [and] adherence to a gluten-free diet does reduce the risk of cancer associated with celiac disease,” she said.

Dr. Denham agreed. “Strict adherence to a gluten-free diet definitely protects against the development of enteropathy-associated T-cell lymphoma but may be protective against non-Hodgkin’s lymphoma and adenocarcinoma of the small intestine as well. All three are associated with long-term nonadherence to a gluten-free diet.”

She also noted that a gluten-free diet may help people with CD manage other autoimmune disorders, which can be complicated by CD.

“Good control of celiac disease will help prevent complications that can worsen symptoms and outcomes of concomitant autoimmune and rheumatologic disorders,” she said.
 

Other factors to consider

Dr. Fasano added that autoimmune disorders can be complicated by CD in cases in which oral medications or healthful foods are not properly absorbed in the intestines.

“For example, with Hashimoto’s disease, if you have hormone replacement with oral treatments and your intestines are not 100% functional because you have inflammation, then you may have a problem [with] the absorption of medications like levothyroxine,” he said.

“It’s the same story with diabetes. You don’t take insulin by mouth, but glucose [control] strongly depends on several factors, mostly what comes from the diet, and if it’s erratic, that can be a problem. ... So, the treatment of autoimmune diseases can be influenced by celiac disease,” he said.

In addition, Dr. Fasano and others believe that people with CD and other autoimmune disorders should be managed by a team of experts who can personalize the care on the basis of specific needs of the individual patient. These should include specialists, dietitians, mental health counselors, and family social workers.

“It has to be a multidisciplinary approach to maintain the good health of an individual,” Dr. Fasano said. “Celiac disease is the quintessential example in which the primary care physician needs to be the quarterback of the team, the patient is active in his or her health, and [specialists] not only deliver personalized care but also preventive intervention, particularly the prevention of comorbidities.”

Financial disclosures for those quoted in this article were not available at the time of publication.

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

Boston dietitian Katarina Mollo, MEd, RDN, LDN, has virtually no memory of life without celiac disease (CD). Diagnosed at age 4, Dr. Mollo has been on a gluten-free diet for 41 years, which she says has kept her healthy and may also be why she hasn’t developed other autoimmune diseases. It’s also played a part in her thinking about screening patients with CD.

“I think [physicians] should definitely be screening people with celiac disease for autoimmune disorders, especially if they see things like anemia or if a child has dropped on the growth chart and has nutrient deficiencies,” said Dr. Mollo, whose daughter also has the disease. “I would recommend that they see someone who specializes in celiac disease so they can get monitored and have regular follow-up checks for nutrient deficiencies and other autoimmune disorders.”

Dr. Mollo’s views on screening are echoed by many CD specialists and physicians, who cite multiple studies that have found that people with the disease face higher risks for diabetes, thyroid conditions, arthritis, and other autoimmune disorders.

Gastroenterologist Alessio Fasano, MD, with Massachusetts General Hospital, Boston, said there has been a “shift in the paradigm in thinking” about cross-screening for CD and autoimmune disorders. As result, he believes the answer to the question of whether to routinely do so is a no-brainer.

“The bottom line is, if you have CD, it [should be] routine that during your annual follow-ups you check for the possibility of the onset of other autoimmune disease. And people with other autoimmune diseases, like type 1 diabetes, should also be screened for CD because of the comorbidity,” said Dr. Fasano, professor of pediatrics and gastroenterology at Harvard Medical School and professor of nutrition at the Harvard School of Public Health, both in Boston. “This is what we call good clinical practice.”
 

Screening, despite lack of consensus guidelines

Other CD specialists differ on the need for universal cross-screening but agree that, at least in some cases, people with one autoimmune disorder should be tested for others.

Jolanda Denham, MD, a pediatric gastroenterologist affiliated with Nemours Children’s Hospital in Orlando, routinely recommends that her patients with CD be screened for certain autoimmune disorders – such as type 1 diabetes and autoimmune thyroid and liver diseases – even though medical organizations have not developed clear consensus or standard guidelines on cross-screening.

“There currently is no evidence to support the screening of celiac patients for all autoimmune and rheumatologic disorders,” she said. “It is true that celiac disease is an autoimmune disorder, and as such, there is a definite increased risk of these disorders in patients with celiac disease and vice versa.”

Echoing Dr. Denham, New York–based gastroenterologist Benjamin Lebwohl, MD, president of the Society for the Study of Celiac Disease, urges physicians to look beyond consensus guidelines and to err on the side of caution and make the best decisions for their patients on a case-by-case basis.

“Given the increased risk of certain autoimmune conditions in people with celiac disease, it behooves physicians to have a low threshold to evaluate for these conditions if any suggestive symptoms are present,” said Dr. Lebwohl, director of clinical research at the Celiac Disease Center at Columbia University, New York.

“Whether to screen for these conditions among people who are entirely without symptoms is less certain, and there is no consensus on that. But it is reasonable and common to include some basic tests with annual blood work, such as thyroid function and a liver profile, since both autoimmune thyroid disease and autoimmune liver disease can be silent early on and the patient would potentially benefit from identification and treatment of these conditions,” he said.

The American Diabetes Association and the International Society of Pediatric and Adolescent Diabetes do recommend that people with diabetes be screened for CD years after diagnosis, noted Robert Rapaport, MD, a pediatric endocrinologist, with Kravis Children’s Hospital, New York. But in a study published in 2021, he and colleagues found that this wasn’t occurring, which prompted them to recommend yearly screening.

“There is a consensus that in children with type 1 diabetes, we screen them for other autoimmune disorders, specifically for thyroid disease and celiac disease,” said Dr. Rapaport, who is also Emma Elizabeth Sullivan Professor of Pediatric Endocrinology and Diabetes at Icahn School of Medicine at Mount Sinai, New York. “But there is no consensus going the other way – for patients with celiac disease, what other autoimmune conditions they should be screened for.”

This hasn’t kept some doctors from extending cross-screening efforts to their patients.

“At our center, we screen ... for thyroid disease and autoimmune liver disease as part of routine healthcare maintenance for our celiac disease patients. We discuss symptoms of diabetes and send screening with [hemoglobin] A1c for anyone who has symptoms,” said Lui Edwin, MD, a pediatric gastroenterologist with Children’s Hospital Colorado, Aurora, and director of the Colorado Center for Celiac Disease, who delivered a lecture on CD-autoimmune screening at the International Celiac Disease Symposium in October.

“It is definitely worth screening for celiac disease in [those with] other autoimmune disorders,” Dr. Edwin added.

“The symptoms can be very heterogeneous. Diagnosing and treating celiac disease can make a huge impact with respect to symptoms, quality of life, and preventing disease-related complications,” he said.
 

Mounting evidence linking CD to autoimmune disorders

Many studies have linked CD to a variety of other autoimmune disorders. The association could be due to common genetic factors or because CD might lead to such conditions. Researchers have found that people diagnosed with CD later in life are more likely to develop other autoimmune disorders.

Going gluten free has preventive advantages

In a landmark 2012 study, researchers with the Celiac Disease Center at Columbia University stopped short of recommending routine screening for the general public or asymptomatic individuals in high-prevalence groups. But they concluded that more screening of symptomatic individuals – and close relatives – would speed treatment for those with more than one autoimmune disorder.

They also noted that some studies have found that a gluten-free diet might help prevent the development of other autoimmune disorders.

Marisa Gallant Stahl, MD, a gastroenterologist with Children’s Hospital Colorado, agreed that it is important that physicians keep gluten-free diets in mind when determining which patients to cross-screen.

“The literature is mixed, but some studies suggest that treating celiac disease with a gluten-free diet actually augments the treatment and control of other autoimmune disorders [and] adherence to a gluten-free diet does reduce the risk of cancer associated with celiac disease,” she said.

Dr. Denham agreed. “Strict adherence to a gluten-free diet definitely protects against the development of enteropathy-associated T-cell lymphoma but may be protective against non-Hodgkin’s lymphoma and adenocarcinoma of the small intestine as well. All three are associated with long-term nonadherence to a gluten-free diet.”

She also noted that a gluten-free diet may help people with CD manage other autoimmune disorders, which can be complicated by CD.

“Good control of celiac disease will help prevent complications that can worsen symptoms and outcomes of concomitant autoimmune and rheumatologic disorders,” she said.
 

Other factors to consider

Dr. Fasano added that autoimmune disorders can be complicated by CD in cases in which oral medications or healthful foods are not properly absorbed in the intestines.

“For example, with Hashimoto’s disease, if you have hormone replacement with oral treatments and your intestines are not 100% functional because you have inflammation, then you may have a problem [with] the absorption of medications like levothyroxine,” he said.

“It’s the same story with diabetes. You don’t take insulin by mouth, but glucose [control] strongly depends on several factors, mostly what comes from the diet, and if it’s erratic, that can be a problem. ... So, the treatment of autoimmune diseases can be influenced by celiac disease,” he said.

In addition, Dr. Fasano and others believe that people with CD and other autoimmune disorders should be managed by a team of experts who can personalize the care on the basis of specific needs of the individual patient. These should include specialists, dietitians, mental health counselors, and family social workers.

“It has to be a multidisciplinary approach to maintain the good health of an individual,” Dr. Fasano said. “Celiac disease is the quintessential example in which the primary care physician needs to be the quarterback of the team, the patient is active in his or her health, and [specialists] not only deliver personalized care but also preventive intervention, particularly the prevention of comorbidities.”

Financial disclosures for those quoted in this article were not available at the time of publication.

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