Lupus & Connective Tissue Diseases

At the time of a nephritis flare in patients with systemic lupus erythematosus (SLE), elevated levels of two neutrophil extracellular trap (NET) protein complexes, elastase-DNA and HMGB1-DNA, predict declining renal function, poor response to therapy, and adverse renal outcomes, according to work presented at the annual meeting of the Canadian Rheumatology Association.

“These proteins are not only predominantly elevated in patients with proliferative lupus nephritis, but they correlate with adverse renal outcomes when patients are followed over 24 months,” reported Laura P. Whittall-Garcia, MD, a clinical fellow in rheumatology at the University of Toronto.

Lupus nephritis is common in SLE, developing in about 50% of patients, according to Dr. Whittall-Garcia. Of these, up to 20% will not respond to standard therapies, typically resulting in end-stage renal disease. Up until now, there has been no reliable method of predicting this adverse clinical course.
 

Proteins identified in NETs

The series of studies conducted by Dr. Whittall-Garcia and coinvestigators were focused on NETs, a network of strings of DNA that typically bind pathogenic microbes to prevent infection but can participate in the pathology of immune-mediated conditions. As Dr. Whittall-Garcia explained, DNA extruded from NETs has been a source of autoantigens.

Based on earlier work, they pursued the hypothesis that high mobility group box 1 (HMGB1) and elastase, which are both NET components, mediate NETosis, the immune response that protects against microbes in healthy individuals but contributes to tissue damage in patients with immune-related disorders. The first aim of this work was to confirm that elevations of elastase-DNA and HMGB1-DNA correlate with active lupus nephritis. The second aim was to determine if levels of these proteins at the time of lupus nephritis flare predicted renal outcomes at 12 and 24 months.

To pursue the first hypothesis, 49 patients with active SLE (18 of whom had active lupus nephritis) were evaluated along with 23 patients with inactive SLE and 20 healthy controls.

Highest levels seen in proliferative nephritis

Relative to healthy controls, patients with active SLE have highly significantly increased levels of both proteins (P < .0001). And relative to those with inactive SLE, the levels of active patients were higher but fell short of statistical significance. However, when the researchers compared those with active lupus nephritis with those who had active SLE but no nephritis, both proteins were significantly higher (P < .04), and the levels in patients with proliferative relative to nonproliferative lupus nephritis were higher still (P < .009).

To pursue the second aim of the study, the researchers retrospectively evaluated 109 patients with SLE. All had active lupus nephritis, a baseline estimated glomerular filtration rate (eGFR) greater than 30 mL/min prior to the flare, and at least 2 years of follow-up. They evaluated complete response at 12 and 24 months, percent decline in eGFR, and severe renal impairment (eGFR ≤ 30 mL/min) in the context of levels of elastase and HMGB1.

With elevations in either NET remnant, the odds ratio of failing to achieve a complete response at 24 months were approximately doubled for elastase-DNA (OR, 1.96; P = .01) and for HMGB1 (OR, 2.61; P = .02). For the endpoint of severe renal impairment 24 months after a lupus nephritis flare, there was also a positive association with both elastase-DNA (OR, 1.55; P = .005) and HMBG1-DNA (OR, 1.91; P = .01).

“For every 100-unit increase in elastase-DNA complexes, there is a 4.8% decrease in eGFR,” reported Dr. Whittall-Garcia, who noted this relationship was highly statistically significant (P < .0001). For HMGB1-DNA, each 100-unit increase was associated with a 5.3% decrease in eGFR (P = .0006).
 

No other biomarkers compare for prognosis

“After adjusting for multiple variables, these protein levels at the time of the flare outperformed all conventional biomarkers, including proteinuria and complement levels,” Dr. Whittall-Garcia said.

Larger validating studies are needed, but Dr. Whittall-Garcia is optimistic that measuring these NET remnant levels will prove useful for monitoring patients at the time of the lupus nephritis flare and over time for the purposes of predicting adverse outcomes and response to therapy.

Although more work is needed, Adegbenga A. Bankole, MD, associate professor of medicine at Virginia Tech University and chief of the rheumatology division at the Carilion Clinic, both in Roanoke, agreed that this is a promising research direction. He reported that NETs have been attracting interest at several research centers for their potential in helping to understand the pathogenesis of lupus nephritis.

“It is unlikely that any one test will ever be a panacea in the diagnosis or predictor of outcomes in lupus nephritis,” Dr. Bankole said in an interview, but “given the importance of NETosis in the development of this disease, studies like this will form the basis of the multistep process through which we will improve patient care.”

With further progress in this area, Dr. Bankole predicted that these studies will lead to clinical applications.

“Dr. Whittall-Garcia and her team will help in the development of diagnostic and/or predictive algorithms that may go on to help improve survival of future patients with SLE,” he said.Dr. Whittall-Garcia and Dr. Bankole report they have no relevant financial relationships.

At the time of a nephritis flare in patients with systemic lupus erythematosus (SLE), elevated levels of two neutrophil extracellular trap (NET) protein complexes, elastase-DNA and HMGB1-DNA, predict declining renal function, poor response to therapy, and adverse renal outcomes, according to work presented at the annual meeting of the Canadian Rheumatology Association.

“These proteins are not only predominantly elevated in patients with proliferative lupus nephritis, but they correlate with adverse renal outcomes when patients are followed over 24 months,” reported Laura P. Whittall-Garcia, MD, a clinical fellow in rheumatology at the University of Toronto.

Lupus nephritis is common in SLE, developing in about 50% of patients, according to Dr. Whittall-Garcia. Of these, up to 20% will not respond to standard therapies, typically resulting in end-stage renal disease. Up until now, there has been no reliable method of predicting this adverse clinical course.
 

Proteins identified in NETs

The series of studies conducted by Dr. Whittall-Garcia and coinvestigators were focused on NETs, a network of strings of DNA that typically bind pathogenic microbes to prevent infection but can participate in the pathology of immune-mediated conditions. As Dr. Whittall-Garcia explained, DNA extruded from NETs has been a source of autoantigens.

Based on earlier work, they pursued the hypothesis that high mobility group box 1 (HMGB1) and elastase, which are both NET components, mediate NETosis, the immune response that protects against microbes in healthy individuals but contributes to tissue damage in patients with immune-related disorders. The first aim of this work was to confirm that elevations of elastase-DNA and HMGB1-DNA correlate with active lupus nephritis. The second aim was to determine if levels of these proteins at the time of lupus nephritis flare predicted renal outcomes at 12 and 24 months.

To pursue the first hypothesis, 49 patients with active SLE (18 of whom had active lupus nephritis) were evaluated along with 23 patients with inactive SLE and 20 healthy controls.

Highest levels seen in proliferative nephritis

Relative to healthy controls, patients with active SLE have highly significantly increased levels of both proteins (P < .0001). And relative to those with inactive SLE, the levels of active patients were higher but fell short of statistical significance. However, when the researchers compared those with active lupus nephritis with those who had active SLE but no nephritis, both proteins were significantly higher (P < .04), and the levels in patients with proliferative relative to nonproliferative lupus nephritis were higher still (P < .009).

To pursue the second aim of the study, the researchers retrospectively evaluated 109 patients with SLE. All had active lupus nephritis, a baseline estimated glomerular filtration rate (eGFR) greater than 30 mL/min prior to the flare, and at least 2 years of follow-up. They evaluated complete response at 12 and 24 months, percent decline in eGFR, and severe renal impairment (eGFR ≤ 30 mL/min) in the context of levels of elastase and HMGB1.

With elevations in either NET remnant, the odds ratio of failing to achieve a complete response at 24 months were approximately doubled for elastase-DNA (OR, 1.96; P = .01) and for HMGB1 (OR, 2.61; P = .02). For the endpoint of severe renal impairment 24 months after a lupus nephritis flare, there was also a positive association with both elastase-DNA (OR, 1.55; P = .005) and HMBG1-DNA (OR, 1.91; P = .01).

“For every 100-unit increase in elastase-DNA complexes, there is a 4.8% decrease in eGFR,” reported Dr. Whittall-Garcia, who noted this relationship was highly statistically significant (P < .0001). For HMGB1-DNA, each 100-unit increase was associated with a 5.3% decrease in eGFR (P = .0006).
 

No other biomarkers compare for prognosis

“After adjusting for multiple variables, these protein levels at the time of the flare outperformed all conventional biomarkers, including proteinuria and complement levels,” Dr. Whittall-Garcia said.

Larger validating studies are needed, but Dr. Whittall-Garcia is optimistic that measuring these NET remnant levels will prove useful for monitoring patients at the time of the lupus nephritis flare and over time for the purposes of predicting adverse outcomes and response to therapy.

Although more work is needed, Adegbenga A. Bankole, MD, associate professor of medicine at Virginia Tech University and chief of the rheumatology division at the Carilion Clinic, both in Roanoke, agreed that this is a promising research direction. He reported that NETs have been attracting interest at several research centers for their potential in helping to understand the pathogenesis of lupus nephritis.

“It is unlikely that any one test will ever be a panacea in the diagnosis or predictor of outcomes in lupus nephritis,” Dr. Bankole said in an interview, but “given the importance of NETosis in the development of this disease, studies like this will form the basis of the multistep process through which we will improve patient care.”

With further progress in this area, Dr. Bankole predicted that these studies will lead to clinical applications.

“Dr. Whittall-Garcia and her team will help in the development of diagnostic and/or predictive algorithms that may go on to help improve survival of future patients with SLE,” he said.Dr. Whittall-Garcia and Dr. Bankole report they have no relevant financial relationships.

At the time of a nephritis flare in patients with systemic lupus erythematosus (SLE), elevated levels of two neutrophil extracellular trap (NET) protein complexes, elastase-DNA and HMGB1-DNA, predict declining renal function, poor response to therapy, and adverse renal outcomes, according to work presented at the annual meeting of the Canadian Rheumatology Association.

“These proteins are not only predominantly elevated in patients with proliferative lupus nephritis, but they correlate with adverse renal outcomes when patients are followed over 24 months,” reported Laura P. Whittall-Garcia, MD, a clinical fellow in rheumatology at the University of Toronto.

Lupus nephritis is common in SLE, developing in about 50% of patients, according to Dr. Whittall-Garcia. Of these, up to 20% will not respond to standard therapies, typically resulting in end-stage renal disease. Up until now, there has been no reliable method of predicting this adverse clinical course.
 

Proteins identified in NETs

The series of studies conducted by Dr. Whittall-Garcia and coinvestigators were focused on NETs, a network of strings of DNA that typically bind pathogenic microbes to prevent infection but can participate in the pathology of immune-mediated conditions. As Dr. Whittall-Garcia explained, DNA extruded from NETs has been a source of autoantigens.

Based on earlier work, they pursued the hypothesis that high mobility group box 1 (HMGB1) and elastase, which are both NET components, mediate NETosis, the immune response that protects against microbes in healthy individuals but contributes to tissue damage in patients with immune-related disorders. The first aim of this work was to confirm that elevations of elastase-DNA and HMGB1-DNA correlate with active lupus nephritis. The second aim was to determine if levels of these proteins at the time of lupus nephritis flare predicted renal outcomes at 12 and 24 months.

To pursue the first hypothesis, 49 patients with active SLE (18 of whom had active lupus nephritis) were evaluated along with 23 patients with inactive SLE and 20 healthy controls.

Highest levels seen in proliferative nephritis

Relative to healthy controls, patients with active SLE have highly significantly increased levels of both proteins (P < .0001). And relative to those with inactive SLE, the levels of active patients were higher but fell short of statistical significance. However, when the researchers compared those with active lupus nephritis with those who had active SLE but no nephritis, both proteins were significantly higher (P < .04), and the levels in patients with proliferative relative to nonproliferative lupus nephritis were higher still (P < .009).

To pursue the second aim of the study, the researchers retrospectively evaluated 109 patients with SLE. All had active lupus nephritis, a baseline estimated glomerular filtration rate (eGFR) greater than 30 mL/min prior to the flare, and at least 2 years of follow-up. They evaluated complete response at 12 and 24 months, percent decline in eGFR, and severe renal impairment (eGFR ≤ 30 mL/min) in the context of levels of elastase and HMGB1.

With elevations in either NET remnant, the odds ratio of failing to achieve a complete response at 24 months were approximately doubled for elastase-DNA (OR, 1.96; P = .01) and for HMGB1 (OR, 2.61; P = .02). For the endpoint of severe renal impairment 24 months after a lupus nephritis flare, there was also a positive association with both elastase-DNA (OR, 1.55; P = .005) and HMBG1-DNA (OR, 1.91; P = .01).

“For every 100-unit increase in elastase-DNA complexes, there is a 4.8% decrease in eGFR,” reported Dr. Whittall-Garcia, who noted this relationship was highly statistically significant (P < .0001). For HMGB1-DNA, each 100-unit increase was associated with a 5.3% decrease in eGFR (P = .0006).
 

No other biomarkers compare for prognosis

“After adjusting for multiple variables, these protein levels at the time of the flare outperformed all conventional biomarkers, including proteinuria and complement levels,” Dr. Whittall-Garcia said.

Larger validating studies are needed, but Dr. Whittall-Garcia is optimistic that measuring these NET remnant levels will prove useful for monitoring patients at the time of the lupus nephritis flare and over time for the purposes of predicting adverse outcomes and response to therapy.

Although more work is needed, Adegbenga A. Bankole, MD, associate professor of medicine at Virginia Tech University and chief of the rheumatology division at the Carilion Clinic, both in Roanoke, agreed that this is a promising research direction. He reported that NETs have been attracting interest at several research centers for their potential in helping to understand the pathogenesis of lupus nephritis.

“It is unlikely that any one test will ever be a panacea in the diagnosis or predictor of outcomes in lupus nephritis,” Dr. Bankole said in an interview, but “given the importance of NETosis in the development of this disease, studies like this will form the basis of the multistep process through which we will improve patient care.”

With further progress in this area, Dr. Bankole predicted that these studies will lead to clinical applications.

“Dr. Whittall-Garcia and her team will help in the development of diagnostic and/or predictive algorithms that may go on to help improve survival of future patients with SLE,” he said.Dr. Whittall-Garcia and Dr. Bankole report they have no relevant financial relationships.

Adults with rheumatoid arthritis or primary Sjogren’s syndrome plus interstitial lung disease had higher levels of systemic sclerosis–specific antibodies than those without lung disease, based on data from 101 individuals.

Systemic sclerosis (SSc) has been associated with the development of interstitial lung disease (ILD), but the prevalence of SSc autoantibodies in patients with rheumatoid arthritis (RA) and primary Sjogren’s syndrome (SS) has not been explored, wrote Vasilike Koulouri, MD, of Kapodistrian University of Athens, and colleagues.

In a study published in the Journal of Translational Autoimmunity, the researchers reviewed serum data from patients with RA and SS using immunoblot assays to determine the prevalence of SSc-specific and anti-Ro52 autoantibodies, both of which have been associated with ILD in SSc patients.

The study population included 28 RA patients with ILD, 32 RA patients without ILD, 9 primary SS patients with ILD, and 32 primary SS patients with no ILD. The mean age of the RA participants was 63.4 years, 70% were women, and the mean age at RA diagnosis was 50.2 years. The mean age of the primary SS group was 60.3 years, 87.8% were female, and the mean age at diagnosis was 52.7 years.

Overall, SSc-specific antibodies across all titers were detected more frequently in RA patients with ILD compared with those with no ILD, though not statistically significant (42.9% vs. 21.9%, P = .08). However, “This trend was mainly attributed to the statistically significant difference between the two groups at strong titers (25% vs. 3.1%, P = .01),” the researchers wrote. Notably, RA patients with strong titer SSc-specific antibodies showed an 11-fold increased risk for ILD, they added.

No significant differences appeared in the prevalence of SSc-specific or Ro52 autoantibodies between primary SS patients with and without ILD, which might be attributable in part to the increased prevalence of anticentromere antibodies in primary SS, the researchers said.

RA patients who were positive for SSc-specific antibodies at strong titers were significantly more likely to have respiratory abnormalities than those who were negative (87.5% vs. 47.2%, P = .04), but no such differences appeared in primary SS patients.

“Early detection of SSc antibodies could be important in clinical practice as it may mandate further diagnostic (for example, screening for pulmonary hypertension) and therapeutic approaches of these patients,” the researchers wrote in their discussion.

The study findings were limited by several factors, mainly the small sample size, but also the potential for false-positive results on antibody titers, lack of data on the clinical significance of medium autoantibody titers, and the lack of long-term follow-up data, the researchers noted.

However, the results suggest that many seropositive RA patients with evidence of ILD “may evolve to a clinically evident overlap of RA and SSc” that would benefit from targeted treatment, they concluded.

The study was supported by a grant from Novartis AG and by the Molecular Immunology and Clinical Applications Unit, Department of Physiology, School of Medicine, National and Kapodistrian University of Athens. The researchers had no financial conflicts to disclose.

Adults with rheumatoid arthritis or primary Sjogren’s syndrome plus interstitial lung disease had higher levels of systemic sclerosis–specific antibodies than those without lung disease, based on data from 101 individuals.

Systemic sclerosis (SSc) has been associated with the development of interstitial lung disease (ILD), but the prevalence of SSc autoantibodies in patients with rheumatoid arthritis (RA) and primary Sjogren’s syndrome (SS) has not been explored, wrote Vasilike Koulouri, MD, of Kapodistrian University of Athens, and colleagues.

In a study published in the Journal of Translational Autoimmunity, the researchers reviewed serum data from patients with RA and SS using immunoblot assays to determine the prevalence of SSc-specific and anti-Ro52 autoantibodies, both of which have been associated with ILD in SSc patients.

The study population included 28 RA patients with ILD, 32 RA patients without ILD, 9 primary SS patients with ILD, and 32 primary SS patients with no ILD. The mean age of the RA participants was 63.4 years, 70% were women, and the mean age at RA diagnosis was 50.2 years. The mean age of the primary SS group was 60.3 years, 87.8% were female, and the mean age at diagnosis was 52.7 years.

Overall, SSc-specific antibodies across all titers were detected more frequently in RA patients with ILD compared with those with no ILD, though not statistically significant (42.9% vs. 21.9%, P = .08). However, “This trend was mainly attributed to the statistically significant difference between the two groups at strong titers (25% vs. 3.1%, P = .01),” the researchers wrote. Notably, RA patients with strong titer SSc-specific antibodies showed an 11-fold increased risk for ILD, they added.

No significant differences appeared in the prevalence of SSc-specific or Ro52 autoantibodies between primary SS patients with and without ILD, which might be attributable in part to the increased prevalence of anticentromere antibodies in primary SS, the researchers said.

RA patients who were positive for SSc-specific antibodies at strong titers were significantly more likely to have respiratory abnormalities than those who were negative (87.5% vs. 47.2%, P = .04), but no such differences appeared in primary SS patients.

“Early detection of SSc antibodies could be important in clinical practice as it may mandate further diagnostic (for example, screening for pulmonary hypertension) and therapeutic approaches of these patients,” the researchers wrote in their discussion.

The study findings were limited by several factors, mainly the small sample size, but also the potential for false-positive results on antibody titers, lack of data on the clinical significance of medium autoantibody titers, and the lack of long-term follow-up data, the researchers noted.

However, the results suggest that many seropositive RA patients with evidence of ILD “may evolve to a clinically evident overlap of RA and SSc” that would benefit from targeted treatment, they concluded.

The study was supported by a grant from Novartis AG and by the Molecular Immunology and Clinical Applications Unit, Department of Physiology, School of Medicine, National and Kapodistrian University of Athens. The researchers had no financial conflicts to disclose.

Adults with rheumatoid arthritis or primary Sjogren’s syndrome plus interstitial lung disease had higher levels of systemic sclerosis–specific antibodies than those without lung disease, based on data from 101 individuals.

Systemic sclerosis (SSc) has been associated with the development of interstitial lung disease (ILD), but the prevalence of SSc autoantibodies in patients with rheumatoid arthritis (RA) and primary Sjogren’s syndrome (SS) has not been explored, wrote Vasilike Koulouri, MD, of Kapodistrian University of Athens, and colleagues.

In a study published in the Journal of Translational Autoimmunity, the researchers reviewed serum data from patients with RA and SS using immunoblot assays to determine the prevalence of SSc-specific and anti-Ro52 autoantibodies, both of which have been associated with ILD in SSc patients.

The study population included 28 RA patients with ILD, 32 RA patients without ILD, 9 primary SS patients with ILD, and 32 primary SS patients with no ILD. The mean age of the RA participants was 63.4 years, 70% were women, and the mean age at RA diagnosis was 50.2 years. The mean age of the primary SS group was 60.3 years, 87.8% were female, and the mean age at diagnosis was 52.7 years.

Overall, SSc-specific antibodies across all titers were detected more frequently in RA patients with ILD compared with those with no ILD, though not statistically significant (42.9% vs. 21.9%, P = .08). However, “This trend was mainly attributed to the statistically significant difference between the two groups at strong titers (25% vs. 3.1%, P = .01),” the researchers wrote. Notably, RA patients with strong titer SSc-specific antibodies showed an 11-fold increased risk for ILD, they added.

No significant differences appeared in the prevalence of SSc-specific or Ro52 autoantibodies between primary SS patients with and without ILD, which might be attributable in part to the increased prevalence of anticentromere antibodies in primary SS, the researchers said.

RA patients who were positive for SSc-specific antibodies at strong titers were significantly more likely to have respiratory abnormalities than those who were negative (87.5% vs. 47.2%, P = .04), but no such differences appeared in primary SS patients.

“Early detection of SSc antibodies could be important in clinical practice as it may mandate further diagnostic (for example, screening for pulmonary hypertension) and therapeutic approaches of these patients,” the researchers wrote in their discussion.

The study findings were limited by several factors, mainly the small sample size, but also the potential for false-positive results on antibody titers, lack of data on the clinical significance of medium autoantibody titers, and the lack of long-term follow-up data, the researchers noted.

However, the results suggest that many seropositive RA patients with evidence of ILD “may evolve to a clinically evident overlap of RA and SSc” that would benefit from targeted treatment, they concluded.

The study was supported by a grant from Novartis AG and by the Molecular Immunology and Clinical Applications Unit, Department of Physiology, School of Medicine, National and Kapodistrian University of Athens. The researchers had no financial conflicts to disclose.

If you could go back in time 75 years and tell Dr. Sidney Farber, the developer of methotrexate for cancer therapy, that 21st-century medicine would utilize his specially designed drug more in rheumatology than oncology, he might be surprised. He might scratch his head even more, hearing of his drug sparking interest in still other medical fields, like cardiology.

But drug repurposing is not so uncommon. One classic example is aspirin. Once the most common pain medication and used also in rheumatology, aspirin now finds a range of applications, from colorectal cancer to the prevention of cardiovascular and cerebrovascular thrombosis. Minoxidil is another example, developed for hypertension but used today mostly to stop hair loss. Perhaps most ironic is thalidomide, utilized today for leprosy and multiple myeloma, yet actually contraindicated for its original application, nausea of pregnancy.

Courtesy NIH

Methotrexate, thus, has much in common with other medical treatments, and yet its origin story is as unique and as fascinating as the story of Dr. Farber himself. While this is a rheumatology article, it’s also a story about the origin of a particular rheumatologic treatment, and so the story of that origin will take us mostly through a discussion of hematologic malignancy and of the clinical researcher who dared search for a cure.

Born in 1903, in Buffalo, New York, third of fourteen children of Jewish immigrants from Poland, Dr. Farber grew up in a household that was crowded but academically rigorous. His father, Simon, routinely brought home textbooks, assigning each child a book to read and on which to write a report. His mother, Matilda, was as devoted as her husband to raising the children to succeed in their adopted new country. Upstairs, the children were permitted to speak Yiddish, but downstairs they were required to use only English and German.

As a teen, Dr. Farber lived through the 1918 influenza pandemic that killed at least 50 million people worldwide, including more than 2,000 Buffalonians. This probably helped motivate him to study medicine, but with antisemitism overt in the America of the early 1920s, securing admission to a U.S. medical school was close to impossible. So, in what now seems like the greatest of ironies, Dr. Farber began medical studies in Germany, then transferred for the second year to a U.S. program that seemed adequate – Harvard Medical School, from which he graduated in 1927. From there, he trained as a pathologist, focusing ultimately on pediatric pathology. But, frustrated by case after case of malignancy, whose young victims he’d often have to autopsy, Dr. Farber decided that he wanted to advance the pitiful state of cancer therapeutics, especially for hematologic malignancy.

This was a tall order in the 1930s and early 1940s, when cancer therapeutics consisted only of surgical resection and very primitive forms of radiation therapy. Applicable only to neoplasia that was localized, these options were useless against malignancies in the blood, like acute lymphoblastic leukemia (ALL), but by January 1948 there was at least one glimmer of hope. At that time, one patient with ALL, 2-year-old Robert Sandler, was too ill to join his twin brother Elliott for snow play outside their home in the Dorchester section of Boston. Diagnosed back in August, Robert had suffered multiple episodes of fever, anemia, and thrombocytopenia. His illness had enlarged his spleen dramatically and caused pathologic bone fractures with excruciating bone pain, and for a while he couldn’t walk because of pressure on his lower spinal cord. All of this was the result of uncontrolled mitosis and cell division of lymphoblasts, immature lymphocytes. By December, these out-of-control cells had elevated the boy’s white blood cell count to a peak of 70,000/mcL, more than six times the high end of the normal range (4,500-11,000/mcL). This had happened despite treatment with an experimental drug, developed at Boston Children’s Hospital by Dr. Farber and his team, working on the assumption that inhibition of folate metabolism should slow the growth of tumor cells. On Dec. 28, however, Dr. Farber had switched the child to a new drug with a chemical structure just slightly different from the other agent’s.

Merely another chemical modification in a series of attempts by the research team, the new drug, aminopterin, was not expected to do anything dramatic, but Dr. Farber and the team had come such a long way since the middle of 1947, when he’d actually done the opposite of what he was doing now. On the basis of British research from India showing folic acid deficiency as the basis of a common type of anemia in malnourished people, Dr. Farber had reasoned that children with leukemia, who also suffered from anemia, might also benefit from folic acid supplementation. Even without prior rodent testing, Dr. Farber had tried giving the nutrient to patients with ALL, a strategy made possible by the presence of a spectacular chemist working on folic acid synthesis at Farber’s own hospital to help combat folate deficiency. Born into a poor Brahmin family in India, the chemist, Dr. Yellapragada SubbaRow, had begun life with so much stacked against him as to appear even less likely during childhood than the young Dr. Farber to grow up to make major contributions to medicine. Going through childhood with death all around him, Dr. SubbaRow was motivated to study medicine, but getting into medical school had been an uphill fight, given his family’s economic difficulty. Knowing that he’d also face discrimination on account of his low status after receiving admission to a medical program, SubbaRow could have made things a bit easier for himself by living within the norms of the British Imperial system, but as a supporter of Mohandas Gandhi’s nationalist movement, he boycotted British goods. As a medical student, this meant doing things like wearing Indian-made surgical gloves, instead of the English products that were expected of the students. Such actions led Dr. SubbaRow to receive a kind of second-rate medical degree, rather than the prestigious MBBS.

The political situation also led Dr. SubbaRow to emigrate to the United States, where, ironically, his medical degree initially was taken less seriously than it had been taken in his British-occupied homeland. He thus worked in the capacity of a hospital night porter at Peter Bent Brigham Hospital (the future Brigham and Women’s Hospital), doing menial tasks like changing sheets to make ends meet. He studied, however, and made enough of an impression to gain admission to the same institution that also admitted Farber through the backdoor, Harvard Medical School. This launched him into a research career in which he not only would be instrumental in developing folate antagonists and other classes of drugs, but also would make him the codiscoverer of the role of creatine phosphate and ATP in cellular energy metabolism. Sadly, even after obtaining his top-notch American credentials and contributing through his research to what you might say is a good chunk of the biochemistry pathways that first year medical students memorize without ever learning who discovered them, Dr. SubbaRow still faced prejudice for the rest of his life, which turned out to last only until the age of 53. To add insult to injury, he is rarely remembered for his role.

Dr. Farber proceeded with the folic acid supplementation idea in patients with ALL, even though ALL caused a hypoproliferative anemia, whereas anemia from folate deficiency was megaloblastic, meaning that erythrocytes were produced but they were oversized and dysfunctional. Tragically, folic acid had accelerated the disease process in children with ALL, but the process of chemical experimentation aimed at synthesizing folate also produced some compounds that mimicked chemical precursors of folate in a way that made them antifolates, inhibitors of folate metabolism. If folic acid made lymphoblasts grow faster, Dr. Farber had reasoned that antifolates should inhibit their growth. He thus asked the chemistry lab to focus on folate inhibitors. Testing aminopterin, beginning with young Robert Sandler at the end of December, is what proved his hypothesis correct. By late January, aminopterin had brought the child’s WBC count down to the realm of 12,000, just slightly above normal, with symptoms and signs abating as well, and by February, the child could play with his twin brother. It was not a cure; malignant lymphoblasts still showed on microscopy of Robert’s blood. While he and some 15 other children whom Dr. Farber treated in this early trial would all succumb to ALL, they experienced remission lasting several months.

This was a big deal because the concept of chemotherapy was based only on serendipitous observations of WBC counts dropping in soldiers exposed to nitrogen mustard gas during World War I and during an incident in World War II, yet aminopterin had been designed from the ground up. Though difficult to synthesize in quantities, there was no reason for Dr. Farber’s team not to keep tweaking the drug, and so they did. Replacing one hydrogen atom with a methyl group, they turned it into methotrexate.

Proving easier to synthesize and less toxic, methotrexate would become a workhorse for chemotherapy over the next couple of decades, but the capability of both methotrexate and aminopterin to blunt the growth of white blood cells and other cells did not go unnoticed outside the realm of oncology. As early as the 1950s, dermatologists were using aminopterin to treat psoriasis. This led to the approval of methotrexate for psoriasis in 1972.

Meanwhile, like oncology, infectious diseases, aviation medicine, and so many other areas of practice, rheumatology had gotten a major boost from research stemming from World War II. During the war, Dr. Philip Hench of the Mayo Clinic developed cortisone, which pilots used to stay alert and energetic during trans-Atlantic flights. But it turned out that cortisone had a powerful immunosuppressive effect that dramatically improved rheumatoid arthritis, leading Dr. Hench to receive the Nobel Prize in Physiology or Medicine in 1950. By the end of the 1950s, however, the significant side effects of long-term corticosteroid therapy were very clear, so over the next few decades there was a major effort to develop different treatments for RA and other rheumatologic diseases.

Top on the list of such agents was methotrexate, developed for RA in part by Dr. Michael Weinblatt of Brigham and Women’s Hospital in Boston. In the 1980s, Dr. Weinblatt published the first clinical trial showing the benefits of methotrexate for RA patients. This has since developed into a standard treatment, noticeably different from the original malignancy application in that it is a low-dose regimen. Patients taking methotrexate for RA typically receive no more than 25 mg per week orally, and often much less. Rheumatology today includes expertise in keeping long-term methotrexate therapy safe by monitoring liver function and through other routine tests. The routine nature of the therapy has brought methotrexate to the point of beckoning in a realm that Dr. Farber might not have predicted in his wildest imagination: cardiology. This is on account of the growing appreciation of the inflammatory process in the pathophysiology of atherosclerotic heart disease.

Meanwhile, being an antimetabolite, harmful to rapidly dividing cells, the danger of methotrexate to the embryo and fetus was recognized early. This made methotrexate off-limits to pregnant women, yet it also has made the drug useful as an abortifacient. Though not as good for medication abortion in unwanted but thriving pregnancies, where mifepristone/misoprostol has become the regimen of choice, methotrexate has become a workhorse in other obstetrical settings, such as for ending ectopic pregnancy.

Looking at the present and into the future, the potential for this very old medication looks wide open, as if it could go in any direction, so let’s wind up the discussion with the thought that we may be in for some surprises. Rather than jumping deeply into any rheumatologic issue, we spent most of this article weaving through other medical issues, but does this not make today’s story fairly analogous to rheumatology itself?

Dr. Warmflash is a physician from Portland, Ore. He reported no conflicts of interest.

This story was updated 2/10/2023.

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

If you could go back in time 75 years and tell Dr. Sidney Farber, the developer of methotrexate for cancer therapy, that 21st-century medicine would utilize his specially designed drug more in rheumatology than oncology, he might be surprised. He might scratch his head even more, hearing of his drug sparking interest in still other medical fields, like cardiology.

But drug repurposing is not so uncommon. One classic example is aspirin. Once the most common pain medication and used also in rheumatology, aspirin now finds a range of applications, from colorectal cancer to the prevention of cardiovascular and cerebrovascular thrombosis. Minoxidil is another example, developed for hypertension but used today mostly to stop hair loss. Perhaps most ironic is thalidomide, utilized today for leprosy and multiple myeloma, yet actually contraindicated for its original application, nausea of pregnancy.

Courtesy NIH

Methotrexate, thus, has much in common with other medical treatments, and yet its origin story is as unique and as fascinating as the story of Dr. Farber himself. While this is a rheumatology article, it’s also a story about the origin of a particular rheumatologic treatment, and so the story of that origin will take us mostly through a discussion of hematologic malignancy and of the clinical researcher who dared search for a cure.

Born in 1903, in Buffalo, New York, third of fourteen children of Jewish immigrants from Poland, Dr. Farber grew up in a household that was crowded but academically rigorous. His father, Simon, routinely brought home textbooks, assigning each child a book to read and on which to write a report. His mother, Matilda, was as devoted as her husband to raising the children to succeed in their adopted new country. Upstairs, the children were permitted to speak Yiddish, but downstairs they were required to use only English and German.

As a teen, Dr. Farber lived through the 1918 influenza pandemic that killed at least 50 million people worldwide, including more than 2,000 Buffalonians. This probably helped motivate him to study medicine, but with antisemitism overt in the America of the early 1920s, securing admission to a U.S. medical school was close to impossible. So, in what now seems like the greatest of ironies, Dr. Farber began medical studies in Germany, then transferred for the second year to a U.S. program that seemed adequate – Harvard Medical School, from which he graduated in 1927. From there, he trained as a pathologist, focusing ultimately on pediatric pathology. But, frustrated by case after case of malignancy, whose young victims he’d often have to autopsy, Dr. Farber decided that he wanted to advance the pitiful state of cancer therapeutics, especially for hematologic malignancy.

This was a tall order in the 1930s and early 1940s, when cancer therapeutics consisted only of surgical resection and very primitive forms of radiation therapy. Applicable only to neoplasia that was localized, these options were useless against malignancies in the blood, like acute lymphoblastic leukemia (ALL), but by January 1948 there was at least one glimmer of hope. At that time, one patient with ALL, 2-year-old Robert Sandler, was too ill to join his twin brother Elliott for snow play outside their home in the Dorchester section of Boston. Diagnosed back in August, Robert had suffered multiple episodes of fever, anemia, and thrombocytopenia. His illness had enlarged his spleen dramatically and caused pathologic bone fractures with excruciating bone pain, and for a while he couldn’t walk because of pressure on his lower spinal cord. All of this was the result of uncontrolled mitosis and cell division of lymphoblasts, immature lymphocytes. By December, these out-of-control cells had elevated the boy’s white blood cell count to a peak of 70,000/mcL, more than six times the high end of the normal range (4,500-11,000/mcL). This had happened despite treatment with an experimental drug, developed at Boston Children’s Hospital by Dr. Farber and his team, working on the assumption that inhibition of folate metabolism should slow the growth of tumor cells. On Dec. 28, however, Dr. Farber had switched the child to a new drug with a chemical structure just slightly different from the other agent’s.

Merely another chemical modification in a series of attempts by the research team, the new drug, aminopterin, was not expected to do anything dramatic, but Dr. Farber and the team had come such a long way since the middle of 1947, when he’d actually done the opposite of what he was doing now. On the basis of British research from India showing folic acid deficiency as the basis of a common type of anemia in malnourished people, Dr. Farber had reasoned that children with leukemia, who also suffered from anemia, might also benefit from folic acid supplementation. Even without prior rodent testing, Dr. Farber had tried giving the nutrient to patients with ALL, a strategy made possible by the presence of a spectacular chemist working on folic acid synthesis at Farber’s own hospital to help combat folate deficiency. Born into a poor Brahmin family in India, the chemist, Dr. Yellapragada SubbaRow, had begun life with so much stacked against him as to appear even less likely during childhood than the young Dr. Farber to grow up to make major contributions to medicine. Going through childhood with death all around him, Dr. SubbaRow was motivated to study medicine, but getting into medical school had been an uphill fight, given his family’s economic difficulty. Knowing that he’d also face discrimination on account of his low status after receiving admission to a medical program, SubbaRow could have made things a bit easier for himself by living within the norms of the British Imperial system, but as a supporter of Mohandas Gandhi’s nationalist movement, he boycotted British goods. As a medical student, this meant doing things like wearing Indian-made surgical gloves, instead of the English products that were expected of the students. Such actions led Dr. SubbaRow to receive a kind of second-rate medical degree, rather than the prestigious MBBS.

The political situation also led Dr. SubbaRow to emigrate to the United States, where, ironically, his medical degree initially was taken less seriously than it had been taken in his British-occupied homeland. He thus worked in the capacity of a hospital night porter at Peter Bent Brigham Hospital (the future Brigham and Women’s Hospital), doing menial tasks like changing sheets to make ends meet. He studied, however, and made enough of an impression to gain admission to the same institution that also admitted Farber through the backdoor, Harvard Medical School. This launched him into a research career in which he not only would be instrumental in developing folate antagonists and other classes of drugs, but also would make him the codiscoverer of the role of creatine phosphate and ATP in cellular energy metabolism. Sadly, even after obtaining his top-notch American credentials and contributing through his research to what you might say is a good chunk of the biochemistry pathways that first year medical students memorize without ever learning who discovered them, Dr. SubbaRow still faced prejudice for the rest of his life, which turned out to last only until the age of 53. To add insult to injury, he is rarely remembered for his role.

Dr. Farber proceeded with the folic acid supplementation idea in patients with ALL, even though ALL caused a hypoproliferative anemia, whereas anemia from folate deficiency was megaloblastic, meaning that erythrocytes were produced but they were oversized and dysfunctional. Tragically, folic acid had accelerated the disease process in children with ALL, but the process of chemical experimentation aimed at synthesizing folate also produced some compounds that mimicked chemical precursors of folate in a way that made them antifolates, inhibitors of folate metabolism. If folic acid made lymphoblasts grow faster, Dr. Farber had reasoned that antifolates should inhibit their growth. He thus asked the chemistry lab to focus on folate inhibitors. Testing aminopterin, beginning with young Robert Sandler at the end of December, is what proved his hypothesis correct. By late January, aminopterin had brought the child’s WBC count down to the realm of 12,000, just slightly above normal, with symptoms and signs abating as well, and by February, the child could play with his twin brother. It was not a cure; malignant lymphoblasts still showed on microscopy of Robert’s blood. While he and some 15 other children whom Dr. Farber treated in this early trial would all succumb to ALL, they experienced remission lasting several months.

This was a big deal because the concept of chemotherapy was based only on serendipitous observations of WBC counts dropping in soldiers exposed to nitrogen mustard gas during World War I and during an incident in World War II, yet aminopterin had been designed from the ground up. Though difficult to synthesize in quantities, there was no reason for Dr. Farber’s team not to keep tweaking the drug, and so they did. Replacing one hydrogen atom with a methyl group, they turned it into methotrexate.

Proving easier to synthesize and less toxic, methotrexate would become a workhorse for chemotherapy over the next couple of decades, but the capability of both methotrexate and aminopterin to blunt the growth of white blood cells and other cells did not go unnoticed outside the realm of oncology. As early as the 1950s, dermatologists were using aminopterin to treat psoriasis. This led to the approval of methotrexate for psoriasis in 1972.

Meanwhile, like oncology, infectious diseases, aviation medicine, and so many other areas of practice, rheumatology had gotten a major boost from research stemming from World War II. During the war, Dr. Philip Hench of the Mayo Clinic developed cortisone, which pilots used to stay alert and energetic during trans-Atlantic flights. But it turned out that cortisone had a powerful immunosuppressive effect that dramatically improved rheumatoid arthritis, leading Dr. Hench to receive the Nobel Prize in Physiology or Medicine in 1950. By the end of the 1950s, however, the significant side effects of long-term corticosteroid therapy were very clear, so over the next few decades there was a major effort to develop different treatments for RA and other rheumatologic diseases.

Top on the list of such agents was methotrexate, developed for RA in part by Dr. Michael Weinblatt of Brigham and Women’s Hospital in Boston. In the 1980s, Dr. Weinblatt published the first clinical trial showing the benefits of methotrexate for RA patients. This has since developed into a standard treatment, noticeably different from the original malignancy application in that it is a low-dose regimen. Patients taking methotrexate for RA typically receive no more than 25 mg per week orally, and often much less. Rheumatology today includes expertise in keeping long-term methotrexate therapy safe by monitoring liver function and through other routine tests. The routine nature of the therapy has brought methotrexate to the point of beckoning in a realm that Dr. Farber might not have predicted in his wildest imagination: cardiology. This is on account of the growing appreciation of the inflammatory process in the pathophysiology of atherosclerotic heart disease.

Meanwhile, being an antimetabolite, harmful to rapidly dividing cells, the danger of methotrexate to the embryo and fetus was recognized early. This made methotrexate off-limits to pregnant women, yet it also has made the drug useful as an abortifacient. Though not as good for medication abortion in unwanted but thriving pregnancies, where mifepristone/misoprostol has become the regimen of choice, methotrexate has become a workhorse in other obstetrical settings, such as for ending ectopic pregnancy.

Looking at the present and into the future, the potential for this very old medication looks wide open, as if it could go in any direction, so let’s wind up the discussion with the thought that we may be in for some surprises. Rather than jumping deeply into any rheumatologic issue, we spent most of this article weaving through other medical issues, but does this not make today’s story fairly analogous to rheumatology itself?

Dr. Warmflash is a physician from Portland, Ore. He reported no conflicts of interest.

This story was updated 2/10/2023.

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

If you could go back in time 75 years and tell Dr. Sidney Farber, the developer of methotrexate for cancer therapy, that 21st-century medicine would utilize his specially designed drug more in rheumatology than oncology, he might be surprised. He might scratch his head even more, hearing of his drug sparking interest in still other medical fields, like cardiology.

But drug repurposing is not so uncommon. One classic example is aspirin. Once the most common pain medication and used also in rheumatology, aspirin now finds a range of applications, from colorectal cancer to the prevention of cardiovascular and cerebrovascular thrombosis. Minoxidil is another example, developed for hypertension but used today mostly to stop hair loss. Perhaps most ironic is thalidomide, utilized today for leprosy and multiple myeloma, yet actually contraindicated for its original application, nausea of pregnancy.

Courtesy NIH

Methotrexate, thus, has much in common with other medical treatments, and yet its origin story is as unique and as fascinating as the story of Dr. Farber himself. While this is a rheumatology article, it’s also a story about the origin of a particular rheumatologic treatment, and so the story of that origin will take us mostly through a discussion of hematologic malignancy and of the clinical researcher who dared search for a cure.

Born in 1903, in Buffalo, New York, third of fourteen children of Jewish immigrants from Poland, Dr. Farber grew up in a household that was crowded but academically rigorous. His father, Simon, routinely brought home textbooks, assigning each child a book to read and on which to write a report. His mother, Matilda, was as devoted as her husband to raising the children to succeed in their adopted new country. Upstairs, the children were permitted to speak Yiddish, but downstairs they were required to use only English and German.

As a teen, Dr. Farber lived through the 1918 influenza pandemic that killed at least 50 million people worldwide, including more than 2,000 Buffalonians. This probably helped motivate him to study medicine, but with antisemitism overt in the America of the early 1920s, securing admission to a U.S. medical school was close to impossible. So, in what now seems like the greatest of ironies, Dr. Farber began medical studies in Germany, then transferred for the second year to a U.S. program that seemed adequate – Harvard Medical School, from which he graduated in 1927. From there, he trained as a pathologist, focusing ultimately on pediatric pathology. But, frustrated by case after case of malignancy, whose young victims he’d often have to autopsy, Dr. Farber decided that he wanted to advance the pitiful state of cancer therapeutics, especially for hematologic malignancy.

This was a tall order in the 1930s and early 1940s, when cancer therapeutics consisted only of surgical resection and very primitive forms of radiation therapy. Applicable only to neoplasia that was localized, these options were useless against malignancies in the blood, like acute lymphoblastic leukemia (ALL), but by January 1948 there was at least one glimmer of hope. At that time, one patient with ALL, 2-year-old Robert Sandler, was too ill to join his twin brother Elliott for snow play outside their home in the Dorchester section of Boston. Diagnosed back in August, Robert had suffered multiple episodes of fever, anemia, and thrombocytopenia. His illness had enlarged his spleen dramatically and caused pathologic bone fractures with excruciating bone pain, and for a while he couldn’t walk because of pressure on his lower spinal cord. All of this was the result of uncontrolled mitosis and cell division of lymphoblasts, immature lymphocytes. By December, these out-of-control cells had elevated the boy’s white blood cell count to a peak of 70,000/mcL, more than six times the high end of the normal range (4,500-11,000/mcL). This had happened despite treatment with an experimental drug, developed at Boston Children’s Hospital by Dr. Farber and his team, working on the assumption that inhibition of folate metabolism should slow the growth of tumor cells. On Dec. 28, however, Dr. Farber had switched the child to a new drug with a chemical structure just slightly different from the other agent’s.

Merely another chemical modification in a series of attempts by the research team, the new drug, aminopterin, was not expected to do anything dramatic, but Dr. Farber and the team had come such a long way since the middle of 1947, when he’d actually done the opposite of what he was doing now. On the basis of British research from India showing folic acid deficiency as the basis of a common type of anemia in malnourished people, Dr. Farber had reasoned that children with leukemia, who also suffered from anemia, might also benefit from folic acid supplementation. Even without prior rodent testing, Dr. Farber had tried giving the nutrient to patients with ALL, a strategy made possible by the presence of a spectacular chemist working on folic acid synthesis at Farber’s own hospital to help combat folate deficiency. Born into a poor Brahmin family in India, the chemist, Dr. Yellapragada SubbaRow, had begun life with so much stacked against him as to appear even less likely during childhood than the young Dr. Farber to grow up to make major contributions to medicine. Going through childhood with death all around him, Dr. SubbaRow was motivated to study medicine, but getting into medical school had been an uphill fight, given his family’s economic difficulty. Knowing that he’d also face discrimination on account of his low status after receiving admission to a medical program, SubbaRow could have made things a bit easier for himself by living within the norms of the British Imperial system, but as a supporter of Mohandas Gandhi’s nationalist movement, he boycotted British goods. As a medical student, this meant doing things like wearing Indian-made surgical gloves, instead of the English products that were expected of the students. Such actions led Dr. SubbaRow to receive a kind of second-rate medical degree, rather than the prestigious MBBS.

The political situation also led Dr. SubbaRow to emigrate to the United States, where, ironically, his medical degree initially was taken less seriously than it had been taken in his British-occupied homeland. He thus worked in the capacity of a hospital night porter at Peter Bent Brigham Hospital (the future Brigham and Women’s Hospital), doing menial tasks like changing sheets to make ends meet. He studied, however, and made enough of an impression to gain admission to the same institution that also admitted Farber through the backdoor, Harvard Medical School. This launched him into a research career in which he not only would be instrumental in developing folate antagonists and other classes of drugs, but also would make him the codiscoverer of the role of creatine phosphate and ATP in cellular energy metabolism. Sadly, even after obtaining his top-notch American credentials and contributing through his research to what you might say is a good chunk of the biochemistry pathways that first year medical students memorize without ever learning who discovered them, Dr. SubbaRow still faced prejudice for the rest of his life, which turned out to last only until the age of 53. To add insult to injury, he is rarely remembered for his role.

Dr. Farber proceeded with the folic acid supplementation idea in patients with ALL, even though ALL caused a hypoproliferative anemia, whereas anemia from folate deficiency was megaloblastic, meaning that erythrocytes were produced but they were oversized and dysfunctional. Tragically, folic acid had accelerated the disease process in children with ALL, but the process of chemical experimentation aimed at synthesizing folate also produced some compounds that mimicked chemical precursors of folate in a way that made them antifolates, inhibitors of folate metabolism. If folic acid made lymphoblasts grow faster, Dr. Farber had reasoned that antifolates should inhibit their growth. He thus asked the chemistry lab to focus on folate inhibitors. Testing aminopterin, beginning with young Robert Sandler at the end of December, is what proved his hypothesis correct. By late January, aminopterin had brought the child’s WBC count down to the realm of 12,000, just slightly above normal, with symptoms and signs abating as well, and by February, the child could play with his twin brother. It was not a cure; malignant lymphoblasts still showed on microscopy of Robert’s blood. While he and some 15 other children whom Dr. Farber treated in this early trial would all succumb to ALL, they experienced remission lasting several months.

This was a big deal because the concept of chemotherapy was based only on serendipitous observations of WBC counts dropping in soldiers exposed to nitrogen mustard gas during World War I and during an incident in World War II, yet aminopterin had been designed from the ground up. Though difficult to synthesize in quantities, there was no reason for Dr. Farber’s team not to keep tweaking the drug, and so they did. Replacing one hydrogen atom with a methyl group, they turned it into methotrexate.

Proving easier to synthesize and less toxic, methotrexate would become a workhorse for chemotherapy over the next couple of decades, but the capability of both methotrexate and aminopterin to blunt the growth of white blood cells and other cells did not go unnoticed outside the realm of oncology. As early as the 1950s, dermatologists were using aminopterin to treat psoriasis. This led to the approval of methotrexate for psoriasis in 1972.

Meanwhile, like oncology, infectious diseases, aviation medicine, and so many other areas of practice, rheumatology had gotten a major boost from research stemming from World War II. During the war, Dr. Philip Hench of the Mayo Clinic developed cortisone, which pilots used to stay alert and energetic during trans-Atlantic flights. But it turned out that cortisone had a powerful immunosuppressive effect that dramatically improved rheumatoid arthritis, leading Dr. Hench to receive the Nobel Prize in Physiology or Medicine in 1950. By the end of the 1950s, however, the significant side effects of long-term corticosteroid therapy were very clear, so over the next few decades there was a major effort to develop different treatments for RA and other rheumatologic diseases.

Top on the list of such agents was methotrexate, developed for RA in part by Dr. Michael Weinblatt of Brigham and Women’s Hospital in Boston. In the 1980s, Dr. Weinblatt published the first clinical trial showing the benefits of methotrexate for RA patients. This has since developed into a standard treatment, noticeably different from the original malignancy application in that it is a low-dose regimen. Patients taking methotrexate for RA typically receive no more than 25 mg per week orally, and often much less. Rheumatology today includes expertise in keeping long-term methotrexate therapy safe by monitoring liver function and through other routine tests. The routine nature of the therapy has brought methotrexate to the point of beckoning in a realm that Dr. Farber might not have predicted in his wildest imagination: cardiology. This is on account of the growing appreciation of the inflammatory process in the pathophysiology of atherosclerotic heart disease.

Meanwhile, being an antimetabolite, harmful to rapidly dividing cells, the danger of methotrexate to the embryo and fetus was recognized early. This made methotrexate off-limits to pregnant women, yet it also has made the drug useful as an abortifacient. Though not as good for medication abortion in unwanted but thriving pregnancies, where mifepristone/misoprostol has become the regimen of choice, methotrexate has become a workhorse in other obstetrical settings, such as for ending ectopic pregnancy.

Looking at the present and into the future, the potential for this very old medication looks wide open, as if it could go in any direction, so let’s wind up the discussion with the thought that we may be in for some surprises. Rather than jumping deeply into any rheumatologic issue, we spent most of this article weaving through other medical issues, but does this not make today’s story fairly analogous to rheumatology itself?

Dr. Warmflash is a physician from Portland, Ore. He reported no conflicts of interest.

This story was updated 2/10/2023.

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

Topical cannabidiol (CBD) oil appeared to lower pain scores and reduce painkiller use vs. standard treatment in patients with digital ulcers due to systemic sclerosis, a small new study finds. Patients who received the treatment also showed signs of more healing.

The study, published in Advances in Skin & Wound Care, is far from definitive since it’s retrospective and tracked only 45 patients. But the findings add to other research suggesting dermatologic benefits from the topical use of CBD, an ingredient in cannabis that’s widely available and doesn’t cause people to become high or become addicted.

Anatoliy Sizov/Getty Images

“This is a good first step in trying to address scleroderma digital ulcer pain and healing,” University of Colorado rheumatologist Melissa Griffith, MD, said in an interview. “Digital ulcers cause great impact on quality of life, daily activities of living, and pain, so we are always looking for new, effective tools.”

According to Dr. Griffith, digital ulcers occur in scleroderma due to Raynaud’s phenomenon with reversible vasospasm. “Unlike patients with primary Raynaud’s phenomenon, patients will develop ischemia of digits, leading to digital ulcers due to the vasculopathy or vascular remodeling that occurs in scleroderma,” she said.

Current treatments include removal of causative drugs/toxins and warmth, rest, and pain control, although “no trials exist to compare the scleroderma digital ulcer or digital ischemia treatments to each other,” Dr. Griffith said.

Therapy for vasospasm begins with calcium channel blockers such as amlodipine and nifedipine, she said, followed by phosphodiesterase type 5 inhibitors such as sildenafil or endothelin receptor antagonist medications such as bosentan. “If these fail, we use an IV option – epoprostenol. Other options are sympathectomy surgery, Botox, digital nerve blocks, biofeedback, and SSRIs,” she said. “These treatments work fairly well in most patients, but there are patients who break through these therapies and have ongoing digital ischemia, leading to digital ulcers, pain, infections, acro-osteolysis, and auto-amputation. There is definitely room to improve on our current treatment paradigm.”

For the new study, researchers in Italy led by Amelia Spinella, MD, PhD, of University Hospital of Modena, retrospectively tracked 45 patients with systemic sclerosis and at least one digital ulcer (40 women; average age, 53 years) who were treated in 2019. All patients’ ulcers were resistant to opioid therapy at the maximum tolerated dose, and all had undergone periodic iloprost infusion every 30-40 days. Based on each patient’s clinical situation, they had received calcium-channel blockers, phosphodiesterase type 5 inhibitors (sildenafil), and/or endothelin receptor antagonists (bosentan or macitentan). The researchers noted that all patients underwent surgical debridement regularly following wound bed preparation procedures and received advanced dressings (alginate, hydrocolloid, hydrofiber, hydrogel, and polyurethane foam or film). Of the 45 patients, 25 treated their wounds daily over the course of a month by administering four drops of a preparation of 10% CBD oil in acidic form and 90% hemp oil over the wound bed and perilesional skin and then covering it with a nonadhesive cloth.

“Basal wound-related pain NRS [numeric rating scale] scores decreased from 8.4 (standard deviation [SD], 0.8) at the baseline (T0) to 6.0 (SD, 0.82) after 1 month of CBD treatment (T1; P < .0001),” the researchers reported. “Across the same time period, volitional incident pain NRS scores decreased from 9.32 (SD, 0.75; T0) to 6.8 (SD, 1.12; T1; P < .0001). In addition, mean total hours of sleep per night increased from 2.56 (SD, 1.28) to 5.67 (SD, 0.85) hours (P < .0001).” Twelve of the 25 needed additional painkiller therapy.

Complete digital ulcer healing occurred by the end of the study in 18 of 25 (72%) CBD-treated patients, compared with 6 of 20 (30%) control patients.

In contrast, the control group didn’t see any significant improvement in wound-related pain, volitional incident pain, or sleep. All needed additional painkiller therapy. Six developed ulcer infections and received antibiotics.

No significant adverse effects were reported, although 28% of those in the CBD oil group said they had mild effects such as itch and perilesional erythema.

The authors of the new study called for larger, randomized controlled, multicenter trials to confirm the benefit of CBD topical treatment.

In recent years, researchers have devoted more attention to topical CBD as a treatment for skin conditions. While limited, the evidence suggests they “may be effective for the treatment of various inflammatory skin disorders,” researchers wrote in a 2022 report. “Although promising, additional research is necessary to evaluate efficacy and to determine dosing, safety, and long-term treatment guidelines.”

Dr. Griffith, who did not take part in the new study but is familiar with its findings, said she was especially surprised by the hint that topical CBD improves healing in addition to relieving symptoms. “I thought only pain would be affected. This is a great outcome if it can be replicated.”

As for future research, she said “there are difficulties with reproducing this at a big scale in the U.S. given CBD commercial variability. The big issue is the standardization of CBD extraction and production. It is really hard for us as physicians to know what patients are getting. Some online CBD orders contain THC [the major psychoactive ingredient of cannabis] > 0.3% or no CBD at all.”

Still, she said, “physicians and patients may consider this when standard therapies are not working or causing too many adverse effects,” especially since “the downsides here seem fairly minimal – at worst itchiness and redness that did not prevent patients from continuing in the study.”

No details about study funding were provided. The authors and Dr. Griffith report no disclosures.

Topical cannabidiol (CBD) oil appeared to lower pain scores and reduce painkiller use vs. standard treatment in patients with digital ulcers due to systemic sclerosis, a small new study finds. Patients who received the treatment also showed signs of more healing.

The study, published in Advances in Skin & Wound Care, is far from definitive since it’s retrospective and tracked only 45 patients. But the findings add to other research suggesting dermatologic benefits from the topical use of CBD, an ingredient in cannabis that’s widely available and doesn’t cause people to become high or become addicted.

Anatoliy Sizov/Getty Images

“This is a good first step in trying to address scleroderma digital ulcer pain and healing,” University of Colorado rheumatologist Melissa Griffith, MD, said in an interview. “Digital ulcers cause great impact on quality of life, daily activities of living, and pain, so we are always looking for new, effective tools.”

According to Dr. Griffith, digital ulcers occur in scleroderma due to Raynaud’s phenomenon with reversible vasospasm. “Unlike patients with primary Raynaud’s phenomenon, patients will develop ischemia of digits, leading to digital ulcers due to the vasculopathy or vascular remodeling that occurs in scleroderma,” she said.

Current treatments include removal of causative drugs/toxins and warmth, rest, and pain control, although “no trials exist to compare the scleroderma digital ulcer or digital ischemia treatments to each other,” Dr. Griffith said.

Therapy for vasospasm begins with calcium channel blockers such as amlodipine and nifedipine, she said, followed by phosphodiesterase type 5 inhibitors such as sildenafil or endothelin receptor antagonist medications such as bosentan. “If these fail, we use an IV option – epoprostenol. Other options are sympathectomy surgery, Botox, digital nerve blocks, biofeedback, and SSRIs,” she said. “These treatments work fairly well in most patients, but there are patients who break through these therapies and have ongoing digital ischemia, leading to digital ulcers, pain, infections, acro-osteolysis, and auto-amputation. There is definitely room to improve on our current treatment paradigm.”

For the new study, researchers in Italy led by Amelia Spinella, MD, PhD, of University Hospital of Modena, retrospectively tracked 45 patients with systemic sclerosis and at least one digital ulcer (40 women; average age, 53 years) who were treated in 2019. All patients’ ulcers were resistant to opioid therapy at the maximum tolerated dose, and all had undergone periodic iloprost infusion every 30-40 days. Based on each patient’s clinical situation, they had received calcium-channel blockers, phosphodiesterase type 5 inhibitors (sildenafil), and/or endothelin receptor antagonists (bosentan or macitentan). The researchers noted that all patients underwent surgical debridement regularly following wound bed preparation procedures and received advanced dressings (alginate, hydrocolloid, hydrofiber, hydrogel, and polyurethane foam or film). Of the 45 patients, 25 treated their wounds daily over the course of a month by administering four drops of a preparation of 10% CBD oil in acidic form and 90% hemp oil over the wound bed and perilesional skin and then covering it with a nonadhesive cloth.

“Basal wound-related pain NRS [numeric rating scale] scores decreased from 8.4 (standard deviation [SD], 0.8) at the baseline (T0) to 6.0 (SD, 0.82) after 1 month of CBD treatment (T1; P < .0001),” the researchers reported. “Across the same time period, volitional incident pain NRS scores decreased from 9.32 (SD, 0.75; T0) to 6.8 (SD, 1.12; T1; P < .0001). In addition, mean total hours of sleep per night increased from 2.56 (SD, 1.28) to 5.67 (SD, 0.85) hours (P < .0001).” Twelve of the 25 needed additional painkiller therapy.

Complete digital ulcer healing occurred by the end of the study in 18 of 25 (72%) CBD-treated patients, compared with 6 of 20 (30%) control patients.

In contrast, the control group didn’t see any significant improvement in wound-related pain, volitional incident pain, or sleep. All needed additional painkiller therapy. Six developed ulcer infections and received antibiotics.

No significant adverse effects were reported, although 28% of those in the CBD oil group said they had mild effects such as itch and perilesional erythema.

The authors of the new study called for larger, randomized controlled, multicenter trials to confirm the benefit of CBD topical treatment.

In recent years, researchers have devoted more attention to topical CBD as a treatment for skin conditions. While limited, the evidence suggests they “may be effective for the treatment of various inflammatory skin disorders,” researchers wrote in a 2022 report. “Although promising, additional research is necessary to evaluate efficacy and to determine dosing, safety, and long-term treatment guidelines.”

Dr. Griffith, who did not take part in the new study but is familiar with its findings, said she was especially surprised by the hint that topical CBD improves healing in addition to relieving symptoms. “I thought only pain would be affected. This is a great outcome if it can be replicated.”

As for future research, she said “there are difficulties with reproducing this at a big scale in the U.S. given CBD commercial variability. The big issue is the standardization of CBD extraction and production. It is really hard for us as physicians to know what patients are getting. Some online CBD orders contain THC [the major psychoactive ingredient of cannabis] > 0.3% or no CBD at all.”

Still, she said, “physicians and patients may consider this when standard therapies are not working or causing too many adverse effects,” especially since “the downsides here seem fairly minimal – at worst itchiness and redness that did not prevent patients from continuing in the study.”

No details about study funding were provided. The authors and Dr. Griffith report no disclosures.

Topical cannabidiol (CBD) oil appeared to lower pain scores and reduce painkiller use vs. standard treatment in patients with digital ulcers due to systemic sclerosis, a small new study finds. Patients who received the treatment also showed signs of more healing.

The study, published in Advances in Skin & Wound Care, is far from definitive since it’s retrospective and tracked only 45 patients. But the findings add to other research suggesting dermatologic benefits from the topical use of CBD, an ingredient in cannabis that’s widely available and doesn’t cause people to become high or become addicted.

Anatoliy Sizov/Getty Images

“This is a good first step in trying to address scleroderma digital ulcer pain and healing,” University of Colorado rheumatologist Melissa Griffith, MD, said in an interview. “Digital ulcers cause great impact on quality of life, daily activities of living, and pain, so we are always looking for new, effective tools.”

According to Dr. Griffith, digital ulcers occur in scleroderma due to Raynaud’s phenomenon with reversible vasospasm. “Unlike patients with primary Raynaud’s phenomenon, patients will develop ischemia of digits, leading to digital ulcers due to the vasculopathy or vascular remodeling that occurs in scleroderma,” she said.

Current treatments include removal of causative drugs/toxins and warmth, rest, and pain control, although “no trials exist to compare the scleroderma digital ulcer or digital ischemia treatments to each other,” Dr. Griffith said.

Therapy for vasospasm begins with calcium channel blockers such as amlodipine and nifedipine, she said, followed by phosphodiesterase type 5 inhibitors such as sildenafil or endothelin receptor antagonist medications such as bosentan. “If these fail, we use an IV option – epoprostenol. Other options are sympathectomy surgery, Botox, digital nerve blocks, biofeedback, and SSRIs,” she said. “These treatments work fairly well in most patients, but there are patients who break through these therapies and have ongoing digital ischemia, leading to digital ulcers, pain, infections, acro-osteolysis, and auto-amputation. There is definitely room to improve on our current treatment paradigm.”

For the new study, researchers in Italy led by Amelia Spinella, MD, PhD, of University Hospital of Modena, retrospectively tracked 45 patients with systemic sclerosis and at least one digital ulcer (40 women; average age, 53 years) who were treated in 2019. All patients’ ulcers were resistant to opioid therapy at the maximum tolerated dose, and all had undergone periodic iloprost infusion every 30-40 days. Based on each patient’s clinical situation, they had received calcium-channel blockers, phosphodiesterase type 5 inhibitors (sildenafil), and/or endothelin receptor antagonists (bosentan or macitentan). The researchers noted that all patients underwent surgical debridement regularly following wound bed preparation procedures and received advanced dressings (alginate, hydrocolloid, hydrofiber, hydrogel, and polyurethane foam or film). Of the 45 patients, 25 treated their wounds daily over the course of a month by administering four drops of a preparation of 10% CBD oil in acidic form and 90% hemp oil over the wound bed and perilesional skin and then covering it with a nonadhesive cloth.

“Basal wound-related pain NRS [numeric rating scale] scores decreased from 8.4 (standard deviation [SD], 0.8) at the baseline (T0) to 6.0 (SD, 0.82) after 1 month of CBD treatment (T1; P < .0001),” the researchers reported. “Across the same time period, volitional incident pain NRS scores decreased from 9.32 (SD, 0.75; T0) to 6.8 (SD, 1.12; T1; P < .0001). In addition, mean total hours of sleep per night increased from 2.56 (SD, 1.28) to 5.67 (SD, 0.85) hours (P < .0001).” Twelve of the 25 needed additional painkiller therapy.

Complete digital ulcer healing occurred by the end of the study in 18 of 25 (72%) CBD-treated patients, compared with 6 of 20 (30%) control patients.

In contrast, the control group didn’t see any significant improvement in wound-related pain, volitional incident pain, or sleep. All needed additional painkiller therapy. Six developed ulcer infections and received antibiotics.

No significant adverse effects were reported, although 28% of those in the CBD oil group said they had mild effects such as itch and perilesional erythema.

The authors of the new study called for larger, randomized controlled, multicenter trials to confirm the benefit of CBD topical treatment.

In recent years, researchers have devoted more attention to topical CBD as a treatment for skin conditions. While limited, the evidence suggests they “may be effective for the treatment of various inflammatory skin disorders,” researchers wrote in a 2022 report. “Although promising, additional research is necessary to evaluate efficacy and to determine dosing, safety, and long-term treatment guidelines.”

Dr. Griffith, who did not take part in the new study but is familiar with its findings, said she was especially surprised by the hint that topical CBD improves healing in addition to relieving symptoms. “I thought only pain would be affected. This is a great outcome if it can be replicated.”

As for future research, she said “there are difficulties with reproducing this at a big scale in the U.S. given CBD commercial variability. The big issue is the standardization of CBD extraction and production. It is really hard for us as physicians to know what patients are getting. Some online CBD orders contain THC [the major psychoactive ingredient of cannabis] > 0.3% or no CBD at all.”

Still, she said, “physicians and patients may consider this when standard therapies are not working or causing too many adverse effects,” especially since “the downsides here seem fairly minimal – at worst itchiness and redness that did not prevent patients from continuing in the study.”

No details about study funding were provided. The authors and Dr. Griffith report no disclosures.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Clinical cardiologist Heba Wassif, MD, MPH, knows the value of working with her fellow rheumatologists, surgeons, and other clinicians to establish a care plan for her patients with cardiac conditions and autoimmune diseases.

She is the cofounder of the Cleveland Clinic’s new cardio-rheumatology program, which places an emphasis on multidisciplinary care. In her role, Dr. Wassif closely follows her patients, and if she sees any inflammation or any other condition that requires the rheumatologist, she reaches out to her colleagues to adjust medications if needed.

Collaboration with a rheumatologist was important when a patient with valvular disease was prepping for surgery. The patient was on significant immunosuppressants and the surgery had to be timed appropriately, accounting for any decreases in her immunosuppression, explained Dr. Wassif, director of inpatient clinical cardiology at Cleveland Clinic in Ohio.

Cardio-rheumatology programs are “the newest child” in a series of cardiology offshoots focusing on different populations. Cardio-oncology and cardio-obstetrics took off about 6 years ago, with cardio-rheumatology clinics and interested physicians rising in number over the last several years, Dr. Wassif noted.

The relationship between cardiovascular diseases and rheumatologic conditions is certainly recognized more often, “which means more literature is being published to discuss the link,” according to Rekha Mankad, MD, a trailblazer of this model of care. She directs the Women’s Heart Clinic at Mayo Clinic in Rochester, Minn., which was one of the earliest adopters of a cardio-rheumatology clinic.

Challenges of treating cardiac, rheumatologic conditions

The rise in clinics addresses the longstanding connection between autoimmune disorders and cardiac conditions.

Cardiologists have known that there is an element of inflammation that contributes to atherosclerosis, said Dr. Wassif, who has researched this topic extensively. A recent study she led found a strong association between rheumatic immune-mediated inflammatory diseases (IMIDs) and high risk of acute coronary syndrome in Medicare patients.

“This particular population has a very clear increased risk for cardiovascular conditions, including valve disease and heart failure,” she emphasized.

Patients with rheumatoid arthritis and lupus have up to a twofold and eightfold higher risk of heart disease, respectively, noted Michael S. Garshick, MD, a cardiovascular disease specialist who directs the cardio-rheumatology program at NYU-Langone Health, in New York. Cardiologists “have really developed an understanding that the immune system can impact the heart, and that there’s a need for people to understand the nuance behind how the immune system can affect them and what to do about it,” Dr. Garshick said.

Courtesy Rob Lisak

‘Reading the tea leaves’

Each program has its own unique story. For the Cleveland Clinic, the concept of a cardio-rheumatology program began during the COVID-19 pandemic in 2020. Developing such a concept and gaining institutional acceptance is always a work in process, Dr. Wassif said. “It’s not that you decide one day that you’re going to build a center, and that center is going to come into fruition overnight. You first gauge interest within your division. Who are the individuals that are interested in this area?”

Cleveland Clinic’s center is seeking to build relations between medical disciplines while spotlighting the concept of cardio-rheumatology, said Dr. Wassif, who has been providing education within the clinic and at other health institutions to ensure that patients receive appropriate attention early.

NYU-Langone launched its program amid this heightened awareness that the immune system could affect atherosclerosis, “kind of reading of the tea leaves, so to speak,” Dr. Garshick said.

Several clinical trials served as a catalyst for this movement. “A lot of clinical cardiologists were never 100% convinced that targeting the immune system reduced cardiovascular disease,” he said. Then the CANTOS clinical trial came along and showed for the first time that a therapeutic monoclonal antibody targeting interleukin-1beta, a cytokine central to inflammatory response, could in fact reduce cardiovascular disease.

Trials like this, along with epidemiologic literature connecting the rheumatologic and the autoimmune conditions with cardiovascular disease, pushed this concept to the forefront, Dr. Garshick said.

The notion that a clinic could successfully address cardiac problems in patients with rheumatic diseases yielded promising returns at Women’s College Hospital in Toronto, according to a report presented at the 2018 American College of Rheumatology annual meeting. Researchers reported that patients with rheumatologic conditions who attended a cardio-rheumatology clinic at this center saw improvements in care. The clinic identified increased cardiovascular risk and early atherosclerosis, and 53.8% of patients altered their medications after being seen in the clinic.

A total of 39.7% and 32.1% received lipid lowering and antiplatelet therapies, respectively, and 14% received antihypertensive therapy. A small percentage were treated for heart failure or placed on lifelong anticoagulation therapy for atrial fibrillation, and one patient received a percutaneous coronary stent.
 

Ins and outs of the referral process

Initially designed for preventive cardiac risk assessment, Yale’s program evolved into a multidisciplinary, patient-centered approach for the management of complex cardiovascular conditions in patients with autoimmune rheumatologic diseases.

The program is open to anyone who carries a diagnosis of rheumatologic disease or has elevated inflammatory markers. “Every patient, regardless of the reason for the referral, receives a cardiovascular risk assessment,” Dr. Furman said.

Harold Shapiro

A personalized assessment to reduce cardiac risk

NYU-Langone’s program offers opportunities to educate patients about the link between cardiac and rheumatologic disease.

“Their rheumatologist or their dermatologist will say, ‘Hey, have you heard about the connection between psoriasis, psoriatic or rheumatoid arthritis, and heart disease and the risk of heart attack or stroke?’ ” Dr. Garshick said.

The patients will often say they know nothing about these connections and want to learn more about how to treat it.

“We’ll say, ‘we have someone here that can help you.’ They’ll send them to myself or other colleagues like me across the country. We’ll assess blood pressure, weight, lipids, hemoglobin A1c, and other serologic and oftentimes imaging biomarkers of cardiovascular risk.” The patients will receive a personalized assessment, listing things they can do to lower their risk, whether it’s diet, exercise, or lifestyle. “Many times it can involve medications to reduce heart disease risk,” said Dr. Garshick.

In some instances, a rheumatologist or dermatologist may be concerned about starting a patient on a specific medication for the disease such as a JAK inhibitor. “We’ll help assess their risk because there’s been a lot of literature out in the rheumatology world about the risk of JAK inhibitors and heart disease and blood clots,” said Dr. Garshick.

Dr. Garshick also sees patients with rheumatologic conditions who have a specific cardiovascular concern or complaint such as shortness of breath or chest pain. “We’ll work that up with a specific knowledge of the underlying immune condition and how that may impact their heart,” he said.
 

Advances in research

As they continue to see patients and devise specific care plans, developers of cardio-rheumatology programs have been supplementing their work with ongoing research.

Yale’s clinic is expanding this year to include a new attending physician, Attila Feher, MD, PhD, who has conducted research in autoimmunity and microcirculation using molecular imaging and multimodality imaging techniques. Prevalence of coronary microvascular dysfunction appears to be increased in this patient population, Dr. Furman said.

Dr. Wassif recently coauthored a paper that examined patients with underlying rheumatologic conditions who undergo valvular and aortic valve replacement. “To our surprise, there was really no difference between patients with autoimmune conditions and others with nonautoimmune conditions,” she said, adding that the study had its limitations.

Other work includes data on Medicare patients with ST- and non-ST-elevation myocardial infarctions who have an underlying autoimmune disorder. Dr. Wassif and her colleagues found that their long-term outcomes are worse than those of patients without these conditions. “It’s unclear if worse outcomes are related to complications of autoimmunity versus the extent of their underlying disease. This is a work in progress and certainly an area that is ripe for research.”

Dr. Garshick and other collaborators at NYU have been focusing on the endothelium, specifically platelet biology in patients with psoriasis, psoriatic arthritis, and lupus. “We’re about to start the same research with gout as well,” he said.

“The process we’re most interested in is understanding how these diseases impact the early stages of cholesterol. And the way we’re doing that is evaluating the vasculature, specifically the endothelium,” he said.

He has finished two clinical trials that evaluate how standard heart disease medications such as aspirin and statins impact or can potentially benefit patients with psoriasis and/or psoriatic arthritis. “We have a whole list of other trials in the pipeline with other institutions across the country.”

Through a grant, Dr. Mankad is assessing whether a PET scan could detect inflammation in the hearts of rheumatoid arthritis patients. “We’re looking to see if the reason these patients have heart failure later in life is because their heart muscle actually shows evidence of inflammation, even when they have no symptoms,” she explained.

Other tests such as echocardiogram and CT scans will be used to evaluate coronary disease in about 40-50 patients. The goal of using these multiple imaging tools is to find markers indicating that the heart is affected by rheumatoid arthritis, which may indicate a higher likelihood of developing heart failure, she said.
 

Clinics are popping up

Through these new clinics, some collaborations have emerged. Dr. Garshick works closely with Brigham and Women’s Hospital, which has a similar cardio-rheumatology program, run by Brittany Weber, MD, to exchange ideas, discuss challenging cases, and collaborate.

“There are a lot of clinics like us popping up across the country,” he observed. Every so often, he hears from other institutions that are interested in starting their own cardio-rheumatology programs. “They ask us: How do you start, what should we look for?”

It’s an education process for both patients and providers, Dr. Garshick emphasized. “I also think it’s a bandwidth issue. Many of our rheumatology and dermatology colleagues are acutely aware of the connection, but there may not be enough time at a clinic visit to really go in depth” with these dual conditions, he said.

NYU-Langone Health for the past several years has been holding a symposium to educate people on the cardio-rheumatology connection and treating inflammation in cardiovascular disease. This year’s symposium, held in conjunction with Brigham and Women’s Hospital, is scheduled for April 28. For more information, visit the course website: nyulmc.org/cvinflammationcme.

“What we’re trying to do is help [other institutions] get that bandwidth” to adequately help and serve these patients, he said.

Dr. Garshick has received consultant fees from Abbvie and Horizon therapeutics and an unrestricted research grant from Pfizer. No other sources had relevant financial disclosures.

Clinical cardiologist Heba Wassif, MD, MPH, knows the value of working with her fellow rheumatologists, surgeons, and other clinicians to establish a care plan for her patients with cardiac conditions and autoimmune diseases.

She is the cofounder of the Cleveland Clinic’s new cardio-rheumatology program, which places an emphasis on multidisciplinary care. In her role, Dr. Wassif closely follows her patients, and if she sees any inflammation or any other condition that requires the rheumatologist, she reaches out to her colleagues to adjust medications if needed.

Collaboration with a rheumatologist was important when a patient with valvular disease was prepping for surgery. The patient was on significant immunosuppressants and the surgery had to be timed appropriately, accounting for any decreases in her immunosuppression, explained Dr. Wassif, director of inpatient clinical cardiology at Cleveland Clinic in Ohio.

Cardio-rheumatology programs are “the newest child” in a series of cardiology offshoots focusing on different populations. Cardio-oncology and cardio-obstetrics took off about 6 years ago, with cardio-rheumatology clinics and interested physicians rising in number over the last several years, Dr. Wassif noted.

The relationship between cardiovascular diseases and rheumatologic conditions is certainly recognized more often, “which means more literature is being published to discuss the link,” according to Rekha Mankad, MD, a trailblazer of this model of care. She directs the Women’s Heart Clinic at Mayo Clinic in Rochester, Minn., which was one of the earliest adopters of a cardio-rheumatology clinic.

Challenges of treating cardiac, rheumatologic conditions

The rise in clinics addresses the longstanding connection between autoimmune disorders and cardiac conditions.

Cardiologists have known that there is an element of inflammation that contributes to atherosclerosis, said Dr. Wassif, who has researched this topic extensively. A recent study she led found a strong association between rheumatic immune-mediated inflammatory diseases (IMIDs) and high risk of acute coronary syndrome in Medicare patients.

“This particular population has a very clear increased risk for cardiovascular conditions, including valve disease and heart failure,” she emphasized.

Patients with rheumatoid arthritis and lupus have up to a twofold and eightfold higher risk of heart disease, respectively, noted Michael S. Garshick, MD, a cardiovascular disease specialist who directs the cardio-rheumatology program at NYU-Langone Health, in New York. Cardiologists “have really developed an understanding that the immune system can impact the heart, and that there’s a need for people to understand the nuance behind how the immune system can affect them and what to do about it,” Dr. Garshick said.

Courtesy Rob Lisak

‘Reading the tea leaves’

Each program has its own unique story. For the Cleveland Clinic, the concept of a cardio-rheumatology program began during the COVID-19 pandemic in 2020. Developing such a concept and gaining institutional acceptance is always a work in process, Dr. Wassif said. “It’s not that you decide one day that you’re going to build a center, and that center is going to come into fruition overnight. You first gauge interest within your division. Who are the individuals that are interested in this area?”

Cleveland Clinic’s center is seeking to build relations between medical disciplines while spotlighting the concept of cardio-rheumatology, said Dr. Wassif, who has been providing education within the clinic and at other health institutions to ensure that patients receive appropriate attention early.

NYU-Langone launched its program amid this heightened awareness that the immune system could affect atherosclerosis, “kind of reading of the tea leaves, so to speak,” Dr. Garshick said.

Several clinical trials served as a catalyst for this movement. “A lot of clinical cardiologists were never 100% convinced that targeting the immune system reduced cardiovascular disease,” he said. Then the CANTOS clinical trial came along and showed for the first time that a therapeutic monoclonal antibody targeting interleukin-1beta, a cytokine central to inflammatory response, could in fact reduce cardiovascular disease.

Trials like this, along with epidemiologic literature connecting the rheumatologic and the autoimmune conditions with cardiovascular disease, pushed this concept to the forefront, Dr. Garshick said.

The notion that a clinic could successfully address cardiac problems in patients with rheumatic diseases yielded promising returns at Women’s College Hospital in Toronto, according to a report presented at the 2018 American College of Rheumatology annual meeting. Researchers reported that patients with rheumatologic conditions who attended a cardio-rheumatology clinic at this center saw improvements in care. The clinic identified increased cardiovascular risk and early atherosclerosis, and 53.8% of patients altered their medications after being seen in the clinic.

A total of 39.7% and 32.1% received lipid lowering and antiplatelet therapies, respectively, and 14% received antihypertensive therapy. A small percentage were treated for heart failure or placed on lifelong anticoagulation therapy for atrial fibrillation, and one patient received a percutaneous coronary stent.
 

Ins and outs of the referral process

Initially designed for preventive cardiac risk assessment, Yale’s program evolved into a multidisciplinary, patient-centered approach for the management of complex cardiovascular conditions in patients with autoimmune rheumatologic diseases.

The program is open to anyone who carries a diagnosis of rheumatologic disease or has elevated inflammatory markers. “Every patient, regardless of the reason for the referral, receives a cardiovascular risk assessment,” Dr. Furman said.

Harold Shapiro

A personalized assessment to reduce cardiac risk

NYU-Langone’s program offers opportunities to educate patients about the link between cardiac and rheumatologic disease.

“Their rheumatologist or their dermatologist will say, ‘Hey, have you heard about the connection between psoriasis, psoriatic or rheumatoid arthritis, and heart disease and the risk of heart attack or stroke?’ ” Dr. Garshick said.

The patients will often say they know nothing about these connections and want to learn more about how to treat it.

“We’ll say, ‘we have someone here that can help you.’ They’ll send them to myself or other colleagues like me across the country. We’ll assess blood pressure, weight, lipids, hemoglobin A1c, and other serologic and oftentimes imaging biomarkers of cardiovascular risk.” The patients will receive a personalized assessment, listing things they can do to lower their risk, whether it’s diet, exercise, or lifestyle. “Many times it can involve medications to reduce heart disease risk,” said Dr. Garshick.

In some instances, a rheumatologist or dermatologist may be concerned about starting a patient on a specific medication for the disease such as a JAK inhibitor. “We’ll help assess their risk because there’s been a lot of literature out in the rheumatology world about the risk of JAK inhibitors and heart disease and blood clots,” said Dr. Garshick.

Dr. Garshick also sees patients with rheumatologic conditions who have a specific cardiovascular concern or complaint such as shortness of breath or chest pain. “We’ll work that up with a specific knowledge of the underlying immune condition and how that may impact their heart,” he said.
 

Advances in research

As they continue to see patients and devise specific care plans, developers of cardio-rheumatology programs have been supplementing their work with ongoing research.

Yale’s clinic is expanding this year to include a new attending physician, Attila Feher, MD, PhD, who has conducted research in autoimmunity and microcirculation using molecular imaging and multimodality imaging techniques. Prevalence of coronary microvascular dysfunction appears to be increased in this patient population, Dr. Furman said.

Dr. Wassif recently coauthored a paper that examined patients with underlying rheumatologic conditions who undergo valvular and aortic valve replacement. “To our surprise, there was really no difference between patients with autoimmune conditions and others with nonautoimmune conditions,” she said, adding that the study had its limitations.

Other work includes data on Medicare patients with ST- and non-ST-elevation myocardial infarctions who have an underlying autoimmune disorder. Dr. Wassif and her colleagues found that their long-term outcomes are worse than those of patients without these conditions. “It’s unclear if worse outcomes are related to complications of autoimmunity versus the extent of their underlying disease. This is a work in progress and certainly an area that is ripe for research.”

Dr. Garshick and other collaborators at NYU have been focusing on the endothelium, specifically platelet biology in patients with psoriasis, psoriatic arthritis, and lupus. “We’re about to start the same research with gout as well,” he said.

“The process we’re most interested in is understanding how these diseases impact the early stages of cholesterol. And the way we’re doing that is evaluating the vasculature, specifically the endothelium,” he said.

He has finished two clinical trials that evaluate how standard heart disease medications such as aspirin and statins impact or can potentially benefit patients with psoriasis and/or psoriatic arthritis. “We have a whole list of other trials in the pipeline with other institutions across the country.”

Through a grant, Dr. Mankad is assessing whether a PET scan could detect inflammation in the hearts of rheumatoid arthritis patients. “We’re looking to see if the reason these patients have heart failure later in life is because their heart muscle actually shows evidence of inflammation, even when they have no symptoms,” she explained.

Other tests such as echocardiogram and CT scans will be used to evaluate coronary disease in about 40-50 patients. The goal of using these multiple imaging tools is to find markers indicating that the heart is affected by rheumatoid arthritis, which may indicate a higher likelihood of developing heart failure, she said.
 

Clinics are popping up

Through these new clinics, some collaborations have emerged. Dr. Garshick works closely with Brigham and Women’s Hospital, which has a similar cardio-rheumatology program, run by Brittany Weber, MD, to exchange ideas, discuss challenging cases, and collaborate.

“There are a lot of clinics like us popping up across the country,” he observed. Every so often, he hears from other institutions that are interested in starting their own cardio-rheumatology programs. “They ask us: How do you start, what should we look for?”

It’s an education process for both patients and providers, Dr. Garshick emphasized. “I also think it’s a bandwidth issue. Many of our rheumatology and dermatology colleagues are acutely aware of the connection, but there may not be enough time at a clinic visit to really go in depth” with these dual conditions, he said.

NYU-Langone Health for the past several years has been holding a symposium to educate people on the cardio-rheumatology connection and treating inflammation in cardiovascular disease. This year’s symposium, held in conjunction with Brigham and Women’s Hospital, is scheduled for April 28. For more information, visit the course website: nyulmc.org/cvinflammationcme.

“What we’re trying to do is help [other institutions] get that bandwidth” to adequately help and serve these patients, he said.

Dr. Garshick has received consultant fees from Abbvie and Horizon therapeutics and an unrestricted research grant from Pfizer. No other sources had relevant financial disclosures.

Clinical cardiologist Heba Wassif, MD, MPH, knows the value of working with her fellow rheumatologists, surgeons, and other clinicians to establish a care plan for her patients with cardiac conditions and autoimmune diseases.

She is the cofounder of the Cleveland Clinic’s new cardio-rheumatology program, which places an emphasis on multidisciplinary care. In her role, Dr. Wassif closely follows her patients, and if she sees any inflammation or any other condition that requires the rheumatologist, she reaches out to her colleagues to adjust medications if needed.

Collaboration with a rheumatologist was important when a patient with valvular disease was prepping for surgery. The patient was on significant immunosuppressants and the surgery had to be timed appropriately, accounting for any decreases in her immunosuppression, explained Dr. Wassif, director of inpatient clinical cardiology at Cleveland Clinic in Ohio.

Cardio-rheumatology programs are “the newest child” in a series of cardiology offshoots focusing on different populations. Cardio-oncology and cardio-obstetrics took off about 6 years ago, with cardio-rheumatology clinics and interested physicians rising in number over the last several years, Dr. Wassif noted.

The relationship between cardiovascular diseases and rheumatologic conditions is certainly recognized more often, “which means more literature is being published to discuss the link,” according to Rekha Mankad, MD, a trailblazer of this model of care. She directs the Women’s Heart Clinic at Mayo Clinic in Rochester, Minn., which was one of the earliest adopters of a cardio-rheumatology clinic.

Challenges of treating cardiac, rheumatologic conditions

The rise in clinics addresses the longstanding connection between autoimmune disorders and cardiac conditions.

Cardiologists have known that there is an element of inflammation that contributes to atherosclerosis, said Dr. Wassif, who has researched this topic extensively. A recent study she led found a strong association between rheumatic immune-mediated inflammatory diseases (IMIDs) and high risk of acute coronary syndrome in Medicare patients.

“This particular population has a very clear increased risk for cardiovascular conditions, including valve disease and heart failure,” she emphasized.

Patients with rheumatoid arthritis and lupus have up to a twofold and eightfold higher risk of heart disease, respectively, noted Michael S. Garshick, MD, a cardiovascular disease specialist who directs the cardio-rheumatology program at NYU-Langone Health, in New York. Cardiologists “have really developed an understanding that the immune system can impact the heart, and that there’s a need for people to understand the nuance behind how the immune system can affect them and what to do about it,” Dr. Garshick said.

Courtesy Rob Lisak

‘Reading the tea leaves’

Each program has its own unique story. For the Cleveland Clinic, the concept of a cardio-rheumatology program began during the COVID-19 pandemic in 2020. Developing such a concept and gaining institutional acceptance is always a work in process, Dr. Wassif said. “It’s not that you decide one day that you’re going to build a center, and that center is going to come into fruition overnight. You first gauge interest within your division. Who are the individuals that are interested in this area?”

Cleveland Clinic’s center is seeking to build relations between medical disciplines while spotlighting the concept of cardio-rheumatology, said Dr. Wassif, who has been providing education within the clinic and at other health institutions to ensure that patients receive appropriate attention early.

NYU-Langone launched its program amid this heightened awareness that the immune system could affect atherosclerosis, “kind of reading of the tea leaves, so to speak,” Dr. Garshick said.

Several clinical trials served as a catalyst for this movement. “A lot of clinical cardiologists were never 100% convinced that targeting the immune system reduced cardiovascular disease,” he said. Then the CANTOS clinical trial came along and showed for the first time that a therapeutic monoclonal antibody targeting interleukin-1beta, a cytokine central to inflammatory response, could in fact reduce cardiovascular disease.

Trials like this, along with epidemiologic literature connecting the rheumatologic and the autoimmune conditions with cardiovascular disease, pushed this concept to the forefront, Dr. Garshick said.

The notion that a clinic could successfully address cardiac problems in patients with rheumatic diseases yielded promising returns at Women’s College Hospital in Toronto, according to a report presented at the 2018 American College of Rheumatology annual meeting. Researchers reported that patients with rheumatologic conditions who attended a cardio-rheumatology clinic at this center saw improvements in care. The clinic identified increased cardiovascular risk and early atherosclerosis, and 53.8% of patients altered their medications after being seen in the clinic.

A total of 39.7% and 32.1% received lipid lowering and antiplatelet therapies, respectively, and 14% received antihypertensive therapy. A small percentage were treated for heart failure or placed on lifelong anticoagulation therapy for atrial fibrillation, and one patient received a percutaneous coronary stent.
 

Ins and outs of the referral process

Initially designed for preventive cardiac risk assessment, Yale’s program evolved into a multidisciplinary, patient-centered approach for the management of complex cardiovascular conditions in patients with autoimmune rheumatologic diseases.

The program is open to anyone who carries a diagnosis of rheumatologic disease or has elevated inflammatory markers. “Every patient, regardless of the reason for the referral, receives a cardiovascular risk assessment,” Dr. Furman said.

Harold Shapiro

A personalized assessment to reduce cardiac risk

NYU-Langone’s program offers opportunities to educate patients about the link between cardiac and rheumatologic disease.

“Their rheumatologist or their dermatologist will say, ‘Hey, have you heard about the connection between psoriasis, psoriatic or rheumatoid arthritis, and heart disease and the risk of heart attack or stroke?’ ” Dr. Garshick said.

The patients will often say they know nothing about these connections and want to learn more about how to treat it.

“We’ll say, ‘we have someone here that can help you.’ They’ll send them to myself or other colleagues like me across the country. We’ll assess blood pressure, weight, lipids, hemoglobin A1c, and other serologic and oftentimes imaging biomarkers of cardiovascular risk.” The patients will receive a personalized assessment, listing things they can do to lower their risk, whether it’s diet, exercise, or lifestyle. “Many times it can involve medications to reduce heart disease risk,” said Dr. Garshick.

In some instances, a rheumatologist or dermatologist may be concerned about starting a patient on a specific medication for the disease such as a JAK inhibitor. “We’ll help assess their risk because there’s been a lot of literature out in the rheumatology world about the risk of JAK inhibitors and heart disease and blood clots,” said Dr. Garshick.

Dr. Garshick also sees patients with rheumatologic conditions who have a specific cardiovascular concern or complaint such as shortness of breath or chest pain. “We’ll work that up with a specific knowledge of the underlying immune condition and how that may impact their heart,” he said.
 

Advances in research

As they continue to see patients and devise specific care plans, developers of cardio-rheumatology programs have been supplementing their work with ongoing research.

Yale’s clinic is expanding this year to include a new attending physician, Attila Feher, MD, PhD, who has conducted research in autoimmunity and microcirculation using molecular imaging and multimodality imaging techniques. Prevalence of coronary microvascular dysfunction appears to be increased in this patient population, Dr. Furman said.

Dr. Wassif recently coauthored a paper that examined patients with underlying rheumatologic conditions who undergo valvular and aortic valve replacement. “To our surprise, there was really no difference between patients with autoimmune conditions and others with nonautoimmune conditions,” she said, adding that the study had its limitations.

Other work includes data on Medicare patients with ST- and non-ST-elevation myocardial infarctions who have an underlying autoimmune disorder. Dr. Wassif and her colleagues found that their long-term outcomes are worse than those of patients without these conditions. “It’s unclear if worse outcomes are related to complications of autoimmunity versus the extent of their underlying disease. This is a work in progress and certainly an area that is ripe for research.”

Dr. Garshick and other collaborators at NYU have been focusing on the endothelium, specifically platelet biology in patients with psoriasis, psoriatic arthritis, and lupus. “We’re about to start the same research with gout as well,” he said.

“The process we’re most interested in is understanding how these diseases impact the early stages of cholesterol. And the way we’re doing that is evaluating the vasculature, specifically the endothelium,” he said.

He has finished two clinical trials that evaluate how standard heart disease medications such as aspirin and statins impact or can potentially benefit patients with psoriasis and/or psoriatic arthritis. “We have a whole list of other trials in the pipeline with other institutions across the country.”

Through a grant, Dr. Mankad is assessing whether a PET scan could detect inflammation in the hearts of rheumatoid arthritis patients. “We’re looking to see if the reason these patients have heart failure later in life is because their heart muscle actually shows evidence of inflammation, even when they have no symptoms,” she explained.

Other tests such as echocardiogram and CT scans will be used to evaluate coronary disease in about 40-50 patients. The goal of using these multiple imaging tools is to find markers indicating that the heart is affected by rheumatoid arthritis, which may indicate a higher likelihood of developing heart failure, she said.
 

Clinics are popping up

Through these new clinics, some collaborations have emerged. Dr. Garshick works closely with Brigham and Women’s Hospital, which has a similar cardio-rheumatology program, run by Brittany Weber, MD, to exchange ideas, discuss challenging cases, and collaborate.

“There are a lot of clinics like us popping up across the country,” he observed. Every so often, he hears from other institutions that are interested in starting their own cardio-rheumatology programs. “They ask us: How do you start, what should we look for?”

It’s an education process for both patients and providers, Dr. Garshick emphasized. “I also think it’s a bandwidth issue. Many of our rheumatology and dermatology colleagues are acutely aware of the connection, but there may not be enough time at a clinic visit to really go in depth” with these dual conditions, he said.

NYU-Langone Health for the past several years has been holding a symposium to educate people on the cardio-rheumatology connection and treating inflammation in cardiovascular disease. This year’s symposium, held in conjunction with Brigham and Women’s Hospital, is scheduled for April 28. For more information, visit the course website: nyulmc.org/cvinflammationcme.

“What we’re trying to do is help [other institutions] get that bandwidth” to adequately help and serve these patients, he said.

Dr. Garshick has received consultant fees from Abbvie and Horizon therapeutics and an unrestricted research grant from Pfizer. No other sources had relevant financial disclosures.

A new study likely makes the best estimate yet of the degree of retinopathy risk that patients who take the antimalarial drug hydroxychloroquine (HCQ) can expect, deriving mainly from the cumulative dose taken during the first 5 years of use, according to a study published in Annals of Internal Medicine.

HCQ works to decrease activity in a patient’s immune system, which is effective in many cases of systemic lupus erythematosus, one of the most common indications for the drug. However, an adverse outcome of treatment can be HCQ retinopathy, a progressive form of vision loss in patients taking HCQ over an extended period (mostly for longer than 5 years). The disease is often asymptomatic, although some patients do present a paracentral scotoma and a decrease in color vision. Patients may also notice flashing shapes in their vision and find that they have difficulty reading. Eventually, HCQ retinopathy can lead to loss of visual acuity, loss of peripheral vision, and loss of night vision.

Researchers from Kaiser Permanente Northern California and Harvard Medical School analyzed 3,325 persons who received HCQ for 5 or more years between 2004 and 2020. Their goal was to both characterize the long-term risk for incident HCQ retinopathy and examine the degree to which average HCQ dose within the first 5 years of treatment serves as a prediction of the risk.

The researchers then estimated the risk for developing retinopathy after 15 years, according to patients’ average dosing levels during the first 5 years of therapy. Overall, 81 participants developed HCQ retinopathy with overall cumulative incidences of 2.5% after 10 years and 8.6% after 15 years; the risk was greater for those given a higher dose during the first 5 years of treatment.

The mechanism of how HCQ toxicity may occur is still not completely known. There is evidence that toxicity happens because HCQ binds to melanin in both the retinal pigment epithelium and uvea in high concentrations. HCQ can interfere with lysosomal function, leading to oxidation and accumulation of lysosomes, which can cause dysfunction of the retinal pigment epithelium.

Progressive retinopathy can continue even after the drug is stopped. “It’s thought to be a very mild but important risk,” said Nilanjana Bose, MD, MBA, a rheumatologist with Memorial Hermann Health System in Houston. “Patients taking HCQ must be screened for retinal issues, most certainly elderly patients and patients with any kind of comorbidities.”

“Examination alone is not sufficient to evaluate early changes, and specialized testing must be done. These include color photos, visual field tests, optical coherence tomography, fundus autofluorescence and in some cases, multifocal electroretinogram. Also, the AAO [American Academy of Ophthalmology] has specific recommendations related to Asian patients as they may have a different pattern of retinopathy that must also be considered.”
 

More accurate risk measurements

This news organization asked study coauthor April Jorge, MD, assistant professor of medicine in the division of rheumatology, allergy, and immunology at Massachusetts General Hospital and Harvard Medical School, Boston, to discuss the study, how it correlates to past research, and what it adds that’s new and useful to rheumatologists and ophthalmologists:

Question: Your research found that a higher dose of HCQ in the first 5 years of treatment led to a greater risk of retinopathy. Is there any indication that a lower dose given more frequently, either within that 5-year period or longer, would pose a similar risk?

Answer: In our study, we assessed the HCQ dose in the first 5 years of use but followed patients who continued the medication longer than 5 years, through up to 15 years of use. Therefore, we compared the risk of HCQ retinopathy associated with different HCQ dosages but for the same duration of use. We found that for any dose of HCQ, the risk of retinopathy increases the longer the medication is used. However, patients who used a higher dose of HCQ had a higher risk of developing retinopathy over time.

Also unique to our study, we graded the severity of HCQ retinopathy outcomes. This was important, as we found that the majority of retinopathy cases detected through routine screening are mild and presumed to be asymptomatic. This will likely be reassuring news for patients that we can screen for this adverse event to detect it early and prevent vision loss.

Another important difference was that we assessed the risk of retinopathy associated with using over 6 mg/kg per day, between 5 and 6 mg/kg per day, and less than 5 mg/kg per day, whereas the highest dosing group assessed in the 2014 study included all patients using over 5 mg/kg per day. The risk was considerably higher in the > 6 mg/kg per day group than in the 5-6 mg/kg per day group.

Q: How can rheumatologists and ophthalmologists use this new information specifically to better treat their patients?

A: Our study provides more accurate estimates of the risk of HCQ retinopathy than in prior studies. These risk estimates can be used when rheumatologists (and other clinicians who prescribe HCQ) consider the risks and benefits of this otherwise important and well-tolerated medication. The risk associated with different dose ranges could also inform dosing decisions, since dosing over 6 mg/kg per day may be more of a concern than using doses in the 5-6 mg/kg range. Ophthalmologists can also use these new risk estimates to counsel patients of the importance of HCQ retinopathy screening and can also hopefully provide some reassurance to patients that the risk of severe retinopathy is low as long as they are being monitored.

The study authors were supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Rheumatology Research Foundation. The authors report no relevant financial relationships. Dr. Bose and Dr. Mirza had no relevant disclosures.

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

A new study likely makes the best estimate yet of the degree of retinopathy risk that patients who take the antimalarial drug hydroxychloroquine (HCQ) can expect, deriving mainly from the cumulative dose taken during the first 5 years of use, according to a study published in Annals of Internal Medicine.

HCQ works to decrease activity in a patient’s immune system, which is effective in many cases of systemic lupus erythematosus, one of the most common indications for the drug. However, an adverse outcome of treatment can be HCQ retinopathy, a progressive form of vision loss in patients taking HCQ over an extended period (mostly for longer than 5 years). The disease is often asymptomatic, although some patients do present a paracentral scotoma and a decrease in color vision. Patients may also notice flashing shapes in their vision and find that they have difficulty reading. Eventually, HCQ retinopathy can lead to loss of visual acuity, loss of peripheral vision, and loss of night vision.

Researchers from Kaiser Permanente Northern California and Harvard Medical School analyzed 3,325 persons who received HCQ for 5 or more years between 2004 and 2020. Their goal was to both characterize the long-term risk for incident HCQ retinopathy and examine the degree to which average HCQ dose within the first 5 years of treatment serves as a prediction of the risk.

The researchers then estimated the risk for developing retinopathy after 15 years, according to patients’ average dosing levels during the first 5 years of therapy. Overall, 81 participants developed HCQ retinopathy with overall cumulative incidences of 2.5% after 10 years and 8.6% after 15 years; the risk was greater for those given a higher dose during the first 5 years of treatment.

The mechanism of how HCQ toxicity may occur is still not completely known. There is evidence that toxicity happens because HCQ binds to melanin in both the retinal pigment epithelium and uvea in high concentrations. HCQ can interfere with lysosomal function, leading to oxidation and accumulation of lysosomes, which can cause dysfunction of the retinal pigment epithelium.

Progressive retinopathy can continue even after the drug is stopped. “It’s thought to be a very mild but important risk,” said Nilanjana Bose, MD, MBA, a rheumatologist with Memorial Hermann Health System in Houston. “Patients taking HCQ must be screened for retinal issues, most certainly elderly patients and patients with any kind of comorbidities.”

“Examination alone is not sufficient to evaluate early changes, and specialized testing must be done. These include color photos, visual field tests, optical coherence tomography, fundus autofluorescence and in some cases, multifocal electroretinogram. Also, the AAO [American Academy of Ophthalmology] has specific recommendations related to Asian patients as they may have a different pattern of retinopathy that must also be considered.”
 

More accurate risk measurements

This news organization asked study coauthor April Jorge, MD, assistant professor of medicine in the division of rheumatology, allergy, and immunology at Massachusetts General Hospital and Harvard Medical School, Boston, to discuss the study, how it correlates to past research, and what it adds that’s new and useful to rheumatologists and ophthalmologists:

Question: Your research found that a higher dose of HCQ in the first 5 years of treatment led to a greater risk of retinopathy. Is there any indication that a lower dose given more frequently, either within that 5-year period or longer, would pose a similar risk?

Answer: In our study, we assessed the HCQ dose in the first 5 years of use but followed patients who continued the medication longer than 5 years, through up to 15 years of use. Therefore, we compared the risk of HCQ retinopathy associated with different HCQ dosages but for the same duration of use. We found that for any dose of HCQ, the risk of retinopathy increases the longer the medication is used. However, patients who used a higher dose of HCQ had a higher risk of developing retinopathy over time.

Also unique to our study, we graded the severity of HCQ retinopathy outcomes. This was important, as we found that the majority of retinopathy cases detected through routine screening are mild and presumed to be asymptomatic. This will likely be reassuring news for patients that we can screen for this adverse event to detect it early and prevent vision loss.

Another important difference was that we assessed the risk of retinopathy associated with using over 6 mg/kg per day, between 5 and 6 mg/kg per day, and less than 5 mg/kg per day, whereas the highest dosing group assessed in the 2014 study included all patients using over 5 mg/kg per day. The risk was considerably higher in the > 6 mg/kg per day group than in the 5-6 mg/kg per day group.

Q: How can rheumatologists and ophthalmologists use this new information specifically to better treat their patients?

A: Our study provides more accurate estimates of the risk of HCQ retinopathy than in prior studies. These risk estimates can be used when rheumatologists (and other clinicians who prescribe HCQ) consider the risks and benefits of this otherwise important and well-tolerated medication. The risk associated with different dose ranges could also inform dosing decisions, since dosing over 6 mg/kg per day may be more of a concern than using doses in the 5-6 mg/kg range. Ophthalmologists can also use these new risk estimates to counsel patients of the importance of HCQ retinopathy screening and can also hopefully provide some reassurance to patients that the risk of severe retinopathy is low as long as they are being monitored.

The study authors were supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Rheumatology Research Foundation. The authors report no relevant financial relationships. Dr. Bose and Dr. Mirza had no relevant disclosures.

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

A new study likely makes the best estimate yet of the degree of retinopathy risk that patients who take the antimalarial drug hydroxychloroquine (HCQ) can expect, deriving mainly from the cumulative dose taken during the first 5 years of use, according to a study published in Annals of Internal Medicine.

HCQ works to decrease activity in a patient’s immune system, which is effective in many cases of systemic lupus erythematosus, one of the most common indications for the drug. However, an adverse outcome of treatment can be HCQ retinopathy, a progressive form of vision loss in patients taking HCQ over an extended period (mostly for longer than 5 years). The disease is often asymptomatic, although some patients do present a paracentral scotoma and a decrease in color vision. Patients may also notice flashing shapes in their vision and find that they have difficulty reading. Eventually, HCQ retinopathy can lead to loss of visual acuity, loss of peripheral vision, and loss of night vision.

Researchers from Kaiser Permanente Northern California and Harvard Medical School analyzed 3,325 persons who received HCQ for 5 or more years between 2004 and 2020. Their goal was to both characterize the long-term risk for incident HCQ retinopathy and examine the degree to which average HCQ dose within the first 5 years of treatment serves as a prediction of the risk.

The researchers then estimated the risk for developing retinopathy after 15 years, according to patients’ average dosing levels during the first 5 years of therapy. Overall, 81 participants developed HCQ retinopathy with overall cumulative incidences of 2.5% after 10 years and 8.6% after 15 years; the risk was greater for those given a higher dose during the first 5 years of treatment.

The mechanism of how HCQ toxicity may occur is still not completely known. There is evidence that toxicity happens because HCQ binds to melanin in both the retinal pigment epithelium and uvea in high concentrations. HCQ can interfere with lysosomal function, leading to oxidation and accumulation of lysosomes, which can cause dysfunction of the retinal pigment epithelium.

Progressive retinopathy can continue even after the drug is stopped. “It’s thought to be a very mild but important risk,” said Nilanjana Bose, MD, MBA, a rheumatologist with Memorial Hermann Health System in Houston. “Patients taking HCQ must be screened for retinal issues, most certainly elderly patients and patients with any kind of comorbidities.”

“Examination alone is not sufficient to evaluate early changes, and specialized testing must be done. These include color photos, visual field tests, optical coherence tomography, fundus autofluorescence and in some cases, multifocal electroretinogram. Also, the AAO [American Academy of Ophthalmology] has specific recommendations related to Asian patients as they may have a different pattern of retinopathy that must also be considered.”
 

More accurate risk measurements

This news organization asked study coauthor April Jorge, MD, assistant professor of medicine in the division of rheumatology, allergy, and immunology at Massachusetts General Hospital and Harvard Medical School, Boston, to discuss the study, how it correlates to past research, and what it adds that’s new and useful to rheumatologists and ophthalmologists:

Question: Your research found that a higher dose of HCQ in the first 5 years of treatment led to a greater risk of retinopathy. Is there any indication that a lower dose given more frequently, either within that 5-year period or longer, would pose a similar risk?

Answer: In our study, we assessed the HCQ dose in the first 5 years of use but followed patients who continued the medication longer than 5 years, through up to 15 years of use. Therefore, we compared the risk of HCQ retinopathy associated with different HCQ dosages but for the same duration of use. We found that for any dose of HCQ, the risk of retinopathy increases the longer the medication is used. However, patients who used a higher dose of HCQ had a higher risk of developing retinopathy over time.

Also unique to our study, we graded the severity of HCQ retinopathy outcomes. This was important, as we found that the majority of retinopathy cases detected through routine screening are mild and presumed to be asymptomatic. This will likely be reassuring news for patients that we can screen for this adverse event to detect it early and prevent vision loss.

Another important difference was that we assessed the risk of retinopathy associated with using over 6 mg/kg per day, between 5 and 6 mg/kg per day, and less than 5 mg/kg per day, whereas the highest dosing group assessed in the 2014 study included all patients using over 5 mg/kg per day. The risk was considerably higher in the > 6 mg/kg per day group than in the 5-6 mg/kg per day group.

Q: How can rheumatologists and ophthalmologists use this new information specifically to better treat their patients?

A: Our study provides more accurate estimates of the risk of HCQ retinopathy than in prior studies. These risk estimates can be used when rheumatologists (and other clinicians who prescribe HCQ) consider the risks and benefits of this otherwise important and well-tolerated medication. The risk associated with different dose ranges could also inform dosing decisions, since dosing over 6 mg/kg per day may be more of a concern than using doses in the 5-6 mg/kg range. Ophthalmologists can also use these new risk estimates to counsel patients of the importance of HCQ retinopathy screening and can also hopefully provide some reassurance to patients that the risk of severe retinopathy is low as long as they are being monitored.

The study authors were supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Rheumatology Research Foundation. The authors report no relevant financial relationships. Dr. Bose and Dr. Mirza had no relevant disclosures.

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

The largest combined analysis of birth outcome data for women with systemic lupus erythematosus (SLE) who took belimumab (Benlysta) during pregnancy appears to indicate that the biologic is “unlikely to cause very frequent birth defects,” but the full extent of possible risk remains unknown. The drug’s effect on B cells, immune function, and infections in exposed offspring were not captured in the data, but a separate case report published after the belimumab pregnancy data report indicates that the drug does cross the placenta and builds up in the blood of the newborn, reducing B cells at birth.

Children of women with SLE have increased birth defect risks, and standard SLE therapeutic agents (for example, cyclophosphamide, methotrexate, mycophenolate mofetil) have been implicated in birth defects and pregnancy loss, but birth defect data for biologic drugs such as belimumab are limited. While belimumab animal data revealed no evidence of fetal harm or pregnancy loss rates, there was evidence of immature and mature B-cell count reductions.

Belimumab is approved by the Food and Drug Administration for use in patients aged 5 years and older with active, autoantibody-positive SLE who are taking standard therapy, and also for those with lupus nephritis.

Michelle Petri, MD, of Johns Hopkins University, Baltimore, and coauthors reported in Annals of the Rheumatic Diseases on data they compiled through March 8, 2020, from belimumab clinical trials, the Belimumab Pregnancy Registry (BPR), and postmarketing/spontaneous reports that encompassed 319 pregnancies with known outcomes.

Across 18 clinical trials with 223 live births, birth defects occurred in 4 of 72 (5.6%) belimumab-exposed pregnancies and in 0 of 9 in placebo-exposed pregnancies. Pregnancy loss (excluding elective terminations) occurred in 31.8% (35 of 110) of belimumab-exposed women and 43.8% (7 of 16) of placebo-exposed women in clinical trials. In the BPR retrospective cohort, 4.2% had pregnancy loss. Postmarketing and spontaneous reports had a pregnancy loss rate of 31.4% (43 of 137). Concomitant medications, confounding factors, and/or missing data were noted in all belimumab-exposed women in clinical trials and the BPR cohort. Dr. Petri and colleagues reported no consistent pattern of birth defects across datasets but stated: “Low numbers of exposed pregnancies, presence of confounding factors/other biases, and incomplete information preclude informed recommendations regarding risk of birth defects and pregnancy loss with belimumab use.”

In an interview, coauthor Megan E. B. Clowse, MD, MPH, associate professor of medicine and director of the division of rheumatology and immunology at Duke University, Durham, N.C., said that “the Annals of the Rheumatic Diseases article provides some reassurance that belimumab is unlikely to cause very frequent birth defects. It is clearly not in the risk-range for thalidomide or mycophenolate. However, due to the complexity of collecting these data, this manuscript can’t explore the full extent of possible risks. It also did not provide information about B cells, immune function, or infection risks in exposed offspring.”

A separate case report by Helle Bitter of the department of rheumatology at Sorlandet Hospital Kristiansand (Norway) in Annals of the Rheumatic Diseases is the first to show transplacental passage of belimumab in humans. Other prior reports have shown such transplacental passage for monoclonal IgG antibodies (tumor necrosis factor inhibitors and rituximab). Even though the last infusion was given late in the second trimester, belimumab was present in cord serum at birth, suggesting much higher concentrations before treatment was stopped. While B-cell numbers were reduced at birth, they returned to normal ranges by 4 months post partum when they were undetectable. In the mother, B-cell numbers remained low throughout the study period extending to 7 months after delivery. The authors stated that the child had a normal vaccination response, and except for the reduced B-cell levels at birth, had no adverse effects of prenatal exposure to maternal medication through age 6 years.

“The belimumab transfer in the case report is the level that we would anticipate based on similar studies in infant/mother pairs on other IgG1 antibody biologics like adalimumab – about 60% higher than the maternal level at birth,” Dr. Clowse said. “That the baby has very low B cells at birth is worrisome to me, demonstrating the lasting effect of maternal belimumab on the infant’s immune system, even when the drug was stopped 14 weeks prior to delivery. While this single infant did not have problems with infections, with more widespread use it seems possible that infants would be found to have higher rates of infections after in utero belimumab exposure.”

The field of lupus research greatly needs controlled studies of newer biologics in pregnancy, Dr. Clowse said. “Women with active lupus in pregnancy – particularly with active lupus nephritis – continue to suffer tragic outcomes at an alarming rate. Newer treatments for lupus nephritis provide some hope that we might be able to control lupus nephritis in pregnancy more effectively. The available data suggests the risks of these medications are not so large as to make studies unreasonable. Our current data doesn’t allow us to sufficiently balance the potential risks and benefits in a way that provides clinically useful guidance. Trials of these medications, however, would enable us to identify improved treatment strategies that could result in healthier women, pregnancies, and babies.”

GlaxoSmithKline funded the study. Dr. Clowse reported receiving consulting fees and grants from UCB and GlaxoSmithKline that relate to pregnancy in women with lupus.

The largest combined analysis of birth outcome data for women with systemic lupus erythematosus (SLE) who took belimumab (Benlysta) during pregnancy appears to indicate that the biologic is “unlikely to cause very frequent birth defects,” but the full extent of possible risk remains unknown. The drug’s effect on B cells, immune function, and infections in exposed offspring were not captured in the data, but a separate case report published after the belimumab pregnancy data report indicates that the drug does cross the placenta and builds up in the blood of the newborn, reducing B cells at birth.

Children of women with SLE have increased birth defect risks, and standard SLE therapeutic agents (for example, cyclophosphamide, methotrexate, mycophenolate mofetil) have been implicated in birth defects and pregnancy loss, but birth defect data for biologic drugs such as belimumab are limited. While belimumab animal data revealed no evidence of fetal harm or pregnancy loss rates, there was evidence of immature and mature B-cell count reductions.

Belimumab is approved by the Food and Drug Administration for use in patients aged 5 years and older with active, autoantibody-positive SLE who are taking standard therapy, and also for those with lupus nephritis.

Michelle Petri, MD, of Johns Hopkins University, Baltimore, and coauthors reported in Annals of the Rheumatic Diseases on data they compiled through March 8, 2020, from belimumab clinical trials, the Belimumab Pregnancy Registry (BPR), and postmarketing/spontaneous reports that encompassed 319 pregnancies with known outcomes.

Across 18 clinical trials with 223 live births, birth defects occurred in 4 of 72 (5.6%) belimumab-exposed pregnancies and in 0 of 9 in placebo-exposed pregnancies. Pregnancy loss (excluding elective terminations) occurred in 31.8% (35 of 110) of belimumab-exposed women and 43.8% (7 of 16) of placebo-exposed women in clinical trials. In the BPR retrospective cohort, 4.2% had pregnancy loss. Postmarketing and spontaneous reports had a pregnancy loss rate of 31.4% (43 of 137). Concomitant medications, confounding factors, and/or missing data were noted in all belimumab-exposed women in clinical trials and the BPR cohort. Dr. Petri and colleagues reported no consistent pattern of birth defects across datasets but stated: “Low numbers of exposed pregnancies, presence of confounding factors/other biases, and incomplete information preclude informed recommendations regarding risk of birth defects and pregnancy loss with belimumab use.”

In an interview, coauthor Megan E. B. Clowse, MD, MPH, associate professor of medicine and director of the division of rheumatology and immunology at Duke University, Durham, N.C., said that “the Annals of the Rheumatic Diseases article provides some reassurance that belimumab is unlikely to cause very frequent birth defects. It is clearly not in the risk-range for thalidomide or mycophenolate. However, due to the complexity of collecting these data, this manuscript can’t explore the full extent of possible risks. It also did not provide information about B cells, immune function, or infection risks in exposed offspring.”

A separate case report by Helle Bitter of the department of rheumatology at Sorlandet Hospital Kristiansand (Norway) in Annals of the Rheumatic Diseases is the first to show transplacental passage of belimumab in humans. Other prior reports have shown such transplacental passage for monoclonal IgG antibodies (tumor necrosis factor inhibitors and rituximab). Even though the last infusion was given late in the second trimester, belimumab was present in cord serum at birth, suggesting much higher concentrations before treatment was stopped. While B-cell numbers were reduced at birth, they returned to normal ranges by 4 months post partum when they were undetectable. In the mother, B-cell numbers remained low throughout the study period extending to 7 months after delivery. The authors stated that the child had a normal vaccination response, and except for the reduced B-cell levels at birth, had no adverse effects of prenatal exposure to maternal medication through age 6 years.

“The belimumab transfer in the case report is the level that we would anticipate based on similar studies in infant/mother pairs on other IgG1 antibody biologics like adalimumab – about 60% higher than the maternal level at birth,” Dr. Clowse said. “That the baby has very low B cells at birth is worrisome to me, demonstrating the lasting effect of maternal belimumab on the infant’s immune system, even when the drug was stopped 14 weeks prior to delivery. While this single infant did not have problems with infections, with more widespread use it seems possible that infants would be found to have higher rates of infections after in utero belimumab exposure.”

The field of lupus research greatly needs controlled studies of newer biologics in pregnancy, Dr. Clowse said. “Women with active lupus in pregnancy – particularly with active lupus nephritis – continue to suffer tragic outcomes at an alarming rate. Newer treatments for lupus nephritis provide some hope that we might be able to control lupus nephritis in pregnancy more effectively. The available data suggests the risks of these medications are not so large as to make studies unreasonable. Our current data doesn’t allow us to sufficiently balance the potential risks and benefits in a way that provides clinically useful guidance. Trials of these medications, however, would enable us to identify improved treatment strategies that could result in healthier women, pregnancies, and babies.”

GlaxoSmithKline funded the study. Dr. Clowse reported receiving consulting fees and grants from UCB and GlaxoSmithKline that relate to pregnancy in women with lupus.

The largest combined analysis of birth outcome data for women with systemic lupus erythematosus (SLE) who took belimumab (Benlysta) during pregnancy appears to indicate that the biologic is “unlikely to cause very frequent birth defects,” but the full extent of possible risk remains unknown. The drug’s effect on B cells, immune function, and infections in exposed offspring were not captured in the data, but a separate case report published after the belimumab pregnancy data report indicates that the drug does cross the placenta and builds up in the blood of the newborn, reducing B cells at birth.

Children of women with SLE have increased birth defect risks, and standard SLE therapeutic agents (for example, cyclophosphamide, methotrexate, mycophenolate mofetil) have been implicated in birth defects and pregnancy loss, but birth defect data for biologic drugs such as belimumab are limited. While belimumab animal data revealed no evidence of fetal harm or pregnancy loss rates, there was evidence of immature and mature B-cell count reductions.

Belimumab is approved by the Food and Drug Administration for use in patients aged 5 years and older with active, autoantibody-positive SLE who are taking standard therapy, and also for those with lupus nephritis.

Michelle Petri, MD, of Johns Hopkins University, Baltimore, and coauthors reported in Annals of the Rheumatic Diseases on data they compiled through March 8, 2020, from belimumab clinical trials, the Belimumab Pregnancy Registry (BPR), and postmarketing/spontaneous reports that encompassed 319 pregnancies with known outcomes.

Across 18 clinical trials with 223 live births, birth defects occurred in 4 of 72 (5.6%) belimumab-exposed pregnancies and in 0 of 9 in placebo-exposed pregnancies. Pregnancy loss (excluding elective terminations) occurred in 31.8% (35 of 110) of belimumab-exposed women and 43.8% (7 of 16) of placebo-exposed women in clinical trials. In the BPR retrospective cohort, 4.2% had pregnancy loss. Postmarketing and spontaneous reports had a pregnancy loss rate of 31.4% (43 of 137). Concomitant medications, confounding factors, and/or missing data were noted in all belimumab-exposed women in clinical trials and the BPR cohort. Dr. Petri and colleagues reported no consistent pattern of birth defects across datasets but stated: “Low numbers of exposed pregnancies, presence of confounding factors/other biases, and incomplete information preclude informed recommendations regarding risk of birth defects and pregnancy loss with belimumab use.”

In an interview, coauthor Megan E. B. Clowse, MD, MPH, associate professor of medicine and director of the division of rheumatology and immunology at Duke University, Durham, N.C., said that “the Annals of the Rheumatic Diseases article provides some reassurance that belimumab is unlikely to cause very frequent birth defects. It is clearly not in the risk-range for thalidomide or mycophenolate. However, due to the complexity of collecting these data, this manuscript can’t explore the full extent of possible risks. It also did not provide information about B cells, immune function, or infection risks in exposed offspring.”

A separate case report by Helle Bitter of the department of rheumatology at Sorlandet Hospital Kristiansand (Norway) in Annals of the Rheumatic Diseases is the first to show transplacental passage of belimumab in humans. Other prior reports have shown such transplacental passage for monoclonal IgG antibodies (tumor necrosis factor inhibitors and rituximab). Even though the last infusion was given late in the second trimester, belimumab was present in cord serum at birth, suggesting much higher concentrations before treatment was stopped. While B-cell numbers were reduced at birth, they returned to normal ranges by 4 months post partum when they were undetectable. In the mother, B-cell numbers remained low throughout the study period extending to 7 months after delivery. The authors stated that the child had a normal vaccination response, and except for the reduced B-cell levels at birth, had no adverse effects of prenatal exposure to maternal medication through age 6 years.

“The belimumab transfer in the case report is the level that we would anticipate based on similar studies in infant/mother pairs on other IgG1 antibody biologics like adalimumab – about 60% higher than the maternal level at birth,” Dr. Clowse said. “That the baby has very low B cells at birth is worrisome to me, demonstrating the lasting effect of maternal belimumab on the infant’s immune system, even when the drug was stopped 14 weeks prior to delivery. While this single infant did not have problems with infections, with more widespread use it seems possible that infants would be found to have higher rates of infections after in utero belimumab exposure.”

The field of lupus research greatly needs controlled studies of newer biologics in pregnancy, Dr. Clowse said. “Women with active lupus in pregnancy – particularly with active lupus nephritis – continue to suffer tragic outcomes at an alarming rate. Newer treatments for lupus nephritis provide some hope that we might be able to control lupus nephritis in pregnancy more effectively. The available data suggests the risks of these medications are not so large as to make studies unreasonable. Our current data doesn’t allow us to sufficiently balance the potential risks and benefits in a way that provides clinically useful guidance. Trials of these medications, however, would enable us to identify improved treatment strategies that could result in healthier women, pregnancies, and babies.”

GlaxoSmithKline funded the study. Dr. Clowse reported receiving consulting fees and grants from UCB and GlaxoSmithKline that relate to pregnancy in women with lupus.

A small cohort study of pediatric rheumatology patients with generalized joint hypermobility (GJH) who presented to a specialized rheumatology* clinic suggests that many such patients have abnormal bleeding symptoms, in comparison with health control patients.

The study of 81 patients with GJH found that about three quarters had significantly elevated median bleeding scores, but only 12% had been assessed by hematology for bleeding.

“We propose that screening for bleeding symptoms should be integrated into the routine care for all patients with GJH, with hematology referrals for patients with increased bleeding concerns,” wrote a research team led by Nicole E. Kendel, MD, a pediatric hematologist-oncologist at Akron Children’s Hospital in Ohio, in a study published online in Arthritis Care and Research.

“Further studies are needed to understand the mechanism of bleeding, evaluate comorbidities associated with these bleeding symptoms, and potentially allow for tailored pharmacologic therapy,” the authors stated.
 

Background

Dr. Kendel’s team had reported moderate menstruation-associated limitations in school, social, and physical activities among female adolescents with GJH. “This cohort also experienced nonreproductive bleeding symptoms and demonstrated minimal hemostatic laboratory abnormalities, indicating that this population may be underdiagnosed and subsequently poorly managed,” she said in an interview. “As excessive bleeding symptoms could have a significant impact on overall health and quality of life, we thought it was important to define the incidence and natural course of bleeding symptoms in a more generalized subset of this population.”

Although the investigators hypothesized that there would be a statistically significant increase in bleeding scores, “we were still impressed by the frequency of abnormal scores, particularly when looking at the low percentage of patients [12%] who had previously been referred to hematology,” she said.
 

Study results

The median age of the study cohort was 13 years (interquartile range, 10-16 years), and 72.8% were female. The mean Beighton score, which measures joint flexibility, was 6.2 (range, 4-9). All participants were seen by rheumatologists and were diagnosed for conditions on the hypermobility spectrum. Those conditions ranged from GJH to hypermobile Ehlers-Danlos syndrome (hEDS).

Abnormal bleeding, as measured by the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool, was found in 75% (95% confidence interval [CI], 64%-84%). Overall mean and median bleeding scores were 5.2 and 4, respectively; scores ranged from 0 to 16. Abnormal scores of ≥ 3 were observed for patients < 8 years of age, ≥ 4 for men ≥ 18 years of age, and ≥ 6 for women ≥ 18 years of age. These measures were significantly elevated compared with those reported for historical healthy pediatric control persons (P < .001).

The most common hemorrhagic symptom was oral bleeding (74.1%) that occurred with tooth brushing, flossing, tooth loss, or eruption. Others reported easy bruising (59.3%) and bleeding from minor wounds (42%). In terms of procedures, tooth extraction requiring additional packing was reported by 25.9%, and 22.2% reported significant bleeding after otolaryngologic procedures, such as tonsillectomy/adenoidectomy, septoplasty, and nasal turbinate reduction.

Prolonged or heavy menstrual periods were reported by 37.3% of female patients.

Bleeding scores did not differ by biological sex or NSAID use, nor did any correlation emerge between patients’ bleeding and Beighton scores. However, there was a positive correlation with increasing age, a phenomenon observed with other bleeding disorders and in the healthy population, the authors noted.

Of the 10 study participants who had previously undergone hematologic assessment, one had been diagnosed with acquired, heart disease–related von Willebrand disease, and another with mild bleeding disorder.

Severe connective tissue disorders are associated with increased bleeding symptoms in the adult population, Dr. Kendel said, but few studies have assessed bleeding across the GJH spectrum, particularly in children.

Bleeding is thought to be due to modifications of collagen in the blood vessels. “These modifications create mechanical weakness of the vessel wall, as well as defective subendothelial connective tissue supporting those blood vessels,” Dr. Kendel explained. She noted that altered collagen creates defective interactions between collagen and other coagulation factors.

“Even in the presence of a normal laboratory evaluation, GJH can lead to symptoms consistent with a mild bleeding disorder,” she continued. “These symptoms are both preventable and treatable. I’m hopeful more centers will start routinely evaluating for increased bleeding symptoms, with referral to hematology for those with increased bleeding concerns.”

Commenting on the study’s recommendation, Beth S. Gottlieb, MD, chief of the division of pediatric rheumatology at Northwell Health in New Hyde Park, N.Y., who was not involved in the investigation, said a brief questionnaire on bleeding risk is a reasonable addition to a rheumatology office visit.

“Joint hypermobility is very common, but not all affected children meet the criteria for the hypermobile form of hEDS,” she told this news organization. “Screening for bleeding tendency is often done as routine medical history questions. Once a child is identified as hypermobile, these screening questions are usually asked, but utilizing one of the formal bleeding risk questionnaires is not currently routine.”

According to Dr. Gottlieb, it remains unclear whether screening would have a significant impact on children who have been diagnosed with hypermobility. “Most of these children are young and may not yet have a significant history for bleeding tendency,” she said. “Education of families is always important, and it will be essential to educate without adding unnecessary stress. Screening guidelines may be an important tool that is easy to incorporate into routine clinical practice.”
 

Limitation

The study was limited by selection bias, as patients had all been referred to a specialized rheumatology clinic.

The study was supported by the Clinical and Translational Intramural Funding Program of the Abigail Wexner Research Institute. The authors and Dr. Gottlieb have disclosed no relevant financial relationships.

*Correction, 1/11/2023: An earlier version of this story misstated the type of specialty clinic where patients were first seen. 

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

A small cohort study of pediatric rheumatology patients with generalized joint hypermobility (GJH) who presented to a specialized rheumatology* clinic suggests that many such patients have abnormal bleeding symptoms, in comparison with health control patients.

The study of 81 patients with GJH found that about three quarters had significantly elevated median bleeding scores, but only 12% had been assessed by hematology for bleeding.

“We propose that screening for bleeding symptoms should be integrated into the routine care for all patients with GJH, with hematology referrals for patients with increased bleeding concerns,” wrote a research team led by Nicole E. Kendel, MD, a pediatric hematologist-oncologist at Akron Children’s Hospital in Ohio, in a study published online in Arthritis Care and Research.

“Further studies are needed to understand the mechanism of bleeding, evaluate comorbidities associated with these bleeding symptoms, and potentially allow for tailored pharmacologic therapy,” the authors stated.
 

Background

Dr. Kendel’s team had reported moderate menstruation-associated limitations in school, social, and physical activities among female adolescents with GJH. “This cohort also experienced nonreproductive bleeding symptoms and demonstrated minimal hemostatic laboratory abnormalities, indicating that this population may be underdiagnosed and subsequently poorly managed,” she said in an interview. “As excessive bleeding symptoms could have a significant impact on overall health and quality of life, we thought it was important to define the incidence and natural course of bleeding symptoms in a more generalized subset of this population.”

Although the investigators hypothesized that there would be a statistically significant increase in bleeding scores, “we were still impressed by the frequency of abnormal scores, particularly when looking at the low percentage of patients [12%] who had previously been referred to hematology,” she said.
 

Study results

The median age of the study cohort was 13 years (interquartile range, 10-16 years), and 72.8% were female. The mean Beighton score, which measures joint flexibility, was 6.2 (range, 4-9). All participants were seen by rheumatologists and were diagnosed for conditions on the hypermobility spectrum. Those conditions ranged from GJH to hypermobile Ehlers-Danlos syndrome (hEDS).

Abnormal bleeding, as measured by the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool, was found in 75% (95% confidence interval [CI], 64%-84%). Overall mean and median bleeding scores were 5.2 and 4, respectively; scores ranged from 0 to 16. Abnormal scores of ≥ 3 were observed for patients < 8 years of age, ≥ 4 for men ≥ 18 years of age, and ≥ 6 for women ≥ 18 years of age. These measures were significantly elevated compared with those reported for historical healthy pediatric control persons (P < .001).

The most common hemorrhagic symptom was oral bleeding (74.1%) that occurred with tooth brushing, flossing, tooth loss, or eruption. Others reported easy bruising (59.3%) and bleeding from minor wounds (42%). In terms of procedures, tooth extraction requiring additional packing was reported by 25.9%, and 22.2% reported significant bleeding after otolaryngologic procedures, such as tonsillectomy/adenoidectomy, septoplasty, and nasal turbinate reduction.

Prolonged or heavy menstrual periods were reported by 37.3% of female patients.

Bleeding scores did not differ by biological sex or NSAID use, nor did any correlation emerge between patients’ bleeding and Beighton scores. However, there was a positive correlation with increasing age, a phenomenon observed with other bleeding disorders and in the healthy population, the authors noted.

Of the 10 study participants who had previously undergone hematologic assessment, one had been diagnosed with acquired, heart disease–related von Willebrand disease, and another with mild bleeding disorder.

Severe connective tissue disorders are associated with increased bleeding symptoms in the adult population, Dr. Kendel said, but few studies have assessed bleeding across the GJH spectrum, particularly in children.

Bleeding is thought to be due to modifications of collagen in the blood vessels. “These modifications create mechanical weakness of the vessel wall, as well as defective subendothelial connective tissue supporting those blood vessels,” Dr. Kendel explained. She noted that altered collagen creates defective interactions between collagen and other coagulation factors.

“Even in the presence of a normal laboratory evaluation, GJH can lead to symptoms consistent with a mild bleeding disorder,” she continued. “These symptoms are both preventable and treatable. I’m hopeful more centers will start routinely evaluating for increased bleeding symptoms, with referral to hematology for those with increased bleeding concerns.”

Commenting on the study’s recommendation, Beth S. Gottlieb, MD, chief of the division of pediatric rheumatology at Northwell Health in New Hyde Park, N.Y., who was not involved in the investigation, said a brief questionnaire on bleeding risk is a reasonable addition to a rheumatology office visit.

“Joint hypermobility is very common, but not all affected children meet the criteria for the hypermobile form of hEDS,” she told this news organization. “Screening for bleeding tendency is often done as routine medical history questions. Once a child is identified as hypermobile, these screening questions are usually asked, but utilizing one of the formal bleeding risk questionnaires is not currently routine.”

According to Dr. Gottlieb, it remains unclear whether screening would have a significant impact on children who have been diagnosed with hypermobility. “Most of these children are young and may not yet have a significant history for bleeding tendency,” she said. “Education of families is always important, and it will be essential to educate without adding unnecessary stress. Screening guidelines may be an important tool that is easy to incorporate into routine clinical practice.”
 

Limitation

The study was limited by selection bias, as patients had all been referred to a specialized rheumatology clinic.

The study was supported by the Clinical and Translational Intramural Funding Program of the Abigail Wexner Research Institute. The authors and Dr. Gottlieb have disclosed no relevant financial relationships.

*Correction, 1/11/2023: An earlier version of this story misstated the type of specialty clinic where patients were first seen. 

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

A small cohort study of pediatric rheumatology patients with generalized joint hypermobility (GJH) who presented to a specialized rheumatology* clinic suggests that many such patients have abnormal bleeding symptoms, in comparison with health control patients.

The study of 81 patients with GJH found that about three quarters had significantly elevated median bleeding scores, but only 12% had been assessed by hematology for bleeding.

“We propose that screening for bleeding symptoms should be integrated into the routine care for all patients with GJH, with hematology referrals for patients with increased bleeding concerns,” wrote a research team led by Nicole E. Kendel, MD, a pediatric hematologist-oncologist at Akron Children’s Hospital in Ohio, in a study published online in Arthritis Care and Research.

“Further studies are needed to understand the mechanism of bleeding, evaluate comorbidities associated with these bleeding symptoms, and potentially allow for tailored pharmacologic therapy,” the authors stated.
 

Background

Dr. Kendel’s team had reported moderate menstruation-associated limitations in school, social, and physical activities among female adolescents with GJH. “This cohort also experienced nonreproductive bleeding symptoms and demonstrated minimal hemostatic laboratory abnormalities, indicating that this population may be underdiagnosed and subsequently poorly managed,” she said in an interview. “As excessive bleeding symptoms could have a significant impact on overall health and quality of life, we thought it was important to define the incidence and natural course of bleeding symptoms in a more generalized subset of this population.”

Although the investigators hypothesized that there would be a statistically significant increase in bleeding scores, “we were still impressed by the frequency of abnormal scores, particularly when looking at the low percentage of patients [12%] who had previously been referred to hematology,” she said.
 

Study results

The median age of the study cohort was 13 years (interquartile range, 10-16 years), and 72.8% were female. The mean Beighton score, which measures joint flexibility, was 6.2 (range, 4-9). All participants were seen by rheumatologists and were diagnosed for conditions on the hypermobility spectrum. Those conditions ranged from GJH to hypermobile Ehlers-Danlos syndrome (hEDS).

Abnormal bleeding, as measured by the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool, was found in 75% (95% confidence interval [CI], 64%-84%). Overall mean and median bleeding scores were 5.2 and 4, respectively; scores ranged from 0 to 16. Abnormal scores of ≥ 3 were observed for patients < 8 years of age, ≥ 4 for men ≥ 18 years of age, and ≥ 6 for women ≥ 18 years of age. These measures were significantly elevated compared with those reported for historical healthy pediatric control persons (P < .001).

The most common hemorrhagic symptom was oral bleeding (74.1%) that occurred with tooth brushing, flossing, tooth loss, or eruption. Others reported easy bruising (59.3%) and bleeding from minor wounds (42%). In terms of procedures, tooth extraction requiring additional packing was reported by 25.9%, and 22.2% reported significant bleeding after otolaryngologic procedures, such as tonsillectomy/adenoidectomy, septoplasty, and nasal turbinate reduction.

Prolonged or heavy menstrual periods were reported by 37.3% of female patients.

Bleeding scores did not differ by biological sex or NSAID use, nor did any correlation emerge between patients’ bleeding and Beighton scores. However, there was a positive correlation with increasing age, a phenomenon observed with other bleeding disorders and in the healthy population, the authors noted.

Of the 10 study participants who had previously undergone hematologic assessment, one had been diagnosed with acquired, heart disease–related von Willebrand disease, and another with mild bleeding disorder.

Severe connective tissue disorders are associated with increased bleeding symptoms in the adult population, Dr. Kendel said, but few studies have assessed bleeding across the GJH spectrum, particularly in children.

Bleeding is thought to be due to modifications of collagen in the blood vessels. “These modifications create mechanical weakness of the vessel wall, as well as defective subendothelial connective tissue supporting those blood vessels,” Dr. Kendel explained. She noted that altered collagen creates defective interactions between collagen and other coagulation factors.

“Even in the presence of a normal laboratory evaluation, GJH can lead to symptoms consistent with a mild bleeding disorder,” she continued. “These symptoms are both preventable and treatable. I’m hopeful more centers will start routinely evaluating for increased bleeding symptoms, with referral to hematology for those with increased bleeding concerns.”

Commenting on the study’s recommendation, Beth S. Gottlieb, MD, chief of the division of pediatric rheumatology at Northwell Health in New Hyde Park, N.Y., who was not involved in the investigation, said a brief questionnaire on bleeding risk is a reasonable addition to a rheumatology office visit.

“Joint hypermobility is very common, but not all affected children meet the criteria for the hypermobile form of hEDS,” she told this news organization. “Screening for bleeding tendency is often done as routine medical history questions. Once a child is identified as hypermobile, these screening questions are usually asked, but utilizing one of the formal bleeding risk questionnaires is not currently routine.”

According to Dr. Gottlieb, it remains unclear whether screening would have a significant impact on children who have been diagnosed with hypermobility. “Most of these children are young and may not yet have a significant history for bleeding tendency,” she said. “Education of families is always important, and it will be essential to educate without adding unnecessary stress. Screening guidelines may be an important tool that is easy to incorporate into routine clinical practice.”
 

Limitation

The study was limited by selection bias, as patients had all been referred to a specialized rheumatology clinic.

The study was supported by the Clinical and Translational Intramural Funding Program of the Abigail Wexner Research Institute. The authors and Dr. Gottlieb have disclosed no relevant financial relationships.

*Correction, 1/11/2023: An earlier version of this story misstated the type of specialty clinic where patients were first seen. 

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

Patients with thrombotic antiphospholipid syndrome are better treated with a vitamin K antagonist, such as warfarin, rather than a direct oral anticoagulant (DOAC), a new systematic review and meta-analysis suggests.

“Our study is showing that in randomized controlled trials in patients with thrombotic antiphospholipid syndrome, the risk of arterial thrombotic events, particularly stroke, is significantly increased with DOACs vs. vitamin K antagonists,” senior author, Behnood Bikdeli, MD, Brigham and Women’s Hospital, Boston, told this news organization. “These results probably suggest that DOACs are not the optimal regimen for patients with thrombotic antiphospholipid syndrome.”

The study was published online in the Journal of the American College of Cardiology.
 

Autoimmune disorder

Thrombotic antiphospholipid syndrome is a systemic autoimmune disorder characterized by recurrent arterial and/or venous thrombotic events.

Dr. Bikdeli estimates that antiphospholipid syndrome is the cause of 50,000-100,000 strokes, 100,000 cases of myocardial infarction, and 30,000 cases of deep vein thrombosis every year.

“It is a serious condition, and these are a high-risk and complex group of patients,” he said.

The standard treatment has been anticoagulation with a vitamin K antagonist such as warfarin. “But this is a cumbersome treatment, with many drug interactions and the need for INR [International Normalized Ratio] monitoring, which can be difficult to manage in patients with antiphospholipid syndrome as there can sometimes be falsely abnormal numbers,” Dr. Bikdeli noted. “Because of these challenges, it looked very promising to explore the use of DOACs in this population.”

Four main randomized trials have been conducted to investigate the use of DOACs in antiphospholipid syndrome – three with rivaroxaban and one with apixaban. “These trials were all quite small and, while they did not show definite results, some of them suggested nonsignificant findings of slightly worse outcomes for DOACs vs. vitamin K antagonists. But there is a lot of uncertainty, and it is difficult to look at subgroups in such small trials,” Dr. Bikdeli said. “There are many questions remaining about whether we should use DOACs in patients with antiphospholipid syndrome and, if so, which particular subgroups.”

The authors therefore performed a systematic review and meta-analysis of randomized controlled trials that compared DOACs with vitamin K antagonists in patients with antiphospholipid syndrome. They also contacted the principal investigators of the trials to obtain additional unpublished aggregate level data on specific subgroups.

Four open-label randomized controlled trials involving 472 patients were included in the meta-analysis.

Overall, the use of DOACs, compared with vitamin K antagonists, was associated with increased odds of subsequent arterial thrombotic events (odds ratio, 5.43; P < .001), especially stroke.

The odds of subsequent venous thrombotic events or major bleeding were not significantly different between the two groups. Most findings were consistent within subgroups.

“Our results show that use of DOACs vs. vitamin K antagonists is associated with increased risk of arterial thrombotic events – a risk that is primarily driven by a significant increase in the risk of stroke,” Dr. Bikdeli commented.

When looking at subgroups of interest, it was previously thought that DOACs may not be so effective in the so-called “triple-positive” antiphospholipid patients. These patients have three different types of antibodies and have the highest risk of thrombosis, Dr. Bikdeli noted.

“But one of the interesting findings of our study is that the results are actually consistent in women vs. men and in people who have triple-positive antibodies and those who had double- or single-positive antibodies,” he said. “Our analyses did not show effect modification by antibody subgroups. They suggest similar trends towards worse outcomes in all subgroups.”   

“From these results, I would be similarly concerned to use DOACs even if someone has double-positive or single-positive antiphospholipid antibodies,” he added.

Dr. Bikdeli said he would still recommend shared decision-making with patients. “If I have a patient who has thrombotic antiphospholipid syndrome, I would share my reservation about DOACs, but there are multiple factors that come into decision-making. If someone has difficulty with checking INRs, we may make an informed choice and still use a DOAC, but patients need to know that there is likely an excess risk of subsequent arterial events with DOACs, compared with a vitamin K antagonist.”

He noted that it is still not completely clear on the situation for people with single-positive antiphospholipid syndrome or the type of antibody that is present. It is also possible that a higher dose of DOAC could be more effective, a strategy that is being investigated in a separate randomized trial currently ongoing.

“But for routine practice I would have concerns about using DOACs in antiphospholipid syndrome patients in general,” he said. “For triple positive there is more data and greater concern, but I wouldn’t give a pass for a double- or single-positive patient either.”

The reason why DOACs would be less effective than vitamin K antagonists in antiphospholipid syndrome is not known.

“That is the million-dollar question,” Dr. Bikdeli commented. “DOACs have been such helpful drugs for many patients and clinicians as well. But we have seen that they are not optimal in a series of scenarios now – patients with mechanical heart valves, patients with rheumatic [atrial fibrillaton], and now patients with thrombotic antiphospholipid syndrome.”

One hypothesis is that these patients have some more components of inflammation and are more prone to blood clots, and because vitamin K antagonists work at several parts of the coagulation cascade, they might be more successful, compared with the more targeted DOAC therapy. “But I think we need more studies to fully understand this,” he said.

‘Important implications’

In an accompanying editorial,Mark A. Crowther, MD, McMaster University, Hamilton, Ont., and Aubrey E. Jones, PharmD, and Daniel M. Witt, PharmD, both of the University of Utah College of Pharmacy, Salt Lake City, say that: “As the quality of the evidence was rated ‘high’ for the arterial thrombosis outcome and ‘moderate’ for the venous thrombosis and bleeding outcomes, these results should lead to a revision of evidence-based guidelines to recommend against using DOACs as an option for most patients with thrombotic antiphospholipid syndrome.”

They add that this recommendation for vitamin K antagonists also applies to patients previously thought to be at lower risk from antiphospholipid syndrome – including those with only one or two positive serological tests and those with only prior venous thrombosis.

The editorialists point out that this will have important implications, particularly for the accurate diagnosis of antiphospholipid syndrome, including confirmation and documentation of positive laboratory tests at least 12 weeks after the initial positive test.

They recommend that while awaiting confirmatory testing, patients with suspected antiphospholipid syndrome should avoid DOACs, and that “strong consideration” should be given to switching essentially all antiphospholipid syndrome patients currently receiving DOACs to vitamin K antagonists.

Dr. Bikdeli is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters and is supported by the Scott Schoen and Nancy Adams IGNITE Award from the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital and a Career Development Award from the American Heart Association and VIVA Physicians. Dr. Crowther has received personal funding from AstraZeneca, Precision Biologics, Hemostasis Reference Laboratories, Syneos Health, Bayer, Pfizer, and CSL Behring; and holds the Leo Pharma Chair in Thromboembolism Research, which is endowed at McMaster University. Dr. Jones is supported by a career development award from the National Heart, Lung, and Blood Institute; and Dr. Witt is supported by grant funding from the Agency for Healthcare Research and Quality.

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

Patients with thrombotic antiphospholipid syndrome are better treated with a vitamin K antagonist, such as warfarin, rather than a direct oral anticoagulant (DOAC), a new systematic review and meta-analysis suggests.

“Our study is showing that in randomized controlled trials in patients with thrombotic antiphospholipid syndrome, the risk of arterial thrombotic events, particularly stroke, is significantly increased with DOACs vs. vitamin K antagonists,” senior author, Behnood Bikdeli, MD, Brigham and Women’s Hospital, Boston, told this news organization. “These results probably suggest that DOACs are not the optimal regimen for patients with thrombotic antiphospholipid syndrome.”

The study was published online in the Journal of the American College of Cardiology.
 

Autoimmune disorder

Thrombotic antiphospholipid syndrome is a systemic autoimmune disorder characterized by recurrent arterial and/or venous thrombotic events.

Dr. Bikdeli estimates that antiphospholipid syndrome is the cause of 50,000-100,000 strokes, 100,000 cases of myocardial infarction, and 30,000 cases of deep vein thrombosis every year.

“It is a serious condition, and these are a high-risk and complex group of patients,” he said.

The standard treatment has been anticoagulation with a vitamin K antagonist such as warfarin. “But this is a cumbersome treatment, with many drug interactions and the need for INR [International Normalized Ratio] monitoring, which can be difficult to manage in patients with antiphospholipid syndrome as there can sometimes be falsely abnormal numbers,” Dr. Bikdeli noted. “Because of these challenges, it looked very promising to explore the use of DOACs in this population.”

Four main randomized trials have been conducted to investigate the use of DOACs in antiphospholipid syndrome – three with rivaroxaban and one with apixaban. “These trials were all quite small and, while they did not show definite results, some of them suggested nonsignificant findings of slightly worse outcomes for DOACs vs. vitamin K antagonists. But there is a lot of uncertainty, and it is difficult to look at subgroups in such small trials,” Dr. Bikdeli said. “There are many questions remaining about whether we should use DOACs in patients with antiphospholipid syndrome and, if so, which particular subgroups.”

The authors therefore performed a systematic review and meta-analysis of randomized controlled trials that compared DOACs with vitamin K antagonists in patients with antiphospholipid syndrome. They also contacted the principal investigators of the trials to obtain additional unpublished aggregate level data on specific subgroups.

Four open-label randomized controlled trials involving 472 patients were included in the meta-analysis.

Overall, the use of DOACs, compared with vitamin K antagonists, was associated with increased odds of subsequent arterial thrombotic events (odds ratio, 5.43; P < .001), especially stroke.

The odds of subsequent venous thrombotic events or major bleeding were not significantly different between the two groups. Most findings were consistent within subgroups.

“Our results show that use of DOACs vs. vitamin K antagonists is associated with increased risk of arterial thrombotic events – a risk that is primarily driven by a significant increase in the risk of stroke,” Dr. Bikdeli commented.

When looking at subgroups of interest, it was previously thought that DOACs may not be so effective in the so-called “triple-positive” antiphospholipid patients. These patients have three different types of antibodies and have the highest risk of thrombosis, Dr. Bikdeli noted.

“But one of the interesting findings of our study is that the results are actually consistent in women vs. men and in people who have triple-positive antibodies and those who had double- or single-positive antibodies,” he said. “Our analyses did not show effect modification by antibody subgroups. They suggest similar trends towards worse outcomes in all subgroups.”   

“From these results, I would be similarly concerned to use DOACs even if someone has double-positive or single-positive antiphospholipid antibodies,” he added.

Dr. Bikdeli said he would still recommend shared decision-making with patients. “If I have a patient who has thrombotic antiphospholipid syndrome, I would share my reservation about DOACs, but there are multiple factors that come into decision-making. If someone has difficulty with checking INRs, we may make an informed choice and still use a DOAC, but patients need to know that there is likely an excess risk of subsequent arterial events with DOACs, compared with a vitamin K antagonist.”

He noted that it is still not completely clear on the situation for people with single-positive antiphospholipid syndrome or the type of antibody that is present. It is also possible that a higher dose of DOAC could be more effective, a strategy that is being investigated in a separate randomized trial currently ongoing.

“But for routine practice I would have concerns about using DOACs in antiphospholipid syndrome patients in general,” he said. “For triple positive there is more data and greater concern, but I wouldn’t give a pass for a double- or single-positive patient either.”

The reason why DOACs would be less effective than vitamin K antagonists in antiphospholipid syndrome is not known.

“That is the million-dollar question,” Dr. Bikdeli commented. “DOACs have been such helpful drugs for many patients and clinicians as well. But we have seen that they are not optimal in a series of scenarios now – patients with mechanical heart valves, patients with rheumatic [atrial fibrillaton], and now patients with thrombotic antiphospholipid syndrome.”

One hypothesis is that these patients have some more components of inflammation and are more prone to blood clots, and because vitamin K antagonists work at several parts of the coagulation cascade, they might be more successful, compared with the more targeted DOAC therapy. “But I think we need more studies to fully understand this,” he said.

‘Important implications’

In an accompanying editorial,Mark A. Crowther, MD, McMaster University, Hamilton, Ont., and Aubrey E. Jones, PharmD, and Daniel M. Witt, PharmD, both of the University of Utah College of Pharmacy, Salt Lake City, say that: “As the quality of the evidence was rated ‘high’ for the arterial thrombosis outcome and ‘moderate’ for the venous thrombosis and bleeding outcomes, these results should lead to a revision of evidence-based guidelines to recommend against using DOACs as an option for most patients with thrombotic antiphospholipid syndrome.”

They add that this recommendation for vitamin K antagonists also applies to patients previously thought to be at lower risk from antiphospholipid syndrome – including those with only one or two positive serological tests and those with only prior venous thrombosis.

The editorialists point out that this will have important implications, particularly for the accurate diagnosis of antiphospholipid syndrome, including confirmation and documentation of positive laboratory tests at least 12 weeks after the initial positive test.

They recommend that while awaiting confirmatory testing, patients with suspected antiphospholipid syndrome should avoid DOACs, and that “strong consideration” should be given to switching essentially all antiphospholipid syndrome patients currently receiving DOACs to vitamin K antagonists.

Dr. Bikdeli is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters and is supported by the Scott Schoen and Nancy Adams IGNITE Award from the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital and a Career Development Award from the American Heart Association and VIVA Physicians. Dr. Crowther has received personal funding from AstraZeneca, Precision Biologics, Hemostasis Reference Laboratories, Syneos Health, Bayer, Pfizer, and CSL Behring; and holds the Leo Pharma Chair in Thromboembolism Research, which is endowed at McMaster University. Dr. Jones is supported by a career development award from the National Heart, Lung, and Blood Institute; and Dr. Witt is supported by grant funding from the Agency for Healthcare Research and Quality.

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

Patients with thrombotic antiphospholipid syndrome are better treated with a vitamin K antagonist, such as warfarin, rather than a direct oral anticoagulant (DOAC), a new systematic review and meta-analysis suggests.

“Our study is showing that in randomized controlled trials in patients with thrombotic antiphospholipid syndrome, the risk of arterial thrombotic events, particularly stroke, is significantly increased with DOACs vs. vitamin K antagonists,” senior author, Behnood Bikdeli, MD, Brigham and Women’s Hospital, Boston, told this news organization. “These results probably suggest that DOACs are not the optimal regimen for patients with thrombotic antiphospholipid syndrome.”

The study was published online in the Journal of the American College of Cardiology.
 

Autoimmune disorder

Thrombotic antiphospholipid syndrome is a systemic autoimmune disorder characterized by recurrent arterial and/or venous thrombotic events.

Dr. Bikdeli estimates that antiphospholipid syndrome is the cause of 50,000-100,000 strokes, 100,000 cases of myocardial infarction, and 30,000 cases of deep vein thrombosis every year.

“It is a serious condition, and these are a high-risk and complex group of patients,” he said.

The standard treatment has been anticoagulation with a vitamin K antagonist such as warfarin. “But this is a cumbersome treatment, with many drug interactions and the need for INR [International Normalized Ratio] monitoring, which can be difficult to manage in patients with antiphospholipid syndrome as there can sometimes be falsely abnormal numbers,” Dr. Bikdeli noted. “Because of these challenges, it looked very promising to explore the use of DOACs in this population.”

Four main randomized trials have been conducted to investigate the use of DOACs in antiphospholipid syndrome – three with rivaroxaban and one with apixaban. “These trials were all quite small and, while they did not show definite results, some of them suggested nonsignificant findings of slightly worse outcomes for DOACs vs. vitamin K antagonists. But there is a lot of uncertainty, and it is difficult to look at subgroups in such small trials,” Dr. Bikdeli said. “There are many questions remaining about whether we should use DOACs in patients with antiphospholipid syndrome and, if so, which particular subgroups.”

The authors therefore performed a systematic review and meta-analysis of randomized controlled trials that compared DOACs with vitamin K antagonists in patients with antiphospholipid syndrome. They also contacted the principal investigators of the trials to obtain additional unpublished aggregate level data on specific subgroups.

Four open-label randomized controlled trials involving 472 patients were included in the meta-analysis.

Overall, the use of DOACs, compared with vitamin K antagonists, was associated with increased odds of subsequent arterial thrombotic events (odds ratio, 5.43; P < .001), especially stroke.

The odds of subsequent venous thrombotic events or major bleeding were not significantly different between the two groups. Most findings were consistent within subgroups.

“Our results show that use of DOACs vs. vitamin K antagonists is associated with increased risk of arterial thrombotic events – a risk that is primarily driven by a significant increase in the risk of stroke,” Dr. Bikdeli commented.

When looking at subgroups of interest, it was previously thought that DOACs may not be so effective in the so-called “triple-positive” antiphospholipid patients. These patients have three different types of antibodies and have the highest risk of thrombosis, Dr. Bikdeli noted.

“But one of the interesting findings of our study is that the results are actually consistent in women vs. men and in people who have triple-positive antibodies and those who had double- or single-positive antibodies,” he said. “Our analyses did not show effect modification by antibody subgroups. They suggest similar trends towards worse outcomes in all subgroups.”   

“From these results, I would be similarly concerned to use DOACs even if someone has double-positive or single-positive antiphospholipid antibodies,” he added.

Dr. Bikdeli said he would still recommend shared decision-making with patients. “If I have a patient who has thrombotic antiphospholipid syndrome, I would share my reservation about DOACs, but there are multiple factors that come into decision-making. If someone has difficulty with checking INRs, we may make an informed choice and still use a DOAC, but patients need to know that there is likely an excess risk of subsequent arterial events with DOACs, compared with a vitamin K antagonist.”

He noted that it is still not completely clear on the situation for people with single-positive antiphospholipid syndrome or the type of antibody that is present. It is also possible that a higher dose of DOAC could be more effective, a strategy that is being investigated in a separate randomized trial currently ongoing.

“But for routine practice I would have concerns about using DOACs in antiphospholipid syndrome patients in general,” he said. “For triple positive there is more data and greater concern, but I wouldn’t give a pass for a double- or single-positive patient either.”

The reason why DOACs would be less effective than vitamin K antagonists in antiphospholipid syndrome is not known.

“That is the million-dollar question,” Dr. Bikdeli commented. “DOACs have been such helpful drugs for many patients and clinicians as well. But we have seen that they are not optimal in a series of scenarios now – patients with mechanical heart valves, patients with rheumatic [atrial fibrillaton], and now patients with thrombotic antiphospholipid syndrome.”

One hypothesis is that these patients have some more components of inflammation and are more prone to blood clots, and because vitamin K antagonists work at several parts of the coagulation cascade, they might be more successful, compared with the more targeted DOAC therapy. “But I think we need more studies to fully understand this,” he said.

‘Important implications’

In an accompanying editorial,Mark A. Crowther, MD, McMaster University, Hamilton, Ont., and Aubrey E. Jones, PharmD, and Daniel M. Witt, PharmD, both of the University of Utah College of Pharmacy, Salt Lake City, say that: “As the quality of the evidence was rated ‘high’ for the arterial thrombosis outcome and ‘moderate’ for the venous thrombosis and bleeding outcomes, these results should lead to a revision of evidence-based guidelines to recommend against using DOACs as an option for most patients with thrombotic antiphospholipid syndrome.”

They add that this recommendation for vitamin K antagonists also applies to patients previously thought to be at lower risk from antiphospholipid syndrome – including those with only one or two positive serological tests and those with only prior venous thrombosis.

The editorialists point out that this will have important implications, particularly for the accurate diagnosis of antiphospholipid syndrome, including confirmation and documentation of positive laboratory tests at least 12 weeks after the initial positive test.

They recommend that while awaiting confirmatory testing, patients with suspected antiphospholipid syndrome should avoid DOACs, and that “strong consideration” should be given to switching essentially all antiphospholipid syndrome patients currently receiving DOACs to vitamin K antagonists.

Dr. Bikdeli is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters and is supported by the Scott Schoen and Nancy Adams IGNITE Award from the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital and a Career Development Award from the American Heart Association and VIVA Physicians. Dr. Crowther has received personal funding from AstraZeneca, Precision Biologics, Hemostasis Reference Laboratories, Syneos Health, Bayer, Pfizer, and CSL Behring; and holds the Leo Pharma Chair in Thromboembolism Research, which is endowed at McMaster University. Dr. Jones is supported by a career development award from the National Heart, Lung, and Blood Institute; and Dr. Witt is supported by grant funding from the Agency for Healthcare Research and Quality.

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