Rare Diseases

THE CASE

A 34-year-old man was referred to the sports medicine clinic for evaluation of lumbar radiculopathy. He had a 2-year history of chronic lower back pain that started while he was working on power line towers in Puerto Rico. The back pain was achy, burning, shooting, and stabbing in nature. He had been treated with anti-inflammatories by a company health care provider while in Puerto Rico, but he did not have any imaging done.

At that time, he had tingling and burning that radiated down his left leg to his ankle. The patient also had leg spasms—in his left leg more than his right—and needed a cane when walking. His symptoms did not worsen at any particular time of day or with activity. He had no history of eating exotic foods or sustaining any venomous bites/stings. Ultimately, the back pain and leg spasms forced him to leave his job and return home to Louisiana.

Upon presentation to the sports medicine clinic, he explained that things had worsened since his return home. The pain and burning in his left leg had increased and were now present in his right leg, as well (bilateral paresthesias). In addition, he said he was feeling anxious (and described symptoms of forgetfulness, confusion, and agitation), was sleeping less, and was experiencing worsening fatigue.

Work-ups over the course of the previous 2 years had shed little light on the cause of his symptoms. X-rays of his lumbar spine revealed moderate degenerative changes at L5-S1. A lab work-up was negative and included a complete blood count, testing for HIV and herpes, a hepatitis panel, an antinuclear antibody screen, a C-reactive protein test, and a comprehensive metabolic panel. Thyroid-stimulating hormone, creatine kinase, rapid plasma reagin, and human leukocyte antigen B27 tests were also normal.

Magnetic resonance imaging (MRI) revealed a cystic lesion in the right ilium near the sacroiliac joint. A more recent follow-up MRI and computed tomography scan of the pelvis found the cyst to be stable and well marginalized, with no cortical erosion. Attempts at physical therapy had been unsuccessful because of the pain and decreasing muscle strength in his lower extremities. The patient’s primary care provider was treating him with meloxicam 15 mg/d and duloxetine 60 mg/d, but that had not provided any relief.

Our physical examination revealed a patient who was in mild distress and had limited lumbar spine range of motion (secondary to pain in all planes) and significant paraspinal spasms on the right side in both the lumbar and thoracic regions. The patient had reduced vibratory sensation on his left side vs the right, with a 256-Hz tuning fork at the great toe, as well as reduced sensation to fine touch with a cotton swab and a positive Babinski sign bilaterally. Lower extremity reflexes were hyperreflexic on the left compared with the right. He had no pronator drift; Trendelenburg, straight leg raise, Hoover sign, and slump tests were all negative. His gait was antalgic with a cane, as he described bilateral paresthesias.

THE DIAGNOSIS

The differential diagnosis for low back pain is quite extensive and includes simple mechanical low back pain, lumbar radiculopathy, facet arthritis, spinal stenosis, spondylolysis/spondylolisthesis, and referred pain from the hip, knee, or upper back. It can also be caused by referred pain from visceral organs such as the liver, colon, or kidneys. Low back pain can also signal primary or metastatic disease. However, most of these potential diagnoses had been ruled out with imaging and lab tests.

Continue to: Two things caught our attention

Two things caught our attention. First: Mechanical low back pain and the associated discogenic radiculopathy would be unilateral, manifesting with asymmetric paresthesias and pain. Our patient had weakness in gait and pain and burning in both of his legs. Second: Our patient described decreased sleep and feeling anxious, with symptoms of forgetfulness, confusion, and agitation. These factors prompted us to look beyond the normal differential and consider a potential toxicity. A heavy metal screen was ordered, and the results were positive for arsenic toxicity.

DISCUSSION

Arsenic toxicity is a global health problem that affects millions of people.^1,2 Arsenic has been used for centuries in depilatories, cosmetics, poisons, and therapeutic agents. Today it is used as a treatment for leukemia and in several ayurvedic and homeopathic remedies.^3-7 It is a common earth element found in ground water and a waste product from mining and the manufacturing of glass, computer chips, wood preservatives, and various pesticides.^2,3,7,8

A great masquerader. Once in the body, arsenic can cause many serious ailments ranging from urinary tract, liver, and skin cancers to various peripheral and central nervous system disorders.² Arsenic can cause symmetrical peripheral neuropathy characterized by sensory nerves being more sensitive than motor nerves.^2,3,5,6 Clinically, it causes numbness and paresthesias of the distal extremities, with the lower extremities more severely affected.^3,6 Symptoms can develop within 2 hours to 2 years of exposure, with vomiting, diarrhea, or both preceding the onset of the neuropathy.^2,3,5,6 Arsenic is linked to forgetfulness, confusion, visual distortion, sleep disturbances, decreased concentration, disorientation, severe agitation, paranoid ideation, emotional lability, and decreases in locomotor activity.^3,5,6

Testing and treatment. Arsenic levels in the body are measured by blood and urine testing. Blood arsenic levels are typically detectable immediately after exposure and with continued exposure, but quickly normalize as the metal integrates into the nonvascular tissues. Urine arsenic levels can be detected for weeks. Normal levels for arsenic in both urine and blood are ≤ 12 µg/L.³ Anything greater than 12 µg/L is considered high; critically high values are those above 50 µg/L.^3,5 Our patient’s blood arsenic level was 13 µg/L.

Several of the patient’s symptoms prompted us to look beyond the normal differential and consider a potential toxicity.

Treatment involves removing the source of the arsenic. Chelation therapy should be pursued when urine arsenic levels are greater than 50 µg/L or when removing the source of the arsenic fails to reduce arsenic levels. Chelation therapy should be continued until urine arsenic levels are below 20 µg/L.^5,6

Continue to: After discussing potential sources of exposure

After discussing potential sources of exposure, our patient decided to move out of the house he shared with his ex-wife. He started to recover soon after moving out. Two weeks after his clinic visit, he no longer needed a cane to walk, and his blood arsenic level had dropped to 6 µg/L. Two months after his clinic visit, the patient’s blood arsenic level was undetectable. The patient’s peripheral neuropathy symptoms continued to improve.

The source of this patient’s arsenic exposure was never confirmed. The exposure could have occurred in Puerto Rico or in Louisiana. Even though no one else in the Louisiana home became ill, the patient was instructed to contact the local health department and water department to have the water tested. However, when he returned to the clinic for follow-up, he had not followed through.

THE TAKEAWAY

When evaluating causes of peripheral neuropathy, consider the possibility of heavy metal toxicity, which can be easily overlooked by the busy clinician. In this case, the patient initially experienced asymmetric paresthesia that gradually increased to burning pain and weakness, with reduced motor control bilaterally. This was significant because mechanical low back pain and the associated discogenic radiculopathy would be unilateral, manifesting with asymmetric paresthesias and pain.

Our patient’s leg symptoms, the constellation of forgetfulness, confusion, and agitation, and his sleep issues prompted us to look outside our normal differential. Fortunately, once arsenic exposure ceases, patients will gradually improve because arsenic is rapidly cleared from the bloodstream.^3,6

CORRESPONDENCE
Charles W. Webb, DO, CAQSM, FAMSSM, FAAFP, Department of Family Medicine, 1501 Kings Highway, PO Box 33932, Shreveport, LA 71130-3932; [email protected]

THE CASE

A 34-year-old man was referred to the sports medicine clinic for evaluation of lumbar radiculopathy. He had a 2-year history of chronic lower back pain that started while he was working on power line towers in Puerto Rico. The back pain was achy, burning, shooting, and stabbing in nature. He had been treated with anti-inflammatories by a company health care provider while in Puerto Rico, but he did not have any imaging done.

At that time, he had tingling and burning that radiated down his left leg to his ankle. The patient also had leg spasms—in his left leg more than his right—and needed a cane when walking. His symptoms did not worsen at any particular time of day or with activity. He had no history of eating exotic foods or sustaining any venomous bites/stings. Ultimately, the back pain and leg spasms forced him to leave his job and return home to Louisiana.

Upon presentation to the sports medicine clinic, he explained that things had worsened since his return home. The pain and burning in his left leg had increased and were now present in his right leg, as well (bilateral paresthesias). In addition, he said he was feeling anxious (and described symptoms of forgetfulness, confusion, and agitation), was sleeping less, and was experiencing worsening fatigue.

Work-ups over the course of the previous 2 years had shed little light on the cause of his symptoms. X-rays of his lumbar spine revealed moderate degenerative changes at L5-S1. A lab work-up was negative and included a complete blood count, testing for HIV and herpes, a hepatitis panel, an antinuclear antibody screen, a C-reactive protein test, and a comprehensive metabolic panel. Thyroid-stimulating hormone, creatine kinase, rapid plasma reagin, and human leukocyte antigen B27 tests were also normal.

Magnetic resonance imaging (MRI) revealed a cystic lesion in the right ilium near the sacroiliac joint. A more recent follow-up MRI and computed tomography scan of the pelvis found the cyst to be stable and well marginalized, with no cortical erosion. Attempts at physical therapy had been unsuccessful because of the pain and decreasing muscle strength in his lower extremities. The patient’s primary care provider was treating him with meloxicam 15 mg/d and duloxetine 60 mg/d, but that had not provided any relief.

Our physical examination revealed a patient who was in mild distress and had limited lumbar spine range of motion (secondary to pain in all planes) and significant paraspinal spasms on the right side in both the lumbar and thoracic regions. The patient had reduced vibratory sensation on his left side vs the right, with a 256-Hz tuning fork at the great toe, as well as reduced sensation to fine touch with a cotton swab and a positive Babinski sign bilaterally. Lower extremity reflexes were hyperreflexic on the left compared with the right. He had no pronator drift; Trendelenburg, straight leg raise, Hoover sign, and slump tests were all negative. His gait was antalgic with a cane, as he described bilateral paresthesias.

THE DIAGNOSIS

The differential diagnosis for low back pain is quite extensive and includes simple mechanical low back pain, lumbar radiculopathy, facet arthritis, spinal stenosis, spondylolysis/spondylolisthesis, and referred pain from the hip, knee, or upper back. It can also be caused by referred pain from visceral organs such as the liver, colon, or kidneys. Low back pain can also signal primary or metastatic disease. However, most of these potential diagnoses had been ruled out with imaging and lab tests.

Continue to: Two things caught our attention

Two things caught our attention. First: Mechanical low back pain and the associated discogenic radiculopathy would be unilateral, manifesting with asymmetric paresthesias and pain. Our patient had weakness in gait and pain and burning in both of his legs. Second: Our patient described decreased sleep and feeling anxious, with symptoms of forgetfulness, confusion, and agitation. These factors prompted us to look beyond the normal differential and consider a potential toxicity. A heavy metal screen was ordered, and the results were positive for arsenic toxicity.

DISCUSSION

Arsenic toxicity is a global health problem that affects millions of people.^1,2 Arsenic has been used for centuries in depilatories, cosmetics, poisons, and therapeutic agents. Today it is used as a treatment for leukemia and in several ayurvedic and homeopathic remedies.^3-7 It is a common earth element found in ground water and a waste product from mining and the manufacturing of glass, computer chips, wood preservatives, and various pesticides.^2,3,7,8

A great masquerader. Once in the body, arsenic can cause many serious ailments ranging from urinary tract, liver, and skin cancers to various peripheral and central nervous system disorders.² Arsenic can cause symmetrical peripheral neuropathy characterized by sensory nerves being more sensitive than motor nerves.^2,3,5,6 Clinically, it causes numbness and paresthesias of the distal extremities, with the lower extremities more severely affected.^3,6 Symptoms can develop within 2 hours to 2 years of exposure, with vomiting, diarrhea, or both preceding the onset of the neuropathy.^2,3,5,6 Arsenic is linked to forgetfulness, confusion, visual distortion, sleep disturbances, decreased concentration, disorientation, severe agitation, paranoid ideation, emotional lability, and decreases in locomotor activity.^3,5,6

Testing and treatment. Arsenic levels in the body are measured by blood and urine testing. Blood arsenic levels are typically detectable immediately after exposure and with continued exposure, but quickly normalize as the metal integrates into the nonvascular tissues. Urine arsenic levels can be detected for weeks. Normal levels for arsenic in both urine and blood are ≤ 12 µg/L.³ Anything greater than 12 µg/L is considered high; critically high values are those above 50 µg/L.^3,5 Our patient’s blood arsenic level was 13 µg/L.

Several of the patient’s symptoms prompted us to look beyond the normal differential and consider a potential toxicity.

Treatment involves removing the source of the arsenic. Chelation therapy should be pursued when urine arsenic levels are greater than 50 µg/L or when removing the source of the arsenic fails to reduce arsenic levels. Chelation therapy should be continued until urine arsenic levels are below 20 µg/L.^5,6

Continue to: After discussing potential sources of exposure

After discussing potential sources of exposure, our patient decided to move out of the house he shared with his ex-wife. He started to recover soon after moving out. Two weeks after his clinic visit, he no longer needed a cane to walk, and his blood arsenic level had dropped to 6 µg/L. Two months after his clinic visit, the patient’s blood arsenic level was undetectable. The patient’s peripheral neuropathy symptoms continued to improve.

The source of this patient’s arsenic exposure was never confirmed. The exposure could have occurred in Puerto Rico or in Louisiana. Even though no one else in the Louisiana home became ill, the patient was instructed to contact the local health department and water department to have the water tested. However, when he returned to the clinic for follow-up, he had not followed through.

THE TAKEAWAY

When evaluating causes of peripheral neuropathy, consider the possibility of heavy metal toxicity, which can be easily overlooked by the busy clinician. In this case, the patient initially experienced asymmetric paresthesia that gradually increased to burning pain and weakness, with reduced motor control bilaterally. This was significant because mechanical low back pain and the associated discogenic radiculopathy would be unilateral, manifesting with asymmetric paresthesias and pain.

Our patient’s leg symptoms, the constellation of forgetfulness, confusion, and agitation, and his sleep issues prompted us to look outside our normal differential. Fortunately, once arsenic exposure ceases, patients will gradually improve because arsenic is rapidly cleared from the bloodstream.^3,6

CORRESPONDENCE
Charles W. Webb, DO, CAQSM, FAMSSM, FAAFP, Department of Family Medicine, 1501 Kings Highway, PO Box 33932, Shreveport, LA 71130-3932; [email protected]

THE CASE

A 34-year-old man was referred to the sports medicine clinic for evaluation of lumbar radiculopathy. He had a 2-year history of chronic lower back pain that started while he was working on power line towers in Puerto Rico. The back pain was achy, burning, shooting, and stabbing in nature. He had been treated with anti-inflammatories by a company health care provider while in Puerto Rico, but he did not have any imaging done.

At that time, he had tingling and burning that radiated down his left leg to his ankle. The patient also had leg spasms—in his left leg more than his right—and needed a cane when walking. His symptoms did not worsen at any particular time of day or with activity. He had no history of eating exotic foods or sustaining any venomous bites/stings. Ultimately, the back pain and leg spasms forced him to leave his job and return home to Louisiana.

Upon presentation to the sports medicine clinic, he explained that things had worsened since his return home. The pain and burning in his left leg had increased and were now present in his right leg, as well (bilateral paresthesias). In addition, he said he was feeling anxious (and described symptoms of forgetfulness, confusion, and agitation), was sleeping less, and was experiencing worsening fatigue.

Work-ups over the course of the previous 2 years had shed little light on the cause of his symptoms. X-rays of his lumbar spine revealed moderate degenerative changes at L5-S1. A lab work-up was negative and included a complete blood count, testing for HIV and herpes, a hepatitis panel, an antinuclear antibody screen, a C-reactive protein test, and a comprehensive metabolic panel. Thyroid-stimulating hormone, creatine kinase, rapid plasma reagin, and human leukocyte antigen B27 tests were also normal.

Magnetic resonance imaging (MRI) revealed a cystic lesion in the right ilium near the sacroiliac joint. A more recent follow-up MRI and computed tomography scan of the pelvis found the cyst to be stable and well marginalized, with no cortical erosion. Attempts at physical therapy had been unsuccessful because of the pain and decreasing muscle strength in his lower extremities. The patient’s primary care provider was treating him with meloxicam 15 mg/d and duloxetine 60 mg/d, but that had not provided any relief.

Our physical examination revealed a patient who was in mild distress and had limited lumbar spine range of motion (secondary to pain in all planes) and significant paraspinal spasms on the right side in both the lumbar and thoracic regions. The patient had reduced vibratory sensation on his left side vs the right, with a 256-Hz tuning fork at the great toe, as well as reduced sensation to fine touch with a cotton swab and a positive Babinski sign bilaterally. Lower extremity reflexes were hyperreflexic on the left compared with the right. He had no pronator drift; Trendelenburg, straight leg raise, Hoover sign, and slump tests were all negative. His gait was antalgic with a cane, as he described bilateral paresthesias.

THE DIAGNOSIS

The differential diagnosis for low back pain is quite extensive and includes simple mechanical low back pain, lumbar radiculopathy, facet arthritis, spinal stenosis, spondylolysis/spondylolisthesis, and referred pain from the hip, knee, or upper back. It can also be caused by referred pain from visceral organs such as the liver, colon, or kidneys. Low back pain can also signal primary or metastatic disease. However, most of these potential diagnoses had been ruled out with imaging and lab tests.

Continue to: Two things caught our attention

Two things caught our attention. First: Mechanical low back pain and the associated discogenic radiculopathy would be unilateral, manifesting with asymmetric paresthesias and pain. Our patient had weakness in gait and pain and burning in both of his legs. Second: Our patient described decreased sleep and feeling anxious, with symptoms of forgetfulness, confusion, and agitation. These factors prompted us to look beyond the normal differential and consider a potential toxicity. A heavy metal screen was ordered, and the results were positive for arsenic toxicity.

DISCUSSION

Arsenic toxicity is a global health problem that affects millions of people.^1,2 Arsenic has been used for centuries in depilatories, cosmetics, poisons, and therapeutic agents. Today it is used as a treatment for leukemia and in several ayurvedic and homeopathic remedies.^3-7 It is a common earth element found in ground water and a waste product from mining and the manufacturing of glass, computer chips, wood preservatives, and various pesticides.^2,3,7,8

A great masquerader. Once in the body, arsenic can cause many serious ailments ranging from urinary tract, liver, and skin cancers to various peripheral and central nervous system disorders.² Arsenic can cause symmetrical peripheral neuropathy characterized by sensory nerves being more sensitive than motor nerves.^2,3,5,6 Clinically, it causes numbness and paresthesias of the distal extremities, with the lower extremities more severely affected.^3,6 Symptoms can develop within 2 hours to 2 years of exposure, with vomiting, diarrhea, or both preceding the onset of the neuropathy.^2,3,5,6 Arsenic is linked to forgetfulness, confusion, visual distortion, sleep disturbances, decreased concentration, disorientation, severe agitation, paranoid ideation, emotional lability, and decreases in locomotor activity.^3,5,6

Testing and treatment. Arsenic levels in the body are measured by blood and urine testing. Blood arsenic levels are typically detectable immediately after exposure and with continued exposure, but quickly normalize as the metal integrates into the nonvascular tissues. Urine arsenic levels can be detected for weeks. Normal levels for arsenic in both urine and blood are ≤ 12 µg/L.³ Anything greater than 12 µg/L is considered high; critically high values are those above 50 µg/L.^3,5 Our patient’s blood arsenic level was 13 µg/L.

Several of the patient’s symptoms prompted us to look beyond the normal differential and consider a potential toxicity.

Treatment involves removing the source of the arsenic. Chelation therapy should be pursued when urine arsenic levels are greater than 50 µg/L or when removing the source of the arsenic fails to reduce arsenic levels. Chelation therapy should be continued until urine arsenic levels are below 20 µg/L.^5,6

Continue to: After discussing potential sources of exposure

After discussing potential sources of exposure, our patient decided to move out of the house he shared with his ex-wife. He started to recover soon after moving out. Two weeks after his clinic visit, he no longer needed a cane to walk, and his blood arsenic level had dropped to 6 µg/L. Two months after his clinic visit, the patient’s blood arsenic level was undetectable. The patient’s peripheral neuropathy symptoms continued to improve.

The source of this patient’s arsenic exposure was never confirmed. The exposure could have occurred in Puerto Rico or in Louisiana. Even though no one else in the Louisiana home became ill, the patient was instructed to contact the local health department and water department to have the water tested. However, when he returned to the clinic for follow-up, he had not followed through.

THE TAKEAWAY

When evaluating causes of peripheral neuropathy, consider the possibility of heavy metal toxicity, which can be easily overlooked by the busy clinician. In this case, the patient initially experienced asymmetric paresthesia that gradually increased to burning pain and weakness, with reduced motor control bilaterally. This was significant because mechanical low back pain and the associated discogenic radiculopathy would be unilateral, manifesting with asymmetric paresthesias and pain.

Our patient’s leg symptoms, the constellation of forgetfulness, confusion, and agitation, and his sleep issues prompted us to look outside our normal differential. Fortunately, once arsenic exposure ceases, patients will gradually improve because arsenic is rapidly cleared from the bloodstream.^3,6

CORRESPONDENCE
Charles W. Webb, DO, CAQSM, FAMSSM, FAAFP, Department of Family Medicine, 1501 Kings Highway, PO Box 33932, Shreveport, LA 71130-3932; [email protected]

PHILADELPHIA – Combining the immunomodulatory agent mycophenolate with the antifibrotic pirfenidone led to more rapid improvement and showed a trend to be more effective than mycophenolate mofetil alone for treating the signs and symptoms of scleroderma-related interstitial lung disease, but the combination therapy came with an increase in side effects, according to results from the Scleroderma Lung Study III.

Dinesh Khanna, MBBS, MSc, of the University of Michigan, Ann Arbor, presented the results at the annual meeting of the American College of Rheumatology. He noted some problems with the study – namely its small size, enrolling only 51 patients, about one-third of its original goal. But he also said it showed a potential signal for efficacy and that the study itself could serve as a “template” for future studies of combination mycophenolate mofetil (MMF) plus pirfenidone therapy for scleroderma-related interstitial lung disease (SSc-ILD).

“The pirfenidone patients had quite a bit more GI side effects and photosensitivity, and those are known side effects,” Dr. Khanna said in an interview. “So the combination therapy had more side effects but trends to higher efficacy.”

The design of SLS-III, a phase 2 clinical trial, was a challenge, Dr. Khanna explained. The goal was to enroll 150 SSc-ILD patients who hadn’t had any previous treatment for their disease. Finding those patients proved difficult. “In fact, if you look at the recent history, 70% of the patients with early diffuse scleroderma are on MMF,” he said in his presentation. Compounding low study enrollment was the intervening COVID-19 pandemic, he added.
 

Testing a faster-acting combination

Nonetheless, the trial managed to enroll 27 patients in the combination therapy group and 24 in the MMF-plus-placebo group and compared their outcomes over 18 months. Study dosing was 1,500 mg MMF twice daily and pirfenidone 801 mg three times daily, titrated to the tolerable dose.

Despite the study’s being underpowered, Dr. Khanna said, it still reported some notable outcomes that merit further investigation. “I think what was intriguing in the study was the long-term benefit in the patient-reported outcomes and the structural changes,” he said in the interview.

Among those notable outcomes was a clinically significant change in forced vital capacity (FVC) percentage for the combination vs. the placebo groups: 2.24% vs. 2.09%. He also noted that the combination group saw a somewhat more robust improvement in FVC at six months: 2.59% (± 0.98%) vs. 0.92% (± 1.1%) in the placebo group.

The combination group showed greater improvements in high-resolution computed tomography-evaluated lung involvement and lung fibrosis and patient-reported outcomes, including a statistically significant 3.67-point greater improvement in PROMIS-29 physical function score (4.42 vs. 0.75).

The patients on combination therapy had higher rates of serious adverse events (SAEs), and seven discontinued one or both study drugs early, all in the combined arm. Four combination therapy patients had six SAEs, compared to two placebo patients with three SAEs. In the combination group, SAEs included chest pain, herpes zoster ophthalmicus, nodular basal cell cancer, marginal zone B cell lymphoma, renal crisis, and dyspnea. SAEs in the placebo group were colitis, COVID-19 and hypoxic respiratory failure.

Study design challenges

Nonetheless, Dr. Khanna said the SLS-III data are consistent with the SLS-II findings, with mean improvements in FVC of 2.24% and 2.1%, respectively.

“The next study may be able to replicate what we tried to do, keeping in mind that there are really no MMF-naive patients who are walking around,” Dr. Khanna said. “So the challenge is about the feasibility of recruiting within a trial vs. trying to show a statistical difference between the drug and placebo.”

This study could serve as a foundation for future studies of MMF in patients with SSc-ILD, Robert Spiera, MD, of the Hospital for Special Surgery in New York, said in an interview. “There are lessons to be learned both from the study but also from prior studies looking at MMF use in the background in patients treated with other drugs in clinical trials,” he said.

Dr. Spiera noted that the study had other challenges besides the difficulty in recruiting patients who hadn’t been on MMF therapy. “A great challenge is that the benefit with regard to the impact on the lungs from MMF seems most prominent in the first 6 months to a year to even 2 years that somebody is on the drug,” he said.

The other challenge with this study is that a large proportion of patients had limited systemic disease and relatively lower levels of skin disease compared with other studies of patients on MMF, Dr. Spiera said.

“The optimal treatment of scleroderma-associated lung disease remains a very important and not-adequately met need,” he said. “Particularly, we’re looking for drugs that are tolerable in a patient population that are very prone to GI side effects in general. This study and others have taught us a lot about trial design, and I think more globally this will allow us to move this field forward.”

Dr. Khanna disclosed relationships with Actelion, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Horizon Therapeutics USA, Janssen Global Services, Prometheus Biosciences, Mitsubishi Tanabe Pharma Corp., Genentech/Roche, Theraly, and Pfizer. Genentech provided funding for the study and pirfenidone and placebo drugs at no cost.

Dr. Spiera disclosed relationships with GlaxoSmithKline, Boehringer-Ingelheim, Corbus Pharmaceutical, InflaRx, AbbVie/Abbott, Sanofi, Novartis, Chemocentryx, Roche and Vera.

PHILADELPHIA – Combining the immunomodulatory agent mycophenolate with the antifibrotic pirfenidone led to more rapid improvement and showed a trend to be more effective than mycophenolate mofetil alone for treating the signs and symptoms of scleroderma-related interstitial lung disease, but the combination therapy came with an increase in side effects, according to results from the Scleroderma Lung Study III.

Dinesh Khanna, MBBS, MSc, of the University of Michigan, Ann Arbor, presented the results at the annual meeting of the American College of Rheumatology. He noted some problems with the study – namely its small size, enrolling only 51 patients, about one-third of its original goal. But he also said it showed a potential signal for efficacy and that the study itself could serve as a “template” for future studies of combination mycophenolate mofetil (MMF) plus pirfenidone therapy for scleroderma-related interstitial lung disease (SSc-ILD).

“The pirfenidone patients had quite a bit more GI side effects and photosensitivity, and those are known side effects,” Dr. Khanna said in an interview. “So the combination therapy had more side effects but trends to higher efficacy.”

The design of SLS-III, a phase 2 clinical trial, was a challenge, Dr. Khanna explained. The goal was to enroll 150 SSc-ILD patients who hadn’t had any previous treatment for their disease. Finding those patients proved difficult. “In fact, if you look at the recent history, 70% of the patients with early diffuse scleroderma are on MMF,” he said in his presentation. Compounding low study enrollment was the intervening COVID-19 pandemic, he added.
 

Testing a faster-acting combination

Nonetheless, the trial managed to enroll 27 patients in the combination therapy group and 24 in the MMF-plus-placebo group and compared their outcomes over 18 months. Study dosing was 1,500 mg MMF twice daily and pirfenidone 801 mg three times daily, titrated to the tolerable dose.

Despite the study’s being underpowered, Dr. Khanna said, it still reported some notable outcomes that merit further investigation. “I think what was intriguing in the study was the long-term benefit in the patient-reported outcomes and the structural changes,” he said in the interview.

Among those notable outcomes was a clinically significant change in forced vital capacity (FVC) percentage for the combination vs. the placebo groups: 2.24% vs. 2.09%. He also noted that the combination group saw a somewhat more robust improvement in FVC at six months: 2.59% (± 0.98%) vs. 0.92% (± 1.1%) in the placebo group.

The combination group showed greater improvements in high-resolution computed tomography-evaluated lung involvement and lung fibrosis and patient-reported outcomes, including a statistically significant 3.67-point greater improvement in PROMIS-29 physical function score (4.42 vs. 0.75).

The patients on combination therapy had higher rates of serious adverse events (SAEs), and seven discontinued one or both study drugs early, all in the combined arm. Four combination therapy patients had six SAEs, compared to two placebo patients with three SAEs. In the combination group, SAEs included chest pain, herpes zoster ophthalmicus, nodular basal cell cancer, marginal zone B cell lymphoma, renal crisis, and dyspnea. SAEs in the placebo group were colitis, COVID-19 and hypoxic respiratory failure.

Study design challenges

Nonetheless, Dr. Khanna said the SLS-III data are consistent with the SLS-II findings, with mean improvements in FVC of 2.24% and 2.1%, respectively.

“The next study may be able to replicate what we tried to do, keeping in mind that there are really no MMF-naive patients who are walking around,” Dr. Khanna said. “So the challenge is about the feasibility of recruiting within a trial vs. trying to show a statistical difference between the drug and placebo.”

This study could serve as a foundation for future studies of MMF in patients with SSc-ILD, Robert Spiera, MD, of the Hospital for Special Surgery in New York, said in an interview. “There are lessons to be learned both from the study but also from prior studies looking at MMF use in the background in patients treated with other drugs in clinical trials,” he said.

Dr. Spiera noted that the study had other challenges besides the difficulty in recruiting patients who hadn’t been on MMF therapy. “A great challenge is that the benefit with regard to the impact on the lungs from MMF seems most prominent in the first 6 months to a year to even 2 years that somebody is on the drug,” he said.

The other challenge with this study is that a large proportion of patients had limited systemic disease and relatively lower levels of skin disease compared with other studies of patients on MMF, Dr. Spiera said.

“The optimal treatment of scleroderma-associated lung disease remains a very important and not-adequately met need,” he said. “Particularly, we’re looking for drugs that are tolerable in a patient population that are very prone to GI side effects in general. This study and others have taught us a lot about trial design, and I think more globally this will allow us to move this field forward.”

Dr. Khanna disclosed relationships with Actelion, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Horizon Therapeutics USA, Janssen Global Services, Prometheus Biosciences, Mitsubishi Tanabe Pharma Corp., Genentech/Roche, Theraly, and Pfizer. Genentech provided funding for the study and pirfenidone and placebo drugs at no cost.

Dr. Spiera disclosed relationships with GlaxoSmithKline, Boehringer-Ingelheim, Corbus Pharmaceutical, InflaRx, AbbVie/Abbott, Sanofi, Novartis, Chemocentryx, Roche and Vera.

PHILADELPHIA – Combining the immunomodulatory agent mycophenolate with the antifibrotic pirfenidone led to more rapid improvement and showed a trend to be more effective than mycophenolate mofetil alone for treating the signs and symptoms of scleroderma-related interstitial lung disease, but the combination therapy came with an increase in side effects, according to results from the Scleroderma Lung Study III.

Dinesh Khanna, MBBS, MSc, of the University of Michigan, Ann Arbor, presented the results at the annual meeting of the American College of Rheumatology. He noted some problems with the study – namely its small size, enrolling only 51 patients, about one-third of its original goal. But he also said it showed a potential signal for efficacy and that the study itself could serve as a “template” for future studies of combination mycophenolate mofetil (MMF) plus pirfenidone therapy for scleroderma-related interstitial lung disease (SSc-ILD).

“The pirfenidone patients had quite a bit more GI side effects and photosensitivity, and those are known side effects,” Dr. Khanna said in an interview. “So the combination therapy had more side effects but trends to higher efficacy.”

The design of SLS-III, a phase 2 clinical trial, was a challenge, Dr. Khanna explained. The goal was to enroll 150 SSc-ILD patients who hadn’t had any previous treatment for their disease. Finding those patients proved difficult. “In fact, if you look at the recent history, 70% of the patients with early diffuse scleroderma are on MMF,” he said in his presentation. Compounding low study enrollment was the intervening COVID-19 pandemic, he added.
 

Testing a faster-acting combination

Nonetheless, the trial managed to enroll 27 patients in the combination therapy group and 24 in the MMF-plus-placebo group and compared their outcomes over 18 months. Study dosing was 1,500 mg MMF twice daily and pirfenidone 801 mg three times daily, titrated to the tolerable dose.

Despite the study’s being underpowered, Dr. Khanna said, it still reported some notable outcomes that merit further investigation. “I think what was intriguing in the study was the long-term benefit in the patient-reported outcomes and the structural changes,” he said in the interview.

Among those notable outcomes was a clinically significant change in forced vital capacity (FVC) percentage for the combination vs. the placebo groups: 2.24% vs. 2.09%. He also noted that the combination group saw a somewhat more robust improvement in FVC at six months: 2.59% (± 0.98%) vs. 0.92% (± 1.1%) in the placebo group.

The combination group showed greater improvements in high-resolution computed tomography-evaluated lung involvement and lung fibrosis and patient-reported outcomes, including a statistically significant 3.67-point greater improvement in PROMIS-29 physical function score (4.42 vs. 0.75).

The patients on combination therapy had higher rates of serious adverse events (SAEs), and seven discontinued one or both study drugs early, all in the combined arm. Four combination therapy patients had six SAEs, compared to two placebo patients with three SAEs. In the combination group, SAEs included chest pain, herpes zoster ophthalmicus, nodular basal cell cancer, marginal zone B cell lymphoma, renal crisis, and dyspnea. SAEs in the placebo group were colitis, COVID-19 and hypoxic respiratory failure.

Study design challenges

Nonetheless, Dr. Khanna said the SLS-III data are consistent with the SLS-II findings, with mean improvements in FVC of 2.24% and 2.1%, respectively.

“The next study may be able to replicate what we tried to do, keeping in mind that there are really no MMF-naive patients who are walking around,” Dr. Khanna said. “So the challenge is about the feasibility of recruiting within a trial vs. trying to show a statistical difference between the drug and placebo.”

This study could serve as a foundation for future studies of MMF in patients with SSc-ILD, Robert Spiera, MD, of the Hospital for Special Surgery in New York, said in an interview. “There are lessons to be learned both from the study but also from prior studies looking at MMF use in the background in patients treated with other drugs in clinical trials,” he said.

Dr. Spiera noted that the study had other challenges besides the difficulty in recruiting patients who hadn’t been on MMF therapy. “A great challenge is that the benefit with regard to the impact on the lungs from MMF seems most prominent in the first 6 months to a year to even 2 years that somebody is on the drug,” he said.

The other challenge with this study is that a large proportion of patients had limited systemic disease and relatively lower levels of skin disease compared with other studies of patients on MMF, Dr. Spiera said.

“The optimal treatment of scleroderma-associated lung disease remains a very important and not-adequately met need,” he said. “Particularly, we’re looking for drugs that are tolerable in a patient population that are very prone to GI side effects in general. This study and others have taught us a lot about trial design, and I think more globally this will allow us to move this field forward.”

Dr. Khanna disclosed relationships with Actelion, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Horizon Therapeutics USA, Janssen Global Services, Prometheus Biosciences, Mitsubishi Tanabe Pharma Corp., Genentech/Roche, Theraly, and Pfizer. Genentech provided funding for the study and pirfenidone and placebo drugs at no cost.

Dr. Spiera disclosed relationships with GlaxoSmithKline, Boehringer-Ingelheim, Corbus Pharmaceutical, InflaRx, AbbVie/Abbott, Sanofi, Novartis, Chemocentryx, Roche and Vera.

PHILADELPHIA – Aggressive therapy using conventional synthetic disease-modifying antirheumatic drugs (DMARDs) in combination with biologic agents early, soon after a child is diagnosed with polyarticular juvenile idiopathic arthritis (pJIA), enabled more patients to achieve clinical remission and longer times in inactive disease than more conventional therapeutic approaches, 3-year results of prospective, observational study demonstrated.

The results of The Childhood Arthritis and Rheumatology Research Alliance STOP-JIA study, which Yukiko Kimura, MD, presented at the annual meeting of the American College of Rheumatology, showed early combination therapy had benefits, compared with other treatment strategies that were more evident at 3 years than at 1 year of study.

“The STOP-JIA study showed that, after 3 years, patients who started a biologic early on in combination with methotrexate spent more time in inactive disease and achieved clinical remission more often when compared to those started on traditional step-up therapy,” Dr. Kimura, chief of pediatric rheumatology at Hackensack (N.J.) Meridian Health and professor of pediatrics at the Hackensack Meridian School of Medicine, said at a press conference. “This study shows that the treatment of poly-JIA patients receive initially very early on in their disease matters even 3 years after that treatment was started.”

The study compared three CARRA consensus treatment plans (CTP) for untreated pediatric pJIA patients: step-up (SU) – starting conventional synthetic DMARD therapy and adding a biologic if needed after 3 or more months; early-combination (EC) therapy – starting synthetic and biologic DMARDs together; and biologic first (BF) therapy – starting biologic DMARD monotherapy.

Dr. Kimura explained the rationale for the study. “Since biologic treatments were introduced more than 20 years ago, the prognosis for JIA significantly improved. These very effective medicines often work wonders, quickly reducing pain and inflammation in joint disease activity,” she said in the press conference. “What is not known, however, is when is the best time to start these very effective treatments.”

The most common approach is to start with a synthetic DMARD, typically methotrexate, and wait before starting a biologic, Dr. Kimura said.

“But even though methotrexate can work very well by itself, it does not work for every patient, and we don’t know whether waiting months for it to work and then starting a biologic might potentially lessen their effectiveness,” Dr. Kimura added. “We don’t know if there’s a window of opportunity that’s lost while waiting to see whether methotrexate will work.”

The study originally enrolled 400 patients, 297 of whom completed the 3-year visit – 190 in SU, 76 in EC and 31 in BF. At 12 months, the study found no statistically significant difference in clinically inactive disease (CID) between the groups, Dr. Kimura said.

Even at the 3-year visit, the percentage of patients in CID off glucocorticoids and clinical Juvenile Arthritis Disease Activity Score based on 10 joints inactive disease (cJADAS 10 ID) did not differ among the three groups, Dr. Kimura said in presenting the results. “But,” she added, “greater proportions of early-combination CTP group were able to achieve clinical remissions and spend more time with inactive disease in both CID and cJADAS 10.”

A closer look at the outcomes showed some separation between early-combination therapy and the other two treatment plans. The incidence of clinical remission (at any time point over 36 months) was 67.1% in the EC group vs. 49.1% and 47.3%, respectively, in the BF and SU groups, Dr. Kimura said. “The difference between the early-combination and step-up groups was highly significant [P = .007],” she added.

EC also had an edge in the percentage of time patients spent in CID (over 36 months): 39.2% versus 32% and 27.4%, respectively, in the BF and SU groups (P = .006 for EV vs. SU), as well as cJADAS 10 ID (50.6% in EC group vs. 42.8% and 37.5%, respectively in the BF and SU groups; P = .005 for EC vs. SU).

Dr. Kimura said that the STOP JIA trial will continue with longer-term analysis and ongoing monitoring of study patients through the CARRA registry. “These longer-term analyses and readouts will be important because even though the results at 12 months didn’t seem as definitive, it seems the longer we go, the more impact we see of the treatments that were started early on in this disease.”

The findings from this study are “significantly important,” Nina T. Washington, MD, MPH, a pediatric rheumatologist at the University of New Mexico Hospital, Albuquerque, and the Mary Bridge Children’s Hospital in Tacoma, Wash., said in an interview. “At least for the past decade we’ve really been advocating towards earlier and aggressive therapy, and that’s what this study shows: the sooner you can treat this disease, the sooner you can attack those joints that are inflamed, the better outcome you give the patient.”

The study also confirms that pediatric rheumatologists are not overtreating patients with pJIA, she added.

“In a sense we’re actually treating and preventing and if you have a child that has arthritis, it’s okay to treat that child,” Dr. Washington said. “For me that’s the most reassuring thing: that I’m not necessarily going overboard. If I have a child with polyarticular JIA and they have multiple inflamed joints and I have the evidence as they’re sitting in front of me, and I treat them. I’m going to give them the best outcome.”

The Patient Centered Outcomes Research Institute provided study funding. Dr. Kimura is chair of the CARRA JIA disease research committee and cochair of the CARRA Registry and Research Oversight Committee. She disclosed a financial relationship with Genentech. Dr. Washington has no relevant relationships to disclose.
 

PHILADELPHIA – Aggressive therapy using conventional synthetic disease-modifying antirheumatic drugs (DMARDs) in combination with biologic agents early, soon after a child is diagnosed with polyarticular juvenile idiopathic arthritis (pJIA), enabled more patients to achieve clinical remission and longer times in inactive disease than more conventional therapeutic approaches, 3-year results of prospective, observational study demonstrated.

The results of The Childhood Arthritis and Rheumatology Research Alliance STOP-JIA study, which Yukiko Kimura, MD, presented at the annual meeting of the American College of Rheumatology, showed early combination therapy had benefits, compared with other treatment strategies that were more evident at 3 years than at 1 year of study.

“The STOP-JIA study showed that, after 3 years, patients who started a biologic early on in combination with methotrexate spent more time in inactive disease and achieved clinical remission more often when compared to those started on traditional step-up therapy,” Dr. Kimura, chief of pediatric rheumatology at Hackensack (N.J.) Meridian Health and professor of pediatrics at the Hackensack Meridian School of Medicine, said at a press conference. “This study shows that the treatment of poly-JIA patients receive initially very early on in their disease matters even 3 years after that treatment was started.”

The study compared three CARRA consensus treatment plans (CTP) for untreated pediatric pJIA patients: step-up (SU) – starting conventional synthetic DMARD therapy and adding a biologic if needed after 3 or more months; early-combination (EC) therapy – starting synthetic and biologic DMARDs together; and biologic first (BF) therapy – starting biologic DMARD monotherapy.

Dr. Kimura explained the rationale for the study. “Since biologic treatments were introduced more than 20 years ago, the prognosis for JIA significantly improved. These very effective medicines often work wonders, quickly reducing pain and inflammation in joint disease activity,” she said in the press conference. “What is not known, however, is when is the best time to start these very effective treatments.”

The most common approach is to start with a synthetic DMARD, typically methotrexate, and wait before starting a biologic, Dr. Kimura said.

“But even though methotrexate can work very well by itself, it does not work for every patient, and we don’t know whether waiting months for it to work and then starting a biologic might potentially lessen their effectiveness,” Dr. Kimura added. “We don’t know if there’s a window of opportunity that’s lost while waiting to see whether methotrexate will work.”

The study originally enrolled 400 patients, 297 of whom completed the 3-year visit – 190 in SU, 76 in EC and 31 in BF. At 12 months, the study found no statistically significant difference in clinically inactive disease (CID) between the groups, Dr. Kimura said.

Even at the 3-year visit, the percentage of patients in CID off glucocorticoids and clinical Juvenile Arthritis Disease Activity Score based on 10 joints inactive disease (cJADAS 10 ID) did not differ among the three groups, Dr. Kimura said in presenting the results. “But,” she added, “greater proportions of early-combination CTP group were able to achieve clinical remissions and spend more time with inactive disease in both CID and cJADAS 10.”

A closer look at the outcomes showed some separation between early-combination therapy and the other two treatment plans. The incidence of clinical remission (at any time point over 36 months) was 67.1% in the EC group vs. 49.1% and 47.3%, respectively, in the BF and SU groups, Dr. Kimura said. “The difference between the early-combination and step-up groups was highly significant [P = .007],” she added.

EC also had an edge in the percentage of time patients spent in CID (over 36 months): 39.2% versus 32% and 27.4%, respectively, in the BF and SU groups (P = .006 for EV vs. SU), as well as cJADAS 10 ID (50.6% in EC group vs. 42.8% and 37.5%, respectively in the BF and SU groups; P = .005 for EC vs. SU).

Dr. Kimura said that the STOP JIA trial will continue with longer-term analysis and ongoing monitoring of study patients through the CARRA registry. “These longer-term analyses and readouts will be important because even though the results at 12 months didn’t seem as definitive, it seems the longer we go, the more impact we see of the treatments that were started early on in this disease.”

The findings from this study are “significantly important,” Nina T. Washington, MD, MPH, a pediatric rheumatologist at the University of New Mexico Hospital, Albuquerque, and the Mary Bridge Children’s Hospital in Tacoma, Wash., said in an interview. “At least for the past decade we’ve really been advocating towards earlier and aggressive therapy, and that’s what this study shows: the sooner you can treat this disease, the sooner you can attack those joints that are inflamed, the better outcome you give the patient.”

The study also confirms that pediatric rheumatologists are not overtreating patients with pJIA, she added.

“In a sense we’re actually treating and preventing and if you have a child that has arthritis, it’s okay to treat that child,” Dr. Washington said. “For me that’s the most reassuring thing: that I’m not necessarily going overboard. If I have a child with polyarticular JIA and they have multiple inflamed joints and I have the evidence as they’re sitting in front of me, and I treat them. I’m going to give them the best outcome.”

The Patient Centered Outcomes Research Institute provided study funding. Dr. Kimura is chair of the CARRA JIA disease research committee and cochair of the CARRA Registry and Research Oversight Committee. She disclosed a financial relationship with Genentech. Dr. Washington has no relevant relationships to disclose.
 

PHILADELPHIA – Aggressive therapy using conventional synthetic disease-modifying antirheumatic drugs (DMARDs) in combination with biologic agents early, soon after a child is diagnosed with polyarticular juvenile idiopathic arthritis (pJIA), enabled more patients to achieve clinical remission and longer times in inactive disease than more conventional therapeutic approaches, 3-year results of prospective, observational study demonstrated.

The results of The Childhood Arthritis and Rheumatology Research Alliance STOP-JIA study, which Yukiko Kimura, MD, presented at the annual meeting of the American College of Rheumatology, showed early combination therapy had benefits, compared with other treatment strategies that were more evident at 3 years than at 1 year of study.

“The STOP-JIA study showed that, after 3 years, patients who started a biologic early on in combination with methotrexate spent more time in inactive disease and achieved clinical remission more often when compared to those started on traditional step-up therapy,” Dr. Kimura, chief of pediatric rheumatology at Hackensack (N.J.) Meridian Health and professor of pediatrics at the Hackensack Meridian School of Medicine, said at a press conference. “This study shows that the treatment of poly-JIA patients receive initially very early on in their disease matters even 3 years after that treatment was started.”

The study compared three CARRA consensus treatment plans (CTP) for untreated pediatric pJIA patients: step-up (SU) – starting conventional synthetic DMARD therapy and adding a biologic if needed after 3 or more months; early-combination (EC) therapy – starting synthetic and biologic DMARDs together; and biologic first (BF) therapy – starting biologic DMARD monotherapy.

Dr. Kimura explained the rationale for the study. “Since biologic treatments were introduced more than 20 years ago, the prognosis for JIA significantly improved. These very effective medicines often work wonders, quickly reducing pain and inflammation in joint disease activity,” she said in the press conference. “What is not known, however, is when is the best time to start these very effective treatments.”

The most common approach is to start with a synthetic DMARD, typically methotrexate, and wait before starting a biologic, Dr. Kimura said.

“But even though methotrexate can work very well by itself, it does not work for every patient, and we don’t know whether waiting months for it to work and then starting a biologic might potentially lessen their effectiveness,” Dr. Kimura added. “We don’t know if there’s a window of opportunity that’s lost while waiting to see whether methotrexate will work.”

The study originally enrolled 400 patients, 297 of whom completed the 3-year visit – 190 in SU, 76 in EC and 31 in BF. At 12 months, the study found no statistically significant difference in clinically inactive disease (CID) between the groups, Dr. Kimura said.

Even at the 3-year visit, the percentage of patients in CID off glucocorticoids and clinical Juvenile Arthritis Disease Activity Score based on 10 joints inactive disease (cJADAS 10 ID) did not differ among the three groups, Dr. Kimura said in presenting the results. “But,” she added, “greater proportions of early-combination CTP group were able to achieve clinical remissions and spend more time with inactive disease in both CID and cJADAS 10.”

A closer look at the outcomes showed some separation between early-combination therapy and the other two treatment plans. The incidence of clinical remission (at any time point over 36 months) was 67.1% in the EC group vs. 49.1% and 47.3%, respectively, in the BF and SU groups, Dr. Kimura said. “The difference between the early-combination and step-up groups was highly significant [P = .007],” she added.

EC also had an edge in the percentage of time patients spent in CID (over 36 months): 39.2% versus 32% and 27.4%, respectively, in the BF and SU groups (P = .006 for EV vs. SU), as well as cJADAS 10 ID (50.6% in EC group vs. 42.8% and 37.5%, respectively in the BF and SU groups; P = .005 for EC vs. SU).

Dr. Kimura said that the STOP JIA trial will continue with longer-term analysis and ongoing monitoring of study patients through the CARRA registry. “These longer-term analyses and readouts will be important because even though the results at 12 months didn’t seem as definitive, it seems the longer we go, the more impact we see of the treatments that were started early on in this disease.”

The findings from this study are “significantly important,” Nina T. Washington, MD, MPH, a pediatric rheumatologist at the University of New Mexico Hospital, Albuquerque, and the Mary Bridge Children’s Hospital in Tacoma, Wash., said in an interview. “At least for the past decade we’ve really been advocating towards earlier and aggressive therapy, and that’s what this study shows: the sooner you can treat this disease, the sooner you can attack those joints that are inflamed, the better outcome you give the patient.”

The study also confirms that pediatric rheumatologists are not overtreating patients with pJIA, she added.

“In a sense we’re actually treating and preventing and if you have a child that has arthritis, it’s okay to treat that child,” Dr. Washington said. “For me that’s the most reassuring thing: that I’m not necessarily going overboard. If I have a child with polyarticular JIA and they have multiple inflamed joints and I have the evidence as they’re sitting in front of me, and I treat them. I’m going to give them the best outcome.”

The Patient Centered Outcomes Research Institute provided study funding. Dr. Kimura is chair of the CARRA JIA disease research committee and cochair of the CARRA Registry and Research Oversight Committee. She disclosed a financial relationship with Genentech. Dr. Washington has no relevant relationships to disclose.
 

Researchers have found a link between age of diagnosis and various clinical characteristics and outcomes in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV).

The findings, presented at the annual meeting of the American College of Rheumatology, may have implications for research and treatment, especially in children.

AAV is a group of conditions characterized by the development of autoantibodies to the neutrophil proteins proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA).

The rare autoimmune condition can cause systemic inflammation and damage, sometimes permanent, to small- and medium-sized arteries. Clinical presentations vary and can include several organs, including skin, stomach, intestines, lung, and kidney, as well as airways in ear, nose, and throat.
 

Data limited on child vs. adult characteristics

AAV can be diagnosed in any decade of life, but clinical characteristics and outcomes often differ between children and adults, and data are limited. Studies often exclude children.

Lead author Jessica Bloom, MD, MSCS, a pediatric rheumatologist and assistant professor of pediatrics at Children’s Hospital Colorado, Aurora, and colleagues performed an analysis of patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) who were enrolled in the Vasculitis Clinical Research Consortium Longitudinal Studies from 2013 to 2021.

Patients with eosinophilic GPA (EGPA) were analyzed separately. Children and young adults with EGPA were combined because of the small sample size (n = 87).

The groups were sorted by the age they were diagnosed: under 18 years old, 18-40, 40-65, and older than 65.
 

More than 1,000 patients included

Dr. Bloom’s team analyzed data from 1,020 patients: 61 diagnosed as children, 240 as young adults, 560 as middle-aged adults, and 159 diagnosed as older adults. At all ages, about nine out of 10 patients were White.

They found 852 (84%) had GPA and 165 (16%) had MPA. The analysis also showed 893 (92%) of patients with ANCA results were ANCA positive: 637 (65%) with PR3-ANCA, 247 (25%) with MPO-ANCA, and 9 (1%) with both.

Differences between age groups included:

• Children experienced more subglottic stenosis and alveolar hemorrhage than adults with the condition.
• About half of patients diagnosed in childhood received both cyclophosphamide and rituximab. That rate decreased with increasing age of diagnosis to as low as 14% for those diagnosed in older adulthood. 
• More females than males in all age groups were diagnosed with AAV, but the difference was most pronounced when diagnosed in childhood, and female predominance declined as age increased.
• Older adults experienced more neurologic disease and less musculoskeletal and sinus involvement.

Additionally, for those diagnosed after age 65, after adjusting for disease length and whether they were taking cyclophosphamide and/or rituximab, the Vasculitis Damage Index (VDI) and ANCA Vasculitis Index of Damage (AVID) scores were higher than for those diagnosed in childhood.

“However, these differences are no longer significant when medication toxicity and comorbidity-related items are excluded. Thus, differences in the VDI and AVID scores are driven by non–disease-specific damage,” Dr. Bloom said.
 

Bringing children into the clinical discussion

Dr. Bloom said in an interview that many pediatric rheumatologists believe kids with vasculitis are like small adults and should be treated similarly, but she said the picture may be more complex than that.

For example, the findings that children have more subglottic stenosis and alveolar hemorrhage than adults “may warrant more aggressive therapy,” she said. Children also have different growth and psychosocial risk factors during their disease course and may live longer with the disease than those in older age groups.

“Our study helps to point out these differences and bring children into the discussion,” Dr. Bloom said. “It also recognizes that damage scores used in studies and care may not adequately assess disease across the lifespan, as they are largely influenced by items not specific to the disease but rather medication toxicity and comorbidities, such as osteoporosis, cataracts, and malignancy.”

Robert Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at Hospital for Special Surgery, New York, said in an interview that the work highlights interesting information about the fact that disease features are skewed differently in children – “in particular the higher likelihood of upper airway [subglottic] disease, and potentially severe lower airway disease [alveolar hemorrhage].”

However, from a practical standpoint, Dr. Spiera said, “I am not sure that this will change our clinical approach to different patients, but the differences in disease features and even the sex differences in terms of who are afflicted with GPA [more often children and more likely to be female] may offer insights into disease pathogenesis.”

Dr. Bloom received funding from the Vasculitis Clinical Research Consortium and Vasculitis Foundation to conduct this work as a VCRC-VF fellow. Several coauthors reported various conflicts of interest with pharmaceutical companies. Dr. Spiera declared no relevant financial relationships.

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

Researchers have found a link between age of diagnosis and various clinical characteristics and outcomes in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV).

The findings, presented at the annual meeting of the American College of Rheumatology, may have implications for research and treatment, especially in children.

AAV is a group of conditions characterized by the development of autoantibodies to the neutrophil proteins proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA).

The rare autoimmune condition can cause systemic inflammation and damage, sometimes permanent, to small- and medium-sized arteries. Clinical presentations vary and can include several organs, including skin, stomach, intestines, lung, and kidney, as well as airways in ear, nose, and throat.
 

Data limited on child vs. adult characteristics

AAV can be diagnosed in any decade of life, but clinical characteristics and outcomes often differ between children and adults, and data are limited. Studies often exclude children.

Lead author Jessica Bloom, MD, MSCS, a pediatric rheumatologist and assistant professor of pediatrics at Children’s Hospital Colorado, Aurora, and colleagues performed an analysis of patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) who were enrolled in the Vasculitis Clinical Research Consortium Longitudinal Studies from 2013 to 2021.

Patients with eosinophilic GPA (EGPA) were analyzed separately. Children and young adults with EGPA were combined because of the small sample size (n = 87).

The groups were sorted by the age they were diagnosed: under 18 years old, 18-40, 40-65, and older than 65.
 

More than 1,000 patients included

Dr. Bloom’s team analyzed data from 1,020 patients: 61 diagnosed as children, 240 as young adults, 560 as middle-aged adults, and 159 diagnosed as older adults. At all ages, about nine out of 10 patients were White.

They found 852 (84%) had GPA and 165 (16%) had MPA. The analysis also showed 893 (92%) of patients with ANCA results were ANCA positive: 637 (65%) with PR3-ANCA, 247 (25%) with MPO-ANCA, and 9 (1%) with both.

Differences between age groups included:

• Children experienced more subglottic stenosis and alveolar hemorrhage than adults with the condition.
• About half of patients diagnosed in childhood received both cyclophosphamide and rituximab. That rate decreased with increasing age of diagnosis to as low as 14% for those diagnosed in older adulthood. 
• More females than males in all age groups were diagnosed with AAV, but the difference was most pronounced when diagnosed in childhood, and female predominance declined as age increased.
• Older adults experienced more neurologic disease and less musculoskeletal and sinus involvement.

Additionally, for those diagnosed after age 65, after adjusting for disease length and whether they were taking cyclophosphamide and/or rituximab, the Vasculitis Damage Index (VDI) and ANCA Vasculitis Index of Damage (AVID) scores were higher than for those diagnosed in childhood.

“However, these differences are no longer significant when medication toxicity and comorbidity-related items are excluded. Thus, differences in the VDI and AVID scores are driven by non–disease-specific damage,” Dr. Bloom said.
 

Bringing children into the clinical discussion

Dr. Bloom said in an interview that many pediatric rheumatologists believe kids with vasculitis are like small adults and should be treated similarly, but she said the picture may be more complex than that.

For example, the findings that children have more subglottic stenosis and alveolar hemorrhage than adults “may warrant more aggressive therapy,” she said. Children also have different growth and psychosocial risk factors during their disease course and may live longer with the disease than those in older age groups.

“Our study helps to point out these differences and bring children into the discussion,” Dr. Bloom said. “It also recognizes that damage scores used in studies and care may not adequately assess disease across the lifespan, as they are largely influenced by items not specific to the disease but rather medication toxicity and comorbidities, such as osteoporosis, cataracts, and malignancy.”

Robert Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at Hospital for Special Surgery, New York, said in an interview that the work highlights interesting information about the fact that disease features are skewed differently in children – “in particular the higher likelihood of upper airway [subglottic] disease, and potentially severe lower airway disease [alveolar hemorrhage].”

However, from a practical standpoint, Dr. Spiera said, “I am not sure that this will change our clinical approach to different patients, but the differences in disease features and even the sex differences in terms of who are afflicted with GPA [more often children and more likely to be female] may offer insights into disease pathogenesis.”

Dr. Bloom received funding from the Vasculitis Clinical Research Consortium and Vasculitis Foundation to conduct this work as a VCRC-VF fellow. Several coauthors reported various conflicts of interest with pharmaceutical companies. Dr. Spiera declared no relevant financial relationships.

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

Researchers have found a link between age of diagnosis and various clinical characteristics and outcomes in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV).

The findings, presented at the annual meeting of the American College of Rheumatology, may have implications for research and treatment, especially in children.

AAV is a group of conditions characterized by the development of autoantibodies to the neutrophil proteins proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA).

The rare autoimmune condition can cause systemic inflammation and damage, sometimes permanent, to small- and medium-sized arteries. Clinical presentations vary and can include several organs, including skin, stomach, intestines, lung, and kidney, as well as airways in ear, nose, and throat.
 

Data limited on child vs. adult characteristics

AAV can be diagnosed in any decade of life, but clinical characteristics and outcomes often differ between children and adults, and data are limited. Studies often exclude children.

Lead author Jessica Bloom, MD, MSCS, a pediatric rheumatologist and assistant professor of pediatrics at Children’s Hospital Colorado, Aurora, and colleagues performed an analysis of patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) who were enrolled in the Vasculitis Clinical Research Consortium Longitudinal Studies from 2013 to 2021.

Patients with eosinophilic GPA (EGPA) were analyzed separately. Children and young adults with EGPA were combined because of the small sample size (n = 87).

The groups were sorted by the age they were diagnosed: under 18 years old, 18-40, 40-65, and older than 65.
 

More than 1,000 patients included

Dr. Bloom’s team analyzed data from 1,020 patients: 61 diagnosed as children, 240 as young adults, 560 as middle-aged adults, and 159 diagnosed as older adults. At all ages, about nine out of 10 patients were White.

They found 852 (84%) had GPA and 165 (16%) had MPA. The analysis also showed 893 (92%) of patients with ANCA results were ANCA positive: 637 (65%) with PR3-ANCA, 247 (25%) with MPO-ANCA, and 9 (1%) with both.

Differences between age groups included:

• Children experienced more subglottic stenosis and alveolar hemorrhage than adults with the condition.
• About half of patients diagnosed in childhood received both cyclophosphamide and rituximab. That rate decreased with increasing age of diagnosis to as low as 14% for those diagnosed in older adulthood. 
• More females than males in all age groups were diagnosed with AAV, but the difference was most pronounced when diagnosed in childhood, and female predominance declined as age increased.
• Older adults experienced more neurologic disease and less musculoskeletal and sinus involvement.

Additionally, for those diagnosed after age 65, after adjusting for disease length and whether they were taking cyclophosphamide and/or rituximab, the Vasculitis Damage Index (VDI) and ANCA Vasculitis Index of Damage (AVID) scores were higher than for those diagnosed in childhood.

“However, these differences are no longer significant when medication toxicity and comorbidity-related items are excluded. Thus, differences in the VDI and AVID scores are driven by non–disease-specific damage,” Dr. Bloom said.
 

Bringing children into the clinical discussion

Dr. Bloom said in an interview that many pediatric rheumatologists believe kids with vasculitis are like small adults and should be treated similarly, but she said the picture may be more complex than that.

For example, the findings that children have more subglottic stenosis and alveolar hemorrhage than adults “may warrant more aggressive therapy,” she said. Children also have different growth and psychosocial risk factors during their disease course and may live longer with the disease than those in older age groups.

“Our study helps to point out these differences and bring children into the discussion,” Dr. Bloom said. “It also recognizes that damage scores used in studies and care may not adequately assess disease across the lifespan, as they are largely influenced by items not specific to the disease but rather medication toxicity and comorbidities, such as osteoporosis, cataracts, and malignancy.”

Robert Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at Hospital for Special Surgery, New York, said in an interview that the work highlights interesting information about the fact that disease features are skewed differently in children – “in particular the higher likelihood of upper airway [subglottic] disease, and potentially severe lower airway disease [alveolar hemorrhage].”

However, from a practical standpoint, Dr. Spiera said, “I am not sure that this will change our clinical approach to different patients, but the differences in disease features and even the sex differences in terms of who are afflicted with GPA [more often children and more likely to be female] may offer insights into disease pathogenesis.”

Dr. Bloom received funding from the Vasculitis Clinical Research Consortium and Vasculitis Foundation to conduct this work as a VCRC-VF fellow. Several coauthors reported various conflicts of interest with pharmaceutical companies. Dr. Spiera declared no relevant financial relationships.

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

AT ACR 2022

PHILADELPHIA – The first consensus screening guidelines for patients with idiopathic inflammatory myopathy (IIM) provide recommendations on risk stratification for individuals, basic and enhanced screening protocols, and screening frequency.

The recommendations, issued by the International Myositis Assessment and Clinical Studies Group (IMACS), stratify cancer risk for individual patients into low, intermediate, or high categories based on the IIM disease subtype, autoantibody status, and clinical features, reported Alexander Oldroyd, PhD, MSc, MBChB of the University of Manchester, England.

Neil Osterweil/MDedge News

“There’s a big unmet need for cancer screening. One in four adults with myositis has cancer, either 3 years before or after a diagnosis of myositis. It’s one of the leading causes of death in these patients, and they’re overwhelmingly diagnosed at a late stage, so we need standardized approaches to get early diagnosis,” he said in an interview at the annual meeting of the American College of Rheumatology.

Sharon Kolasinski, MD, of the University of Pennsylvania in Philadelphia, said in an interview that the guideline is a welcome development for rheumatologists. Dr. Kolasinski moderated the session where Dr. Oldroyd described the guideline, but she was not involved in its formulation.

“I think that we all have wondered for a very long time: What is the optimal cancer screening for myositis patients? We all worry that the onset of their diseases is associated with a coincident cancer, or that they will develop it soon,” she said.

Dr. Oldroyd emphasized that all patients with myositis have elevated risk for cancer compared with the general population and that the guideline categories of low, intermediate, and high are relative only to patients with IIM.
 

International consensus

The data on which the recommendations are based come from a systematic review and meta-analysis by Dr. Oldroyd and colleagues of 69 studies on cancer risk factors and 9 on IIM-specific cancer screening.

The authors of that paper found that the dermatomyositis subtype, older age, male sex, dysphagia, cutaneous ulceration and antitranscriptional intermediary factor-1 gamma (anti-TIF1-gamma) positivity were associated with significantly increased risk of cancer.

In contrast, polymyositis and clinically amyopathic dermatomyositis subtypes, Raynaud’s phenomenon, interstitial lung disease, very high serum creatine kinase or lactate dehydrogenase levels, and positivity for anti-Jo1 or anti-EJ antibodies were associated with significantly reduced risk of cancer.

The consensus recommendations were developed with anonymous contributions from 75 expert participants in 22 countries, with additional input from 3 patient partners.
 

Do this

The guideline lists 18 recommendations, of which 13 are strong and 5 are conditional.

An example of a strong recommendation is number 3, based on a moderate level of evidences:

“All adult IIM patients, irrespective of cancer risk, should continue to participate in country/region-specific age and sex appropriate cancer screening programs,” the guideline recommends.

Patients with verified inclusion body myositis or juvenile-onset IIM do not, however, require routine screening for myositis-associated cancer, the guideline says (recommendations 1 and 2).

There are also recommendations that all adults with new-onset IIM be tested for myositis-specific and myositis-associated autoantibodies to assist in stratifying patients by risk category.

The guideline divides screening recommendations into basic and enhanced. The basic screening should include a comprehensive history and physical exam, complete blood count, liver functions tests, erythrocyte sedimentation rates/plasma viscosity, serum protein electrophoresis, urinalysis, and chest x-ray.

Adults with IIM who are determined to be at low risk for IIM-related cancer should have basic cancer screening at the time of IIM diagnosis. Adults with intermediate risk should undergo both basic and enhanced screening at the time of IIM diagnosis, and those with high risk should undergo enhanced screening at the time of myositis diagnosis, with basic screening annually for 3 years, the recommendations say.
 

Consider doing this

Conditional recommendations (“clinicians should consider ...”) include the use of PET/CT for adults at high risk for cancer when an underlying cancer has not been detected at the time of IIM diagnosis. They also include a single screening test for anti-TIF1-gamma positive dermatomyositis patients whose disease onset was after age 40 and who have at least one additional risk factor.

Also conditionally recommended are upper and lower gastrointestinal endoscopy for patients at high risk when an underlying cancer is not found at the time of IIM diagnosis, nasoendoscopy in geographical regions with elevated risk for nasopharyngeal cancers, and screening for all IIM patients with red-flag symptoms or clinical features of cancer, including unexplained weight loss, family history of cancer, smoking, unexplained fever, or night sweats.
 

Guided steps

“I think clinicians have a lot of questions such as, ‘well, what should I do, when should I do it?’ These are important clinical questions, and we need guidance about this. We need to balance comprehensiveness with cost-effectiveness, and we need expert opinion about what steps we should take now and which should we take later,” Dr. Kolasinski said.

The guideline development process was supported by the University of Manchester, IMACS, National Institute for Health Research (United Kingdom), National Institutes of Health, National Health Service Northern Care Alliance, The Myositis Association, Myositis UK, University of Pittsburgh, Versus Arthritis, and the Center for Musculoskeletal Research. Dr. Oldroyd and Dr. Kolasinski reported having no relevant conflicts of interest.

AT ACR 2022

PHILADELPHIA – The first consensus screening guidelines for patients with idiopathic inflammatory myopathy (IIM) provide recommendations on risk stratification for individuals, basic and enhanced screening protocols, and screening frequency.

The recommendations, issued by the International Myositis Assessment and Clinical Studies Group (IMACS), stratify cancer risk for individual patients into low, intermediate, or high categories based on the IIM disease subtype, autoantibody status, and clinical features, reported Alexander Oldroyd, PhD, MSc, MBChB of the University of Manchester, England.

Neil Osterweil/MDedge News

“There’s a big unmet need for cancer screening. One in four adults with myositis has cancer, either 3 years before or after a diagnosis of myositis. It’s one of the leading causes of death in these patients, and they’re overwhelmingly diagnosed at a late stage, so we need standardized approaches to get early diagnosis,” he said in an interview at the annual meeting of the American College of Rheumatology.

Sharon Kolasinski, MD, of the University of Pennsylvania in Philadelphia, said in an interview that the guideline is a welcome development for rheumatologists. Dr. Kolasinski moderated the session where Dr. Oldroyd described the guideline, but she was not involved in its formulation.

“I think that we all have wondered for a very long time: What is the optimal cancer screening for myositis patients? We all worry that the onset of their diseases is associated with a coincident cancer, or that they will develop it soon,” she said.

Dr. Oldroyd emphasized that all patients with myositis have elevated risk for cancer compared with the general population and that the guideline categories of low, intermediate, and high are relative only to patients with IIM.
 

International consensus

The data on which the recommendations are based come from a systematic review and meta-analysis by Dr. Oldroyd and colleagues of 69 studies on cancer risk factors and 9 on IIM-specific cancer screening.

The authors of that paper found that the dermatomyositis subtype, older age, male sex, dysphagia, cutaneous ulceration and antitranscriptional intermediary factor-1 gamma (anti-TIF1-gamma) positivity were associated with significantly increased risk of cancer.

In contrast, polymyositis and clinically amyopathic dermatomyositis subtypes, Raynaud’s phenomenon, interstitial lung disease, very high serum creatine kinase or lactate dehydrogenase levels, and positivity for anti-Jo1 or anti-EJ antibodies were associated with significantly reduced risk of cancer.

The consensus recommendations were developed with anonymous contributions from 75 expert participants in 22 countries, with additional input from 3 patient partners.
 

Do this

The guideline lists 18 recommendations, of which 13 are strong and 5 are conditional.

An example of a strong recommendation is number 3, based on a moderate level of evidences:

“All adult IIM patients, irrespective of cancer risk, should continue to participate in country/region-specific age and sex appropriate cancer screening programs,” the guideline recommends.

Patients with verified inclusion body myositis or juvenile-onset IIM do not, however, require routine screening for myositis-associated cancer, the guideline says (recommendations 1 and 2).

There are also recommendations that all adults with new-onset IIM be tested for myositis-specific and myositis-associated autoantibodies to assist in stratifying patients by risk category.

The guideline divides screening recommendations into basic and enhanced. The basic screening should include a comprehensive history and physical exam, complete blood count, liver functions tests, erythrocyte sedimentation rates/plasma viscosity, serum protein electrophoresis, urinalysis, and chest x-ray.

Adults with IIM who are determined to be at low risk for IIM-related cancer should have basic cancer screening at the time of IIM diagnosis. Adults with intermediate risk should undergo both basic and enhanced screening at the time of IIM diagnosis, and those with high risk should undergo enhanced screening at the time of myositis diagnosis, with basic screening annually for 3 years, the recommendations say.
 

Consider doing this

Conditional recommendations (“clinicians should consider ...”) include the use of PET/CT for adults at high risk for cancer when an underlying cancer has not been detected at the time of IIM diagnosis. They also include a single screening test for anti-TIF1-gamma positive dermatomyositis patients whose disease onset was after age 40 and who have at least one additional risk factor.

Also conditionally recommended are upper and lower gastrointestinal endoscopy for patients at high risk when an underlying cancer is not found at the time of IIM diagnosis, nasoendoscopy in geographical regions with elevated risk for nasopharyngeal cancers, and screening for all IIM patients with red-flag symptoms or clinical features of cancer, including unexplained weight loss, family history of cancer, smoking, unexplained fever, or night sweats.
 

Guided steps

“I think clinicians have a lot of questions such as, ‘well, what should I do, when should I do it?’ These are important clinical questions, and we need guidance about this. We need to balance comprehensiveness with cost-effectiveness, and we need expert opinion about what steps we should take now and which should we take later,” Dr. Kolasinski said.

The guideline development process was supported by the University of Manchester, IMACS, National Institute for Health Research (United Kingdom), National Institutes of Health, National Health Service Northern Care Alliance, The Myositis Association, Myositis UK, University of Pittsburgh, Versus Arthritis, and the Center for Musculoskeletal Research. Dr. Oldroyd and Dr. Kolasinski reported having no relevant conflicts of interest.

AT ACR 2022

PHILADELPHIA – The first consensus screening guidelines for patients with idiopathic inflammatory myopathy (IIM) provide recommendations on risk stratification for individuals, basic and enhanced screening protocols, and screening frequency.

The recommendations, issued by the International Myositis Assessment and Clinical Studies Group (IMACS), stratify cancer risk for individual patients into low, intermediate, or high categories based on the IIM disease subtype, autoantibody status, and clinical features, reported Alexander Oldroyd, PhD, MSc, MBChB of the University of Manchester, England.

Neil Osterweil/MDedge News

“There’s a big unmet need for cancer screening. One in four adults with myositis has cancer, either 3 years before or after a diagnosis of myositis. It’s one of the leading causes of death in these patients, and they’re overwhelmingly diagnosed at a late stage, so we need standardized approaches to get early diagnosis,” he said in an interview at the annual meeting of the American College of Rheumatology.

Sharon Kolasinski, MD, of the University of Pennsylvania in Philadelphia, said in an interview that the guideline is a welcome development for rheumatologists. Dr. Kolasinski moderated the session where Dr. Oldroyd described the guideline, but she was not involved in its formulation.

“I think that we all have wondered for a very long time: What is the optimal cancer screening for myositis patients? We all worry that the onset of their diseases is associated with a coincident cancer, or that they will develop it soon,” she said.

Dr. Oldroyd emphasized that all patients with myositis have elevated risk for cancer compared with the general population and that the guideline categories of low, intermediate, and high are relative only to patients with IIM.
 

International consensus

The data on which the recommendations are based come from a systematic review and meta-analysis by Dr. Oldroyd and colleagues of 69 studies on cancer risk factors and 9 on IIM-specific cancer screening.

The authors of that paper found that the dermatomyositis subtype, older age, male sex, dysphagia, cutaneous ulceration and antitranscriptional intermediary factor-1 gamma (anti-TIF1-gamma) positivity were associated with significantly increased risk of cancer.

In contrast, polymyositis and clinically amyopathic dermatomyositis subtypes, Raynaud’s phenomenon, interstitial lung disease, very high serum creatine kinase or lactate dehydrogenase levels, and positivity for anti-Jo1 or anti-EJ antibodies were associated with significantly reduced risk of cancer.

The consensus recommendations were developed with anonymous contributions from 75 expert participants in 22 countries, with additional input from 3 patient partners.
 

Do this

The guideline lists 18 recommendations, of which 13 are strong and 5 are conditional.

An example of a strong recommendation is number 3, based on a moderate level of evidences:

“All adult IIM patients, irrespective of cancer risk, should continue to participate in country/region-specific age and sex appropriate cancer screening programs,” the guideline recommends.

Patients with verified inclusion body myositis or juvenile-onset IIM do not, however, require routine screening for myositis-associated cancer, the guideline says (recommendations 1 and 2).

There are also recommendations that all adults with new-onset IIM be tested for myositis-specific and myositis-associated autoantibodies to assist in stratifying patients by risk category.

The guideline divides screening recommendations into basic and enhanced. The basic screening should include a comprehensive history and physical exam, complete blood count, liver functions tests, erythrocyte sedimentation rates/plasma viscosity, serum protein electrophoresis, urinalysis, and chest x-ray.

Adults with IIM who are determined to be at low risk for IIM-related cancer should have basic cancer screening at the time of IIM diagnosis. Adults with intermediate risk should undergo both basic and enhanced screening at the time of IIM diagnosis, and those with high risk should undergo enhanced screening at the time of myositis diagnosis, with basic screening annually for 3 years, the recommendations say.
 

Consider doing this

Conditional recommendations (“clinicians should consider ...”) include the use of PET/CT for adults at high risk for cancer when an underlying cancer has not been detected at the time of IIM diagnosis. They also include a single screening test for anti-TIF1-gamma positive dermatomyositis patients whose disease onset was after age 40 and who have at least one additional risk factor.

Also conditionally recommended are upper and lower gastrointestinal endoscopy for patients at high risk when an underlying cancer is not found at the time of IIM diagnosis, nasoendoscopy in geographical regions with elevated risk for nasopharyngeal cancers, and screening for all IIM patients with red-flag symptoms or clinical features of cancer, including unexplained weight loss, family history of cancer, smoking, unexplained fever, or night sweats.
 

Guided steps

“I think clinicians have a lot of questions such as, ‘well, what should I do, when should I do it?’ These are important clinical questions, and we need guidance about this. We need to balance comprehensiveness with cost-effectiveness, and we need expert opinion about what steps we should take now and which should we take later,” Dr. Kolasinski said.

The guideline development process was supported by the University of Manchester, IMACS, National Institute for Health Research (United Kingdom), National Institutes of Health, National Health Service Northern Care Alliance, The Myositis Association, Myositis UK, University of Pittsburgh, Versus Arthritis, and the Center for Musculoskeletal Research. Dr. Oldroyd and Dr. Kolasinski reported having no relevant conflicts of interest.

The successful treatment of Pompe disease in utero for the first time may be the start of a new chapter for fetal therapy, researchers said.

A report published online in the New England Journal of Medicine describes in utero enzyme-replacement therapy (ERT) for infantile-onset Pompe disease.

The patient, now a toddler, is thriving, according to the researchers. Her parents previously had children with the same disorder who died.

“This treatment expands the repertoire of fetal therapies in a new direction,” Tippi MacKenzie, MD, a pediatric surgeon with University of California, San Francisco, Benioff Children’s Hospitals and a coauthor of the report, said in a news release. “As new treatments become available for children with genetic conditions, we are developing protocols to apply them before birth.”

Dr. MacKenzie codirects the University of California, San Francisco’s center for maternal-fetal precision medicine and directs the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research.

Pompe disease is caused by mutations in a gene that makes acid alpha-glucosidase. With limited amounts of this enzyme, dangerous amounts of glycogen accumulate in the body. Babies with infantile-onset disease typically have enlarged hearts and die by age 2 years.

The condition, which occurs in an estimated 1 in 40,000 births, is one of several early-onset lysosomal storage disorders. Patients with these diseases “are ideal candidates for prenatal therapy because organ damage starts in utero,” the researchers said.

Newborn screening can lead to early initiation of treatment with recombinant enzymes, “but this strategy does not completely prevent irreversible organ damage,” the authors said.

The patient in the new report received six prenatal ERT treatments at the Ottawa Hospital and is receiving postnatal enzyme therapy at CHEO, a pediatric hospital and research center in Ottawa.

Investigators administered alglucosidase alfa through the umbilical vein. They delivered the first infusion to the fetus at 24 weeks 5 days of gestation. They continued providing infusions at 2-week intervals through 34 weeks 5 days of gestation.

She is doing well at age 16 months, with normal cardiac and motor function, and is meeting developmental milestones, according to the news release.

The successful treatment involved collaboration among the University of California, San Francisco, where researchers are conducting a clinical trial of this treatment approach; CHEO and the Ottawa Hospital; and Duke University, Durham, N.C.

Under normal circumstances, the patient’s family would have traveled to Benioff Children’s Hospitals fetal treatment center to participate in the clinical trial, but COVID-19 restrictions led the researchers to deliver the therapy to Ottawa as part of the trial.

The University of California, San Francisco, has received U.S. Food and Drug Administration approval to treat Pompe disease and several other lysosomal storage disorders in utero as part of a phase 1 clinical trial with 10 patients. The other diseases are mucopolysaccharidosis types 1, 2, 4a, 6, and 7; Gaucher disease types 2 and 3; and Wolman disease.

Patients with Pompe disease might typically be diagnosed clinically at age 3-6 months, said study coauthor Paul Harmatz, MD, with the University of California, San Francisco. With newborn screening, the disease might be diagnosed at 1 week. But intervening before birth may be optimal, Dr. Harmatz said.

Fetal treatment appears to be “revolutionary at this point,” Dr. Harmatz said.

The research was supported by a grant from the National Institutes of Health. Sanofi Genzyme provided the enzyme for the patient.

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

The successful treatment of Pompe disease in utero for the first time may be the start of a new chapter for fetal therapy, researchers said.

A report published online in the New England Journal of Medicine describes in utero enzyme-replacement therapy (ERT) for infantile-onset Pompe disease.

The patient, now a toddler, is thriving, according to the researchers. Her parents previously had children with the same disorder who died.

“This treatment expands the repertoire of fetal therapies in a new direction,” Tippi MacKenzie, MD, a pediatric surgeon with University of California, San Francisco, Benioff Children’s Hospitals and a coauthor of the report, said in a news release. “As new treatments become available for children with genetic conditions, we are developing protocols to apply them before birth.”

Dr. MacKenzie codirects the University of California, San Francisco’s center for maternal-fetal precision medicine and directs the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research.

Pompe disease is caused by mutations in a gene that makes acid alpha-glucosidase. With limited amounts of this enzyme, dangerous amounts of glycogen accumulate in the body. Babies with infantile-onset disease typically have enlarged hearts and die by age 2 years.

The condition, which occurs in an estimated 1 in 40,000 births, is one of several early-onset lysosomal storage disorders. Patients with these diseases “are ideal candidates for prenatal therapy because organ damage starts in utero,” the researchers said.

Newborn screening can lead to early initiation of treatment with recombinant enzymes, “but this strategy does not completely prevent irreversible organ damage,” the authors said.

The patient in the new report received six prenatal ERT treatments at the Ottawa Hospital and is receiving postnatal enzyme therapy at CHEO, a pediatric hospital and research center in Ottawa.

Investigators administered alglucosidase alfa through the umbilical vein. They delivered the first infusion to the fetus at 24 weeks 5 days of gestation. They continued providing infusions at 2-week intervals through 34 weeks 5 days of gestation.

She is doing well at age 16 months, with normal cardiac and motor function, and is meeting developmental milestones, according to the news release.

The successful treatment involved collaboration among the University of California, San Francisco, where researchers are conducting a clinical trial of this treatment approach; CHEO and the Ottawa Hospital; and Duke University, Durham, N.C.

Under normal circumstances, the patient’s family would have traveled to Benioff Children’s Hospitals fetal treatment center to participate in the clinical trial, but COVID-19 restrictions led the researchers to deliver the therapy to Ottawa as part of the trial.

The University of California, San Francisco, has received U.S. Food and Drug Administration approval to treat Pompe disease and several other lysosomal storage disorders in utero as part of a phase 1 clinical trial with 10 patients. The other diseases are mucopolysaccharidosis types 1, 2, 4a, 6, and 7; Gaucher disease types 2 and 3; and Wolman disease.

Patients with Pompe disease might typically be diagnosed clinically at age 3-6 months, said study coauthor Paul Harmatz, MD, with the University of California, San Francisco. With newborn screening, the disease might be diagnosed at 1 week. But intervening before birth may be optimal, Dr. Harmatz said.

Fetal treatment appears to be “revolutionary at this point,” Dr. Harmatz said.

The research was supported by a grant from the National Institutes of Health. Sanofi Genzyme provided the enzyme for the patient.

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

The successful treatment of Pompe disease in utero for the first time may be the start of a new chapter for fetal therapy, researchers said.

A report published online in the New England Journal of Medicine describes in utero enzyme-replacement therapy (ERT) for infantile-onset Pompe disease.

The patient, now a toddler, is thriving, according to the researchers. Her parents previously had children with the same disorder who died.

“This treatment expands the repertoire of fetal therapies in a new direction,” Tippi MacKenzie, MD, a pediatric surgeon with University of California, San Francisco, Benioff Children’s Hospitals and a coauthor of the report, said in a news release. “As new treatments become available for children with genetic conditions, we are developing protocols to apply them before birth.”

Dr. MacKenzie codirects the University of California, San Francisco’s center for maternal-fetal precision medicine and directs the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research.

Pompe disease is caused by mutations in a gene that makes acid alpha-glucosidase. With limited amounts of this enzyme, dangerous amounts of glycogen accumulate in the body. Babies with infantile-onset disease typically have enlarged hearts and die by age 2 years.

The condition, which occurs in an estimated 1 in 40,000 births, is one of several early-onset lysosomal storage disorders. Patients with these diseases “are ideal candidates for prenatal therapy because organ damage starts in utero,” the researchers said.

Newborn screening can lead to early initiation of treatment with recombinant enzymes, “but this strategy does not completely prevent irreversible organ damage,” the authors said.

The patient in the new report received six prenatal ERT treatments at the Ottawa Hospital and is receiving postnatal enzyme therapy at CHEO, a pediatric hospital and research center in Ottawa.

Investigators administered alglucosidase alfa through the umbilical vein. They delivered the first infusion to the fetus at 24 weeks 5 days of gestation. They continued providing infusions at 2-week intervals through 34 weeks 5 days of gestation.

She is doing well at age 16 months, with normal cardiac and motor function, and is meeting developmental milestones, according to the news release.

The successful treatment involved collaboration among the University of California, San Francisco, where researchers are conducting a clinical trial of this treatment approach; CHEO and the Ottawa Hospital; and Duke University, Durham, N.C.

Under normal circumstances, the patient’s family would have traveled to Benioff Children’s Hospitals fetal treatment center to participate in the clinical trial, but COVID-19 restrictions led the researchers to deliver the therapy to Ottawa as part of the trial.

The University of California, San Francisco, has received U.S. Food and Drug Administration approval to treat Pompe disease and several other lysosomal storage disorders in utero as part of a phase 1 clinical trial with 10 patients. The other diseases are mucopolysaccharidosis types 1, 2, 4a, 6, and 7; Gaucher disease types 2 and 3; and Wolman disease.

Patients with Pompe disease might typically be diagnosed clinically at age 3-6 months, said study coauthor Paul Harmatz, MD, with the University of California, San Francisco. With newborn screening, the disease might be diagnosed at 1 week. But intervening before birth may be optimal, Dr. Harmatz said.

Fetal treatment appears to be “revolutionary at this point,” Dr. Harmatz said.

The research was supported by a grant from the National Institutes of Health. Sanofi Genzyme provided the enzyme for the patient.

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

Acrodermatitis enteropathica (AE) is a rare disorder of zinc metabolism that typically presents in infancy.¹ Although it is clinically characterized by acral and periorificial dermatitis, alopecia, and diarrhea, only 20% of cases present with this triad.² Zinc deficiency in AE can either be acquired or inborn (congenital). Acquired forms can occur from dietary inadequacy or malabsorption, whereas genetic causes are related to an autosomal-recessive disorder affecting zinc transporters.¹ We report a case of a 3-month-old female infant with acquired AE who was successfully treated with zinc supplementation over the course of 3 weeks.

Case Report

A 3-month-old female infant presented to the emergency department with a rash of 2 weeks’ duration. She was born full term with no birth complications. The patient’s mother reported that the rash started on the cheeks, then enlarged and spread to the neck, back, and perineum. The patient also had been having diarrhea during this time. She previously had received mupirocin and cephalexin with no response to treatment. Maternal history was negative for lupus, and the mother’s diet consisted of a variety of foods but not many vegetables. The patient was exclusively breastfed, and there was no pertinent history of similar rashes occurring in other family members.

Physical examination revealed the patient had annular and polycyclic, hyperkeratotic, crusted papules and plaques on the cheeks, neck, back, and axillae, as well as the perineum/groin and perianal regions (Figure 1). The differential diagnosis at the time included neonatal lupus, zinc deficiency, and syphilis. Relevant laboratory testing and a shave biopsy of the left axilla were obtained.

Comment

Etiology of AE—Acrodermatitis enteropathica was first identified in 1942 as an acral rash associated with diarrhea³; in 1973, Barnes and Moynahan⁴ discovered zinc deficiency as a causal agent for these findings. The causes of AE are further subclassified as either an acquired or inborn etiology. Congenital causes commonly are seen in infants within the first few months of life, whereas acquired forms are seen at any age. Acquired forms in infants can occur from failure of the mother to secrete zinc in breast milk, low maternal serum zinc levels, or other reasons causing low nutritional intake. A single mutation in the SLC30A2 gene has been found to markedly reduce zinc concentrations in breast milk, thus causing zinc deficiency in breastfed infants.⁵ Other acquired forms can be caused by malabsorption, sometimes after surgery such as intestinal bypass or from intravenous nutrition without sufficient zinc.¹ The congenital form of AE is an autosomal-recessive disorder occurring from mutations in the SLC39A4 gene located on band 8q24.3. Affected individuals have a decreased ability to absorb zinc in the small intestine because of defects in zinc transporters ZIP and ZnT.⁶ Based on our patient’s laboratory findings and history, it is believed that the zinc deficiency was acquired, as the condition normalized with repletion and has not required any supplementation in the year of follow-up. In addition, the absence of a pertinent family history supported an acquired diagnosis, which has various etiologies, whereas the congenital form primarily is a genetic disease.

Diagnosis of AE—The characteristic clinical features of AE include erythematous, dry, scaly papules and plaques that may evolve into crusted, erosive, pustular lesions. These lesions typically are distributed in a periorificial and acral pattern.^1,2 Although AE includes the clinical triad of acral and periorificial dermatitis, alopecia, and diarrhea, most cases present with only partial features of this syndrome, as seen in our patient, who presented with only 2 symptoms—dermatitis and diarrhea. The diagnosis of AE is based on clinical and laboratory abnormalities, especially a low serum zinc level. Low levels of zinc-dependent enzymes, such as alkaline phosphatase, may support the diagnosis, as seen in our patient. Histologic evaluation is characteristic but is not diagnostic, as the same findings can be seen in other nutritional disorders. Such findings include confluent parakeratosis associated with a reduced granular layer in early lesions and subsequent ballooning of subcorneal keratinocytes, upper epidermal pallor, and intraepidermal clefts. Late lesions exhibit psoriasiform hyperplasia of the epidermis with less epidermal pallor.⁷

Acrodermatitis enteropathica (AE) is a rare disorder of zinc metabolism that typically presents in infancy.¹ Although it is clinically characterized by acral and periorificial dermatitis, alopecia, and diarrhea, only 20% of cases present with this triad.² Zinc deficiency in AE can either be acquired or inborn (congenital). Acquired forms can occur from dietary inadequacy or malabsorption, whereas genetic causes are related to an autosomal-recessive disorder affecting zinc transporters.¹ We report a case of a 3-month-old female infant with acquired AE who was successfully treated with zinc supplementation over the course of 3 weeks.

Case Report

A 3-month-old female infant presented to the emergency department with a rash of 2 weeks’ duration. She was born full term with no birth complications. The patient’s mother reported that the rash started on the cheeks, then enlarged and spread to the neck, back, and perineum. The patient also had been having diarrhea during this time. She previously had received mupirocin and cephalexin with no response to treatment. Maternal history was negative for lupus, and the mother’s diet consisted of a variety of foods but not many vegetables. The patient was exclusively breastfed, and there was no pertinent history of similar rashes occurring in other family members.

Physical examination revealed the patient had annular and polycyclic, hyperkeratotic, crusted papules and plaques on the cheeks, neck, back, and axillae, as well as the perineum/groin and perianal regions (Figure 1). The differential diagnosis at the time included neonatal lupus, zinc deficiency, and syphilis. Relevant laboratory testing and a shave biopsy of the left axilla were obtained.

Comment

Etiology of AE—Acrodermatitis enteropathica was first identified in 1942 as an acral rash associated with diarrhea³; in 1973, Barnes and Moynahan⁴ discovered zinc deficiency as a causal agent for these findings. The causes of AE are further subclassified as either an acquired or inborn etiology. Congenital causes commonly are seen in infants within the first few months of life, whereas acquired forms are seen at any age. Acquired forms in infants can occur from failure of the mother to secrete zinc in breast milk, low maternal serum zinc levels, or other reasons causing low nutritional intake. A single mutation in the SLC30A2 gene has been found to markedly reduce zinc concentrations in breast milk, thus causing zinc deficiency in breastfed infants.⁵ Other acquired forms can be caused by malabsorption, sometimes after surgery such as intestinal bypass or from intravenous nutrition without sufficient zinc.¹ The congenital form of AE is an autosomal-recessive disorder occurring from mutations in the SLC39A4 gene located on band 8q24.3. Affected individuals have a decreased ability to absorb zinc in the small intestine because of defects in zinc transporters ZIP and ZnT.⁶ Based on our patient’s laboratory findings and history, it is believed that the zinc deficiency was acquired, as the condition normalized with repletion and has not required any supplementation in the year of follow-up. In addition, the absence of a pertinent family history supported an acquired diagnosis, which has various etiologies, whereas the congenital form primarily is a genetic disease.

Diagnosis of AE—The characteristic clinical features of AE include erythematous, dry, scaly papules and plaques that may evolve into crusted, erosive, pustular lesions. These lesions typically are distributed in a periorificial and acral pattern.^1,2 Although AE includes the clinical triad of acral and periorificial dermatitis, alopecia, and diarrhea, most cases present with only partial features of this syndrome, as seen in our patient, who presented with only 2 symptoms—dermatitis and diarrhea. The diagnosis of AE is based on clinical and laboratory abnormalities, especially a low serum zinc level. Low levels of zinc-dependent enzymes, such as alkaline phosphatase, may support the diagnosis, as seen in our patient. Histologic evaluation is characteristic but is not diagnostic, as the same findings can be seen in other nutritional disorders. Such findings include confluent parakeratosis associated with a reduced granular layer in early lesions and subsequent ballooning of subcorneal keratinocytes, upper epidermal pallor, and intraepidermal clefts. Late lesions exhibit psoriasiform hyperplasia of the epidermis with less epidermal pallor.⁷

Acrodermatitis enteropathica (AE) is a rare disorder of zinc metabolism that typically presents in infancy.¹ Although it is clinically characterized by acral and periorificial dermatitis, alopecia, and diarrhea, only 20% of cases present with this triad.² Zinc deficiency in AE can either be acquired or inborn (congenital). Acquired forms can occur from dietary inadequacy or malabsorption, whereas genetic causes are related to an autosomal-recessive disorder affecting zinc transporters.¹ We report a case of a 3-month-old female infant with acquired AE who was successfully treated with zinc supplementation over the course of 3 weeks.

Case Report

A 3-month-old female infant presented to the emergency department with a rash of 2 weeks’ duration. She was born full term with no birth complications. The patient’s mother reported that the rash started on the cheeks, then enlarged and spread to the neck, back, and perineum. The patient also had been having diarrhea during this time. She previously had received mupirocin and cephalexin with no response to treatment. Maternal history was negative for lupus, and the mother’s diet consisted of a variety of foods but not many vegetables. The patient was exclusively breastfed, and there was no pertinent history of similar rashes occurring in other family members.

Physical examination revealed the patient had annular and polycyclic, hyperkeratotic, crusted papules and plaques on the cheeks, neck, back, and axillae, as well as the perineum/groin and perianal regions (Figure 1). The differential diagnosis at the time included neonatal lupus, zinc deficiency, and syphilis. Relevant laboratory testing and a shave biopsy of the left axilla were obtained.

Comment

Etiology of AE—Acrodermatitis enteropathica was first identified in 1942 as an acral rash associated with diarrhea³; in 1973, Barnes and Moynahan⁴ discovered zinc deficiency as a causal agent for these findings. The causes of AE are further subclassified as either an acquired or inborn etiology. Congenital causes commonly are seen in infants within the first few months of life, whereas acquired forms are seen at any age. Acquired forms in infants can occur from failure of the mother to secrete zinc in breast milk, low maternal serum zinc levels, or other reasons causing low nutritional intake. A single mutation in the SLC30A2 gene has been found to markedly reduce zinc concentrations in breast milk, thus causing zinc deficiency in breastfed infants.⁵ Other acquired forms can be caused by malabsorption, sometimes after surgery such as intestinal bypass or from intravenous nutrition without sufficient zinc.¹ The congenital form of AE is an autosomal-recessive disorder occurring from mutations in the SLC39A4 gene located on band 8q24.3. Affected individuals have a decreased ability to absorb zinc in the small intestine because of defects in zinc transporters ZIP and ZnT.⁶ Based on our patient’s laboratory findings and history, it is believed that the zinc deficiency was acquired, as the condition normalized with repletion and has not required any supplementation in the year of follow-up. In addition, the absence of a pertinent family history supported an acquired diagnosis, which has various etiologies, whereas the congenital form primarily is a genetic disease.

Diagnosis of AE—The characteristic clinical features of AE include erythematous, dry, scaly papules and plaques that may evolve into crusted, erosive, pustular lesions. These lesions typically are distributed in a periorificial and acral pattern.^1,2 Although AE includes the clinical triad of acral and periorificial dermatitis, alopecia, and diarrhea, most cases present with only partial features of this syndrome, as seen in our patient, who presented with only 2 symptoms—dermatitis and diarrhea. The diagnosis of AE is based on clinical and laboratory abnormalities, especially a low serum zinc level. Low levels of zinc-dependent enzymes, such as alkaline phosphatase, may support the diagnosis, as seen in our patient. Histologic evaluation is characteristic but is not diagnostic, as the same findings can be seen in other nutritional disorders. Such findings include confluent parakeratosis associated with a reduced granular layer in early lesions and subsequent ballooning of subcorneal keratinocytes, upper epidermal pallor, and intraepidermal clefts. Late lesions exhibit psoriasiform hyperplasia of the epidermis with less epidermal pallor.⁷

An “exciting” new gene-editing strategy means those born with a rare inherited disease of the immune system could be treated by repairing a fault in their cells.

Scientists have hailed new research that found faulty cells responsible for the immune system disease CTLA-4 insufficiency can be repaired with a pioneering gene editing technique.

CTLA-4 is a protein produced by T cells that helps to control the activity of the immune system. Most people carry two working copies of the gene responsible for producing CTLA-4, but those who have only one functional copy produce too little of the protein to sufficiently regulate the immune system.

For patients with the condition, CTLA-4 insufficiency causes regulatory T cells to function abnormally, leading to severe autoimmunity. The authors explained that the condition also affects effector T cells and thereby “hampers their immune system’s ‘memory,’ ” meaning patients can “struggle to fight off recurring infections by the same viruses and bacteria.” In some cases, it can also lead to lymphomas.
 

Gene editing to ‘cut’ out faulty genes and ‘paste’ in ‘corrected’ ones

The research, published in Science Translational Medicine, and led by scientists from University College London, demonstrated in human cells and in mice that the cell fault can be repaired.

The scientists used “cut-and-paste” gene-editing techniques. First, they used the CRISPR/Cas9 system to target the faulty gene in human T cells taken from patients with CTLA-4 insufficiency, and then snip the faulty CTLA-4 gene in two. Then, to repair the errors a corrected sequence of DNA – delivered to the cell using a modified virus – was pasted over the faulty part of the gene using a cellular DNA repair mechanism known as homology-directed repair.

The authors explained that this allowed them to “preserve” important sequences within the CTLA-4 gene – known as the intron – that allow it to be switched on and off by the cell only when needed. 

The outcome was “restored levels of CTLA-4 in the cells to those seen in healthy T cells,” the authors said.

Claire Booth, PhD, Mahboubian professor of gene therapy and pediatric immunology, UCL Great Ormond Street Institute of Child Health, and co–senior author, said that it was “really exciting” to think about taking this treatment forward to patients. “If we can improve their symptoms and reduce their risk of getting lymphoproliferative disease this will be a major step forward.”

In addition, the researchers were also able to improve symptoms of the disease in mice with CTLA-4 insufficiency by giving them injections of gene-edited T cells.
 

Technique may help tackle many conditions

The current standard treatment for CTLA-4 insufficiency is a bone marrow transplant to replace the stem cells responsible for producing T cells. However, “transplants are risky” and require high doses of chemotherapy and many weeks in hospital, the authors explained. “Older patients with CTLA-4 insufficiency are typically not well enough to tolerate the transplant procedure.”

Dr. Booth highlighted that the approach has many “positive aspects”. By correcting the patient’s T cells, “we think it can improve many of the symptoms of the disease”, she said, and added that this new approach is much less toxic than a bone marrow transplant. “Collecting the T cells is easier and correcting the T cells is easier. With this approach the amount of time in hospital the patients would need would be far less.”

Emma Morris, PhD, professor of clinical cell and gene therapy and director of UCL’s division of infection and immunity, and co–senior author, said: “Genes that play critical roles in controlling immune responses are not switched on all the time and are very tightly regulated. The technique we have used allows us to leave the natural (endogenous) mechanisms controlling gene expression intact, at the same time as correcting the mistake in the gene itself.”

The researchers explained that, although CTLA-4 insufficiency is rare, the gene editing therapy could be a proof of principle of their approach that could be adapted to tackle other conditions. 

“It’s a way of correcting genetic mutations that could potentially be applicable for other diseases,” suggested Dr. Morris. “The bigger picture is it allows us to correct genes that are dysregulated or overactive, but also allows us to understand much more about gene expression and gene regulation.”

The study was funded by the Wellcome Trust, the Association for Moleculary Pathology, the Medical Research Council, Alzheimer’s Research UK, and the UCLH/UCL NIHR Biomedical Research Centre. Dr. Morris is a founder sharehold of Quell Therapeutics and has received honoraria from Orchard Therapeutics, GlaxoSmithKline, and AstraZeneca. Dr. Booth has performed ad hoc consulting in the past 3 years for SOBI and Novartis and educational material production for SOBI and Chiesi. A patent on the intronic gene editing approach has been filed in the UK. The other authors declared that they have no completing interests.

A version of this article first appeared on Medscape UK.

An “exciting” new gene-editing strategy means those born with a rare inherited disease of the immune system could be treated by repairing a fault in their cells.

Scientists have hailed new research that found faulty cells responsible for the immune system disease CTLA-4 insufficiency can be repaired with a pioneering gene editing technique.

CTLA-4 is a protein produced by T cells that helps to control the activity of the immune system. Most people carry two working copies of the gene responsible for producing CTLA-4, but those who have only one functional copy produce too little of the protein to sufficiently regulate the immune system.

For patients with the condition, CTLA-4 insufficiency causes regulatory T cells to function abnormally, leading to severe autoimmunity. The authors explained that the condition also affects effector T cells and thereby “hampers their immune system’s ‘memory,’ ” meaning patients can “struggle to fight off recurring infections by the same viruses and bacteria.” In some cases, it can also lead to lymphomas.
 

Gene editing to ‘cut’ out faulty genes and ‘paste’ in ‘corrected’ ones

The research, published in Science Translational Medicine, and led by scientists from University College London, demonstrated in human cells and in mice that the cell fault can be repaired.

The scientists used “cut-and-paste” gene-editing techniques. First, they used the CRISPR/Cas9 system to target the faulty gene in human T cells taken from patients with CTLA-4 insufficiency, and then snip the faulty CTLA-4 gene in two. Then, to repair the errors a corrected sequence of DNA – delivered to the cell using a modified virus – was pasted over the faulty part of the gene using a cellular DNA repair mechanism known as homology-directed repair.

The authors explained that this allowed them to “preserve” important sequences within the CTLA-4 gene – known as the intron – that allow it to be switched on and off by the cell only when needed. 

The outcome was “restored levels of CTLA-4 in the cells to those seen in healthy T cells,” the authors said.

Claire Booth, PhD, Mahboubian professor of gene therapy and pediatric immunology, UCL Great Ormond Street Institute of Child Health, and co–senior author, said that it was “really exciting” to think about taking this treatment forward to patients. “If we can improve their symptoms and reduce their risk of getting lymphoproliferative disease this will be a major step forward.”

In addition, the researchers were also able to improve symptoms of the disease in mice with CTLA-4 insufficiency by giving them injections of gene-edited T cells.
 

Technique may help tackle many conditions

The current standard treatment for CTLA-4 insufficiency is a bone marrow transplant to replace the stem cells responsible for producing T cells. However, “transplants are risky” and require high doses of chemotherapy and many weeks in hospital, the authors explained. “Older patients with CTLA-4 insufficiency are typically not well enough to tolerate the transplant procedure.”

Dr. Booth highlighted that the approach has many “positive aspects”. By correcting the patient’s T cells, “we think it can improve many of the symptoms of the disease”, she said, and added that this new approach is much less toxic than a bone marrow transplant. “Collecting the T cells is easier and correcting the T cells is easier. With this approach the amount of time in hospital the patients would need would be far less.”

Emma Morris, PhD, professor of clinical cell and gene therapy and director of UCL’s division of infection and immunity, and co–senior author, said: “Genes that play critical roles in controlling immune responses are not switched on all the time and are very tightly regulated. The technique we have used allows us to leave the natural (endogenous) mechanisms controlling gene expression intact, at the same time as correcting the mistake in the gene itself.”

The researchers explained that, although CTLA-4 insufficiency is rare, the gene editing therapy could be a proof of principle of their approach that could be adapted to tackle other conditions. 

“It’s a way of correcting genetic mutations that could potentially be applicable for other diseases,” suggested Dr. Morris. “The bigger picture is it allows us to correct genes that are dysregulated or overactive, but also allows us to understand much more about gene expression and gene regulation.”

The study was funded by the Wellcome Trust, the Association for Moleculary Pathology, the Medical Research Council, Alzheimer’s Research UK, and the UCLH/UCL NIHR Biomedical Research Centre. Dr. Morris is a founder sharehold of Quell Therapeutics and has received honoraria from Orchard Therapeutics, GlaxoSmithKline, and AstraZeneca. Dr. Booth has performed ad hoc consulting in the past 3 years for SOBI and Novartis and educational material production for SOBI and Chiesi. A patent on the intronic gene editing approach has been filed in the UK. The other authors declared that they have no completing interests.

A version of this article first appeared on Medscape UK.

An “exciting” new gene-editing strategy means those born with a rare inherited disease of the immune system could be treated by repairing a fault in their cells.

Scientists have hailed new research that found faulty cells responsible for the immune system disease CTLA-4 insufficiency can be repaired with a pioneering gene editing technique.

CTLA-4 is a protein produced by T cells that helps to control the activity of the immune system. Most people carry two working copies of the gene responsible for producing CTLA-4, but those who have only one functional copy produce too little of the protein to sufficiently regulate the immune system.

For patients with the condition, CTLA-4 insufficiency causes regulatory T cells to function abnormally, leading to severe autoimmunity. The authors explained that the condition also affects effector T cells and thereby “hampers their immune system’s ‘memory,’ ” meaning patients can “struggle to fight off recurring infections by the same viruses and bacteria.” In some cases, it can also lead to lymphomas.
 

Gene editing to ‘cut’ out faulty genes and ‘paste’ in ‘corrected’ ones

The research, published in Science Translational Medicine, and led by scientists from University College London, demonstrated in human cells and in mice that the cell fault can be repaired.

The scientists used “cut-and-paste” gene-editing techniques. First, they used the CRISPR/Cas9 system to target the faulty gene in human T cells taken from patients with CTLA-4 insufficiency, and then snip the faulty CTLA-4 gene in two. Then, to repair the errors a corrected sequence of DNA – delivered to the cell using a modified virus – was pasted over the faulty part of the gene using a cellular DNA repair mechanism known as homology-directed repair.

The authors explained that this allowed them to “preserve” important sequences within the CTLA-4 gene – known as the intron – that allow it to be switched on and off by the cell only when needed. 

The outcome was “restored levels of CTLA-4 in the cells to those seen in healthy T cells,” the authors said.

Claire Booth, PhD, Mahboubian professor of gene therapy and pediatric immunology, UCL Great Ormond Street Institute of Child Health, and co–senior author, said that it was “really exciting” to think about taking this treatment forward to patients. “If we can improve their symptoms and reduce their risk of getting lymphoproliferative disease this will be a major step forward.”

In addition, the researchers were also able to improve symptoms of the disease in mice with CTLA-4 insufficiency by giving them injections of gene-edited T cells.
 

Technique may help tackle many conditions

The current standard treatment for CTLA-4 insufficiency is a bone marrow transplant to replace the stem cells responsible for producing T cells. However, “transplants are risky” and require high doses of chemotherapy and many weeks in hospital, the authors explained. “Older patients with CTLA-4 insufficiency are typically not well enough to tolerate the transplant procedure.”

Dr. Booth highlighted that the approach has many “positive aspects”. By correcting the patient’s T cells, “we think it can improve many of the symptoms of the disease”, she said, and added that this new approach is much less toxic than a bone marrow transplant. “Collecting the T cells is easier and correcting the T cells is easier. With this approach the amount of time in hospital the patients would need would be far less.”

Emma Morris, PhD, professor of clinical cell and gene therapy and director of UCL’s division of infection and immunity, and co–senior author, said: “Genes that play critical roles in controlling immune responses are not switched on all the time and are very tightly regulated. The technique we have used allows us to leave the natural (endogenous) mechanisms controlling gene expression intact, at the same time as correcting the mistake in the gene itself.”

The researchers explained that, although CTLA-4 insufficiency is rare, the gene editing therapy could be a proof of principle of their approach that could be adapted to tackle other conditions. 

“It’s a way of correcting genetic mutations that could potentially be applicable for other diseases,” suggested Dr. Morris. “The bigger picture is it allows us to correct genes that are dysregulated or overactive, but also allows us to understand much more about gene expression and gene regulation.”

The study was funded by the Wellcome Trust, the Association for Moleculary Pathology, the Medical Research Council, Alzheimer’s Research UK, and the UCLH/UCL NIHR Biomedical Research Centre. Dr. Morris is a founder sharehold of Quell Therapeutics and has received honoraria from Orchard Therapeutics, GlaxoSmithKline, and AstraZeneca. Dr. Booth has performed ad hoc consulting in the past 3 years for SOBI and Novartis and educational material production for SOBI and Chiesi. A patent on the intronic gene editing approach has been filed in the UK. The other authors declared that they have no completing interests.

A version of this article first appeared on Medscape UK.

An international group representing leading endocrinology associations has recommended that the name “diabetes insipidus” – which in some cases has led to harm – be changed to eliminate confusion with “diabetes mellitus” and to reflect the former condition’s pathophysiology.

The new proposed names are arginine vasopressin deficiency (AVP-D) for central (also called “cranial”) etiologies and arginine vasopressin resistance (AVP-R) for nephrogenic (kidney) etiologies.

“What we’re proposing is to rename the disease according to the pathophysiology that defines it,” statement co-author Joseph G. Verbalis, MD, professor of medicine and chief of endocrinology and metabolism at Georgetown University Medical Center, Washington, told this news organization.

The statement advises that henceforth the new names be used in manuscripts and the medical literature while keeping the old names in parentheses during a transition period, as in “AVP-deficiency (cranial diabetes insipidus)” and “AVP-resistance (nephrogenic diabetes insipidus).”

The condition formerly known as diabetes insipidus is relatively rare, occurring in about 1 person per 10-15,000 population. It is caused by either deficient production or resistance in the kidney to the hormone AVP, normally produced by the hypothalamus and stored in the pituitary gland. AVP, also called antidiuretic hormone, regulates the body’s water level and urine production by the kidney.

Both etiologies lead to extreme thirst and excessive production of urine. Common causes of the deficiency include head trauma or brain tumor, while resistance in the kidney is often congenital. It is currently treated with a synthetic form of AVP called desmopressin and fluid replacement.
 

What’s in a name?

The proposal to change the name by the Working Group for Renaming Diabetes Insipidus is endorsed by The Endocrine Society, European Society of Endocrinology, Pituitary Society, Society for Endocrinology, European Society for Paediatric Endocrinology, Endocrine Society of Australia, Brazilian Endocrine Society, and Japanese Endocrine Society and is under review by several other societies. It was published as a position statement in several of those society’s journals, with more to follow.

Historically, the word “diabetes,” a Greek word meaning “siphon,” was used in the 1st and 2nd century BC to describe excess flow of urine. The Latin word “mellitus” or “honey” was added in the late 17th century to describe the sweetness of the urine in the dysglycemic condition.

A century later, the Latin word “insipidus,” meaning insipid or tasteless, was coined to distinguish between the two types of polyuria, the position statement details.

In the late 19th to early 20th century, the vasopressor and antidiuretic actions of posterior pituitary extracts were discovered and used to treat people with both the central and nephrogenic etiologies, which were also recognized around that time, yet the name “diabetes insipidus” has persisted.

“From a historical perspective, the name is perfectly appropriate. At the time it was identified, and it was realized that it was different from diabetes mellitus, that was a perfectly appropriate terminology based on what was known in the late 19th century – but not now. It has persisted through the years simply because in medicine there’s a lot of inertia for change ... It’s just always been called that. If there’s not a compelling reason to change a name, generally there’s no move to change it,” Dr. Verbalis observed.  
 

‘Dramatic cases of patient mismanagement’ due to name confusion

Unfortunately, the urgency for the change arose from tragedy. In 2009, a 22-year-old man was admitted to the orthopedics department of a London teaching hospital for a hip replacement. Despite his known panhypopituitarism and diabetes insipidus, the nurses continually checked his blood glucose but didn’t give him desmopressin or sufficient fluids. Laboratory testing showed normal glucose, but his serum sodium was 149 mmol/L. The morning after his operation, he had a fatal cardiac arrest with a serum sodium of 169 mmol/L. 

“The nurses thought he had diabetes mellitus ... So that was death due to failure to recognize that diabetes insipidus is not diabetes mellitus,” Dr. Verbalis said. “If he had been admitted to endocrinology, this wouldn’t have happened. But he was admitted to orthopedics. Non-endocrinologists are not so aware of diabetes insipidus, because it is a rare disease.”

In 2016, National Health Service England issued a patient safety alert about the “risk of severe harm or death when desmopressin is omitted or delayed in patients with cranial diabetes insipidus,” citing at least four incidents within the prior 7 years where omission of desmopressin had resulted in severe dehydration and death, with another 76 cases of omission or delay that were acted on before the patients became critically ill.

Further impetus for the name change came from the results of an anonymous web-based survey of 1,034 adult and pediatric patients with central diabetes insipidus conducted between August 2021 and February 2022. Overall, 80% reported encountering situations in which their condition had been confused with diabetes mellitus by health care professionals, and 85% supported renaming the disease.

There was some divergence in opinion as to what the new name(s) should be, but clear agreement that the term “diabetes” should not be part of it.  

“We’ve only become recently aware that there are dramatic cases of patient mismanagement due to the confusion caused by the word ‘diabetes.’ We think patients should have a voice. If a legitimate patient survey says over 80% think this name should be changed, then I think we as endocrinologists need to pay attention to that,” Dr. Verbalis said.

But while endocrinologists are the ones who see these patients the most often, Dr. Verbalis said a main aim of the position statement “is really to change the mindset of non-endocrinologist doctors and nurses and other health care professionals that this is not diabetes mellitus. It’s a totally different disease. And if we give it a totally different name, then I think they will better recognize that.”

As to how long Dr. Verbalis thinks it will take for the new names to catch on, he pointed out that it’s taken about a decade for the rheumatology field to fully adopt the name “granulomatosis with polyangiitis” as a replacement for “Wegener’s granulomatosis” after the eponymous physician’s Nazi ties were revealed.

“So we’re not anticipating that this is going to change terminology tomorrow. It’s a long process. We just wanted to get the process started,” he said.

Dr. Verbalis has reported consulting for Otsuka.

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

An international group representing leading endocrinology associations has recommended that the name “diabetes insipidus” – which in some cases has led to harm – be changed to eliminate confusion with “diabetes mellitus” and to reflect the former condition’s pathophysiology.

The new proposed names are arginine vasopressin deficiency (AVP-D) for central (also called “cranial”) etiologies and arginine vasopressin resistance (AVP-R) for nephrogenic (kidney) etiologies.

“What we’re proposing is to rename the disease according to the pathophysiology that defines it,” statement co-author Joseph G. Verbalis, MD, professor of medicine and chief of endocrinology and metabolism at Georgetown University Medical Center, Washington, told this news organization.

The statement advises that henceforth the new names be used in manuscripts and the medical literature while keeping the old names in parentheses during a transition period, as in “AVP-deficiency (cranial diabetes insipidus)” and “AVP-resistance (nephrogenic diabetes insipidus).”

The condition formerly known as diabetes insipidus is relatively rare, occurring in about 1 person per 10-15,000 population. It is caused by either deficient production or resistance in the kidney to the hormone AVP, normally produced by the hypothalamus and stored in the pituitary gland. AVP, also called antidiuretic hormone, regulates the body’s water level and urine production by the kidney.

Both etiologies lead to extreme thirst and excessive production of urine. Common causes of the deficiency include head trauma or brain tumor, while resistance in the kidney is often congenital. It is currently treated with a synthetic form of AVP called desmopressin and fluid replacement.
 

What’s in a name?

The proposal to change the name by the Working Group for Renaming Diabetes Insipidus is endorsed by The Endocrine Society, European Society of Endocrinology, Pituitary Society, Society for Endocrinology, European Society for Paediatric Endocrinology, Endocrine Society of Australia, Brazilian Endocrine Society, and Japanese Endocrine Society and is under review by several other societies. It was published as a position statement in several of those society’s journals, with more to follow.

Historically, the word “diabetes,” a Greek word meaning “siphon,” was used in the 1st and 2nd century BC to describe excess flow of urine. The Latin word “mellitus” or “honey” was added in the late 17th century to describe the sweetness of the urine in the dysglycemic condition.

A century later, the Latin word “insipidus,” meaning insipid or tasteless, was coined to distinguish between the two types of polyuria, the position statement details.

In the late 19th to early 20th century, the vasopressor and antidiuretic actions of posterior pituitary extracts were discovered and used to treat people with both the central and nephrogenic etiologies, which were also recognized around that time, yet the name “diabetes insipidus” has persisted.

“From a historical perspective, the name is perfectly appropriate. At the time it was identified, and it was realized that it was different from diabetes mellitus, that was a perfectly appropriate terminology based on what was known in the late 19th century – but not now. It has persisted through the years simply because in medicine there’s a lot of inertia for change ... It’s just always been called that. If there’s not a compelling reason to change a name, generally there’s no move to change it,” Dr. Verbalis observed.  
 

‘Dramatic cases of patient mismanagement’ due to name confusion

Unfortunately, the urgency for the change arose from tragedy. In 2009, a 22-year-old man was admitted to the orthopedics department of a London teaching hospital for a hip replacement. Despite his known panhypopituitarism and diabetes insipidus, the nurses continually checked his blood glucose but didn’t give him desmopressin or sufficient fluids. Laboratory testing showed normal glucose, but his serum sodium was 149 mmol/L. The morning after his operation, he had a fatal cardiac arrest with a serum sodium of 169 mmol/L. 

“The nurses thought he had diabetes mellitus ... So that was death due to failure to recognize that diabetes insipidus is not diabetes mellitus,” Dr. Verbalis said. “If he had been admitted to endocrinology, this wouldn’t have happened. But he was admitted to orthopedics. Non-endocrinologists are not so aware of diabetes insipidus, because it is a rare disease.”

In 2016, National Health Service England issued a patient safety alert about the “risk of severe harm or death when desmopressin is omitted or delayed in patients with cranial diabetes insipidus,” citing at least four incidents within the prior 7 years where omission of desmopressin had resulted in severe dehydration and death, with another 76 cases of omission or delay that were acted on before the patients became critically ill.

Further impetus for the name change came from the results of an anonymous web-based survey of 1,034 adult and pediatric patients with central diabetes insipidus conducted between August 2021 and February 2022. Overall, 80% reported encountering situations in which their condition had been confused with diabetes mellitus by health care professionals, and 85% supported renaming the disease.

There was some divergence in opinion as to what the new name(s) should be, but clear agreement that the term “diabetes” should not be part of it.  

“We’ve only become recently aware that there are dramatic cases of patient mismanagement due to the confusion caused by the word ‘diabetes.’ We think patients should have a voice. If a legitimate patient survey says over 80% think this name should be changed, then I think we as endocrinologists need to pay attention to that,” Dr. Verbalis said.

But while endocrinologists are the ones who see these patients the most often, Dr. Verbalis said a main aim of the position statement “is really to change the mindset of non-endocrinologist doctors and nurses and other health care professionals that this is not diabetes mellitus. It’s a totally different disease. And if we give it a totally different name, then I think they will better recognize that.”

As to how long Dr. Verbalis thinks it will take for the new names to catch on, he pointed out that it’s taken about a decade for the rheumatology field to fully adopt the name “granulomatosis with polyangiitis” as a replacement for “Wegener’s granulomatosis” after the eponymous physician’s Nazi ties were revealed.

“So we’re not anticipating that this is going to change terminology tomorrow. It’s a long process. We just wanted to get the process started,” he said.

Dr. Verbalis has reported consulting for Otsuka.

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

An international group representing leading endocrinology associations has recommended that the name “diabetes insipidus” – which in some cases has led to harm – be changed to eliminate confusion with “diabetes mellitus” and to reflect the former condition’s pathophysiology.

The new proposed names are arginine vasopressin deficiency (AVP-D) for central (also called “cranial”) etiologies and arginine vasopressin resistance (AVP-R) for nephrogenic (kidney) etiologies.

“What we’re proposing is to rename the disease according to the pathophysiology that defines it,” statement co-author Joseph G. Verbalis, MD, professor of medicine and chief of endocrinology and metabolism at Georgetown University Medical Center, Washington, told this news organization.

The statement advises that henceforth the new names be used in manuscripts and the medical literature while keeping the old names in parentheses during a transition period, as in “AVP-deficiency (cranial diabetes insipidus)” and “AVP-resistance (nephrogenic diabetes insipidus).”

The condition formerly known as diabetes insipidus is relatively rare, occurring in about 1 person per 10-15,000 population. It is caused by either deficient production or resistance in the kidney to the hormone AVP, normally produced by the hypothalamus and stored in the pituitary gland. AVP, also called antidiuretic hormone, regulates the body’s water level and urine production by the kidney.

Both etiologies lead to extreme thirst and excessive production of urine. Common causes of the deficiency include head trauma or brain tumor, while resistance in the kidney is often congenital. It is currently treated with a synthetic form of AVP called desmopressin and fluid replacement.
 

What’s in a name?

The proposal to change the name by the Working Group for Renaming Diabetes Insipidus is endorsed by The Endocrine Society, European Society of Endocrinology, Pituitary Society, Society for Endocrinology, European Society for Paediatric Endocrinology, Endocrine Society of Australia, Brazilian Endocrine Society, and Japanese Endocrine Society and is under review by several other societies. It was published as a position statement in several of those society’s journals, with more to follow.

Historically, the word “diabetes,” a Greek word meaning “siphon,” was used in the 1st and 2nd century BC to describe excess flow of urine. The Latin word “mellitus” or “honey” was added in the late 17th century to describe the sweetness of the urine in the dysglycemic condition.

A century later, the Latin word “insipidus,” meaning insipid or tasteless, was coined to distinguish between the two types of polyuria, the position statement details.

In the late 19th to early 20th century, the vasopressor and antidiuretic actions of posterior pituitary extracts were discovered and used to treat people with both the central and nephrogenic etiologies, which were also recognized around that time, yet the name “diabetes insipidus” has persisted.

“From a historical perspective, the name is perfectly appropriate. At the time it was identified, and it was realized that it was different from diabetes mellitus, that was a perfectly appropriate terminology based on what was known in the late 19th century – but not now. It has persisted through the years simply because in medicine there’s a lot of inertia for change ... It’s just always been called that. If there’s not a compelling reason to change a name, generally there’s no move to change it,” Dr. Verbalis observed.  
 

‘Dramatic cases of patient mismanagement’ due to name confusion

Unfortunately, the urgency for the change arose from tragedy. In 2009, a 22-year-old man was admitted to the orthopedics department of a London teaching hospital for a hip replacement. Despite his known panhypopituitarism and diabetes insipidus, the nurses continually checked his blood glucose but didn’t give him desmopressin or sufficient fluids. Laboratory testing showed normal glucose, but his serum sodium was 149 mmol/L. The morning after his operation, he had a fatal cardiac arrest with a serum sodium of 169 mmol/L. 

“The nurses thought he had diabetes mellitus ... So that was death due to failure to recognize that diabetes insipidus is not diabetes mellitus,” Dr. Verbalis said. “If he had been admitted to endocrinology, this wouldn’t have happened. But he was admitted to orthopedics. Non-endocrinologists are not so aware of diabetes insipidus, because it is a rare disease.”

In 2016, National Health Service England issued a patient safety alert about the “risk of severe harm or death when desmopressin is omitted or delayed in patients with cranial diabetes insipidus,” citing at least four incidents within the prior 7 years where omission of desmopressin had resulted in severe dehydration and death, with another 76 cases of omission or delay that were acted on before the patients became critically ill.

Further impetus for the name change came from the results of an anonymous web-based survey of 1,034 adult and pediatric patients with central diabetes insipidus conducted between August 2021 and February 2022. Overall, 80% reported encountering situations in which their condition had been confused with diabetes mellitus by health care professionals, and 85% supported renaming the disease.

There was some divergence in opinion as to what the new name(s) should be, but clear agreement that the term “diabetes” should not be part of it.  

“We’ve only become recently aware that there are dramatic cases of patient mismanagement due to the confusion caused by the word ‘diabetes.’ We think patients should have a voice. If a legitimate patient survey says over 80% think this name should be changed, then I think we as endocrinologists need to pay attention to that,” Dr. Verbalis said.

But while endocrinologists are the ones who see these patients the most often, Dr. Verbalis said a main aim of the position statement “is really to change the mindset of non-endocrinologist doctors and nurses and other health care professionals that this is not diabetes mellitus. It’s a totally different disease. And if we give it a totally different name, then I think they will better recognize that.”

As to how long Dr. Verbalis thinks it will take for the new names to catch on, he pointed out that it’s taken about a decade for the rheumatology field to fully adopt the name “granulomatosis with polyangiitis” as a replacement for “Wegener’s granulomatosis” after the eponymous physician’s Nazi ties were revealed.

“So we’re not anticipating that this is going to change terminology tomorrow. It’s a long process. We just wanted to get the process started,” he said.

Dr. Verbalis has reported consulting for Otsuka.

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

CINCINNATI – A new analysis of data from a phase 3 clinical trial suggests that an inhaled diazepam nasal spray (Valtoco, Neurelis Inc.) works about as well among patients with Lennox-Gastaut Syndrome (LGS) as it does with other patients with pediatric encephalopathies.

LGS is a severe form of epilepsy that generally begins in early childhood and has a poor prognosis and seizures that are often treatment refractory. The findings of the analysis should be encouraging to physicians who may view patients with LGS as not benefiting from treatment, said Daniel C. Tarquinio, DO, who presented the results at the 2022 annual meeting of the Child Neurology Society.

“Their response to their first appropriate weight-based rescue dose of Valtoco was essentially no different. They were subtly different, but they’re not really meaningful differences. Very few needed a second dose. In practice this is helpful because we know that kids with LGS, we think of them as having worse epilepsy, if you will. But if they need rescue, if we prescribe an appropriate rescue dose based on their weight, that the same rescue will work for them as it will for a kid that doesn’t have – quote unquote – as bad epilepsy that needs rescue,” said Dr. Tarquinio, a child neurologist and epileptologist and founder of the Center for Rare Neurological Diseases.

During the Q&A, Dr. Tarquinio was asked if there is something about the biology of LGS that would suggest it might respond differently to the drug. Dr. Tarquinio said no. “The reason we even looked at this is because many clinicians told us that their sense was [that patients with LGS] did not respond as well to rescue in general no matter what they use. This allowed us to go back and look at a controlled data set and say, at least in our controlled dataset, they respond the same,” he said.

Grace Gombolay, MD, who moderated the session, agreed that the results should be encouraging. “It seems like a lot of clinicians have the sense that Lennox-Gastaut Syndrome is a very terrible refractory epilepsy syndrome, and so doing rescue doesn’t seem to make sense if they don’t really respond. I think it’s helpful to know because there are actually studies showing that Valtoco seems to actually work in those patients, so it’s actually useful clinically to prescribe those patients and give it a shot,” said Dr. Gombolay, director of the Pediatric Neuroimmunology and Multiple Sclerosis Clinic at Emory University, Atlanta.

LGS patients may experience hundreds of seizures per day. “It’s really hard for parents to quantify, did they get better? Did the rescue help or not, because they’re still having some seizures. I think the sense is, ‘oh, this isn’t working.’ That’s probably the bias. I think this is good data that if you are able to get Valtoco for your patients, I think it’s worth a shot even in Lennox-Gastaut,” said Dr. Gombolay.

The researchers conducted a post hoc analysis of the phase 3, open-label, repeat-dose safety study of Valtoco. The study included a 12-month treatment period with visits at day 30 and every 60 days following. Patients had the option of staying on the drug following the end of the treatment period. Seizure and dosing information were obtained from a diary. The study enrolled 163 patients whose physicians believed they would need to be treated with a benzodiazepine at least once every other month to achieve seizure control. Dosing was determined by a combination of age and weight. If a second dose was required, caregivers were instructed to provide it 4-12 hours after the first dose.

In the study cohort, 47.9% of patients were aged 6-17 years. The researchers looked specifically at 73 cases of seizure clusters. In nine cases, the patient had LGS (five male, four female). Nearly all (95.9%) of LGS cluster cases were treated with a single dose and 4.1% were exposed to a second dose. Among 64 cases involving a patient with pediatric epileptic encephalopathies, 89.4% were treated with a single dose and 10.6% received a second. The safety profile was similar between patients with LGS and those with pediatric encephalopathies.

Dr. Gombolay has no relevant financial disclosures.

CINCINNATI – A new analysis of data from a phase 3 clinical trial suggests that an inhaled diazepam nasal spray (Valtoco, Neurelis Inc.) works about as well among patients with Lennox-Gastaut Syndrome (LGS) as it does with other patients with pediatric encephalopathies.

LGS is a severe form of epilepsy that generally begins in early childhood and has a poor prognosis and seizures that are often treatment refractory. The findings of the analysis should be encouraging to physicians who may view patients with LGS as not benefiting from treatment, said Daniel C. Tarquinio, DO, who presented the results at the 2022 annual meeting of the Child Neurology Society.

“Their response to their first appropriate weight-based rescue dose of Valtoco was essentially no different. They were subtly different, but they’re not really meaningful differences. Very few needed a second dose. In practice this is helpful because we know that kids with LGS, we think of them as having worse epilepsy, if you will. But if they need rescue, if we prescribe an appropriate rescue dose based on their weight, that the same rescue will work for them as it will for a kid that doesn’t have – quote unquote – as bad epilepsy that needs rescue,” said Dr. Tarquinio, a child neurologist and epileptologist and founder of the Center for Rare Neurological Diseases.

During the Q&A, Dr. Tarquinio was asked if there is something about the biology of LGS that would suggest it might respond differently to the drug. Dr. Tarquinio said no. “The reason we even looked at this is because many clinicians told us that their sense was [that patients with LGS] did not respond as well to rescue in general no matter what they use. This allowed us to go back and look at a controlled data set and say, at least in our controlled dataset, they respond the same,” he said.

Grace Gombolay, MD, who moderated the session, agreed that the results should be encouraging. “It seems like a lot of clinicians have the sense that Lennox-Gastaut Syndrome is a very terrible refractory epilepsy syndrome, and so doing rescue doesn’t seem to make sense if they don’t really respond. I think it’s helpful to know because there are actually studies showing that Valtoco seems to actually work in those patients, so it’s actually useful clinically to prescribe those patients and give it a shot,” said Dr. Gombolay, director of the Pediatric Neuroimmunology and Multiple Sclerosis Clinic at Emory University, Atlanta.

LGS patients may experience hundreds of seizures per day. “It’s really hard for parents to quantify, did they get better? Did the rescue help or not, because they’re still having some seizures. I think the sense is, ‘oh, this isn’t working.’ That’s probably the bias. I think this is good data that if you are able to get Valtoco for your patients, I think it’s worth a shot even in Lennox-Gastaut,” said Dr. Gombolay.

The researchers conducted a post hoc analysis of the phase 3, open-label, repeat-dose safety study of Valtoco. The study included a 12-month treatment period with visits at day 30 and every 60 days following. Patients had the option of staying on the drug following the end of the treatment period. Seizure and dosing information were obtained from a diary. The study enrolled 163 patients whose physicians believed they would need to be treated with a benzodiazepine at least once every other month to achieve seizure control. Dosing was determined by a combination of age and weight. If a second dose was required, caregivers were instructed to provide it 4-12 hours after the first dose.

In the study cohort, 47.9% of patients were aged 6-17 years. The researchers looked specifically at 73 cases of seizure clusters. In nine cases, the patient had LGS (five male, four female). Nearly all (95.9%) of LGS cluster cases were treated with a single dose and 4.1% were exposed to a second dose. Among 64 cases involving a patient with pediatric epileptic encephalopathies, 89.4% were treated with a single dose and 10.6% received a second. The safety profile was similar between patients with LGS and those with pediatric encephalopathies.

Dr. Gombolay has no relevant financial disclosures.

CINCINNATI – A new analysis of data from a phase 3 clinical trial suggests that an inhaled diazepam nasal spray (Valtoco, Neurelis Inc.) works about as well among patients with Lennox-Gastaut Syndrome (LGS) as it does with other patients with pediatric encephalopathies.

LGS is a severe form of epilepsy that generally begins in early childhood and has a poor prognosis and seizures that are often treatment refractory. The findings of the analysis should be encouraging to physicians who may view patients with LGS as not benefiting from treatment, said Daniel C. Tarquinio, DO, who presented the results at the 2022 annual meeting of the Child Neurology Society.

“Their response to their first appropriate weight-based rescue dose of Valtoco was essentially no different. They were subtly different, but they’re not really meaningful differences. Very few needed a second dose. In practice this is helpful because we know that kids with LGS, we think of them as having worse epilepsy, if you will. But if they need rescue, if we prescribe an appropriate rescue dose based on their weight, that the same rescue will work for them as it will for a kid that doesn’t have – quote unquote – as bad epilepsy that needs rescue,” said Dr. Tarquinio, a child neurologist and epileptologist and founder of the Center for Rare Neurological Diseases.

During the Q&A, Dr. Tarquinio was asked if there is something about the biology of LGS that would suggest it might respond differently to the drug. Dr. Tarquinio said no. “The reason we even looked at this is because many clinicians told us that their sense was [that patients with LGS] did not respond as well to rescue in general no matter what they use. This allowed us to go back and look at a controlled data set and say, at least in our controlled dataset, they respond the same,” he said.

Grace Gombolay, MD, who moderated the session, agreed that the results should be encouraging. “It seems like a lot of clinicians have the sense that Lennox-Gastaut Syndrome is a very terrible refractory epilepsy syndrome, and so doing rescue doesn’t seem to make sense if they don’t really respond. I think it’s helpful to know because there are actually studies showing that Valtoco seems to actually work in those patients, so it’s actually useful clinically to prescribe those patients and give it a shot,” said Dr. Gombolay, director of the Pediatric Neuroimmunology and Multiple Sclerosis Clinic at Emory University, Atlanta.

LGS patients may experience hundreds of seizures per day. “It’s really hard for parents to quantify, did they get better? Did the rescue help or not, because they’re still having some seizures. I think the sense is, ‘oh, this isn’t working.’ That’s probably the bias. I think this is good data that if you are able to get Valtoco for your patients, I think it’s worth a shot even in Lennox-Gastaut,” said Dr. Gombolay.

The researchers conducted a post hoc analysis of the phase 3, open-label, repeat-dose safety study of Valtoco. The study included a 12-month treatment period with visits at day 30 and every 60 days following. Patients had the option of staying on the drug following the end of the treatment period. Seizure and dosing information were obtained from a diary. The study enrolled 163 patients whose physicians believed they would need to be treated with a benzodiazepine at least once every other month to achieve seizure control. Dosing was determined by a combination of age and weight. If a second dose was required, caregivers were instructed to provide it 4-12 hours after the first dose.

In the study cohort, 47.9% of patients were aged 6-17 years. The researchers looked specifically at 73 cases of seizure clusters. In nine cases, the patient had LGS (five male, four female). Nearly all (95.9%) of LGS cluster cases were treated with a single dose and 4.1% were exposed to a second dose. Among 64 cases involving a patient with pediatric epileptic encephalopathies, 89.4% were treated with a single dose and 10.6% received a second. The safety profile was similar between patients with LGS and those with pediatric encephalopathies.

Dr. Gombolay has no relevant financial disclosures.