Rheumatology News

“When 900-years-old you reach, look as good you will not.” –Yoda

I’ve been on a roll lately: 100, 94, 90, 97, 94. These aren’t grades or even what I scratched on my scorecard for 18 holes (that’s more like 112), but rather patients I’ve seen.

Our oldest-old have been in COVID-19 protection for the last couple of years and only now feel safe to come out again. Many have skin cancers. Some of them have many. I’m grateful that for all their health problems, basal cell carcinomas at least I can cure. And while I treat them, I get the benefit of hearing directly from our elders. I love asking them for general life advice. Here are a few things I learned.

From a 94-year-old woman who was just discharged from the hospital for sepsis: First, sepsis can sneak up from behind and jump you when you’re 94. She was sitting in a waiting room for a routine exam when she passed out and woke up in the ICU. She made it home and is back on her feet, literally. When I asked her how she made it though, she was very matter of fact. Trust that the doctors know what’s right. Trust that someone will tell you what to do next. Trust that you know your own body and what you can and cannot do. Ask for help, then simply trust it will all work out. It usually does.

From a 97-year-old fighter pilot who fought in the Korean War: Let regrets drop away and live to fight another day. He’s had multiple marriages, built and lost companies, been fired and fired at, and made some doozy mistakes, some that caused considerable pain and collateral damage. But each day is new and requires your best. He has lived long enough to love dozens of grandkids and give away more than what most people ever make. His bottom line, if you worry and fret and regret, you’ll make even more mistakes ahead. Look ahead, the ground never comes up from behind you.

From a 94-year-old whose son was killed in a car accident nearly 60 years ago: You can be both happy and sad. When she retold the story of how the police knocked on her door with the news that her son was dead, she started to cry. Even 60 years isn’t long enough to blunt such pain. She still thinks of him often and to this day sometimes finds it difficult to believe he’s gone. Such pain never leaves you. But she is still a happy person with countless joys and is still having such fun. If you live long enough, both will likely be true.

From a 90-year old who still played tennis: “Just one and one.” That is, one beer and one shot, every day. No more. No less. I daren’t say I recommend this one; however, it might also be the social aspect of drinking that matters. He also advised to be free with friendships. You’ll have many people come in and out of your life; be open to new ones all the time. Also sometimes let your friends win.

From a 100-year-old, I asked how he managed to get through the Great Depression, WWII, civil unrest of the 1950s, and the Vietnam War. His reply? “To be honest, I’ve never seen anything quite like this before.”

When there’s time, consider asking for advice from those elders who happen to have an appointment with you. Bring you wisdom, they will.

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

“When 900-years-old you reach, look as good you will not.” –Yoda

I’ve been on a roll lately: 100, 94, 90, 97, 94. These aren’t grades or even what I scratched on my scorecard for 18 holes (that’s more like 112), but rather patients I’ve seen.

Our oldest-old have been in COVID-19 protection for the last couple of years and only now feel safe to come out again. Many have skin cancers. Some of them have many. I’m grateful that for all their health problems, basal cell carcinomas at least I can cure. And while I treat them, I get the benefit of hearing directly from our elders. I love asking them for general life advice. Here are a few things I learned.

From a 94-year-old woman who was just discharged from the hospital for sepsis: First, sepsis can sneak up from behind and jump you when you’re 94. She was sitting in a waiting room for a routine exam when she passed out and woke up in the ICU. She made it home and is back on her feet, literally. When I asked her how she made it though, she was very matter of fact. Trust that the doctors know what’s right. Trust that someone will tell you what to do next. Trust that you know your own body and what you can and cannot do. Ask for help, then simply trust it will all work out. It usually does.

From a 97-year-old fighter pilot who fought in the Korean War: Let regrets drop away and live to fight another day. He’s had multiple marriages, built and lost companies, been fired and fired at, and made some doozy mistakes, some that caused considerable pain and collateral damage. But each day is new and requires your best. He has lived long enough to love dozens of grandkids and give away more than what most people ever make. His bottom line, if you worry and fret and regret, you’ll make even more mistakes ahead. Look ahead, the ground never comes up from behind you.

From a 94-year-old whose son was killed in a car accident nearly 60 years ago: You can be both happy and sad. When she retold the story of how the police knocked on her door with the news that her son was dead, she started to cry. Even 60 years isn’t long enough to blunt such pain. She still thinks of him often and to this day sometimes finds it difficult to believe he’s gone. Such pain never leaves you. But she is still a happy person with countless joys and is still having such fun. If you live long enough, both will likely be true.

From a 90-year old who still played tennis: “Just one and one.” That is, one beer and one shot, every day. No more. No less. I daren’t say I recommend this one; however, it might also be the social aspect of drinking that matters. He also advised to be free with friendships. You’ll have many people come in and out of your life; be open to new ones all the time. Also sometimes let your friends win.

From a 100-year-old, I asked how he managed to get through the Great Depression, WWII, civil unrest of the 1950s, and the Vietnam War. His reply? “To be honest, I’ve never seen anything quite like this before.”

When there’s time, consider asking for advice from those elders who happen to have an appointment with you. Bring you wisdom, they will.

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

“When 900-years-old you reach, look as good you will not.” –Yoda

I’ve been on a roll lately: 100, 94, 90, 97, 94. These aren’t grades or even what I scratched on my scorecard for 18 holes (that’s more like 112), but rather patients I’ve seen.

Our oldest-old have been in COVID-19 protection for the last couple of years and only now feel safe to come out again. Many have skin cancers. Some of them have many. I’m grateful that for all their health problems, basal cell carcinomas at least I can cure. And while I treat them, I get the benefit of hearing directly from our elders. I love asking them for general life advice. Here are a few things I learned.

From a 94-year-old woman who was just discharged from the hospital for sepsis: First, sepsis can sneak up from behind and jump you when you’re 94. She was sitting in a waiting room for a routine exam when she passed out and woke up in the ICU. She made it home and is back on her feet, literally. When I asked her how she made it though, she was very matter of fact. Trust that the doctors know what’s right. Trust that someone will tell you what to do next. Trust that you know your own body and what you can and cannot do. Ask for help, then simply trust it will all work out. It usually does.

From a 97-year-old fighter pilot who fought in the Korean War: Let regrets drop away and live to fight another day. He’s had multiple marriages, built and lost companies, been fired and fired at, and made some doozy mistakes, some that caused considerable pain and collateral damage. But each day is new and requires your best. He has lived long enough to love dozens of grandkids and give away more than what most people ever make. His bottom line, if you worry and fret and regret, you’ll make even more mistakes ahead. Look ahead, the ground never comes up from behind you.

From a 94-year-old whose son was killed in a car accident nearly 60 years ago: You can be both happy and sad. When she retold the story of how the police knocked on her door with the news that her son was dead, she started to cry. Even 60 years isn’t long enough to blunt such pain. She still thinks of him often and to this day sometimes finds it difficult to believe he’s gone. Such pain never leaves you. But she is still a happy person with countless joys and is still having such fun. If you live long enough, both will likely be true.

From a 90-year old who still played tennis: “Just one and one.” That is, one beer and one shot, every day. No more. No less. I daren’t say I recommend this one; however, it might also be the social aspect of drinking that matters. He also advised to be free with friendships. You’ll have many people come in and out of your life; be open to new ones all the time. Also sometimes let your friends win.

From a 100-year-old, I asked how he managed to get through the Great Depression, WWII, civil unrest of the 1950s, and the Vietnam War. His reply? “To be honest, I’ve never seen anything quite like this before.”

When there’s time, consider asking for advice from those elders who happen to have an appointment with you. Bring you wisdom, they will.

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

Adding a single cycle of rituximab to belimumab (Benlysta) did not improve disease control for patients with systemic lupus erythematosus (SLE) in comparison with belimumab alone in a phase 3, randomized, controlled trial.

Among patients with SLE who were randomly assigned to receive belimumab with either rituximab, placebo, or standard care, there were no statistically significant differences between the rituximab and placebo arms for the primary endpoint of the proportion of patients with disease control at week 52 or in the secondary endpoints of clinical remission at week 64 or disease control at week 104, Cynthia Aranow, MD, reported in a late-breaking poster session presented during the virtual annual meeting of the American College of Rheumatology.

“Using a new, clinically meaningful endpoint underscores the efficacy of belimumab for disease control, with some patients maintaining disease control with considerable reductions in steroids, and no immunosuppressants,” said Dr. Aranow, a rheumatologist specializing in SLE and RA in New York and director of the Clinical Autoimmunity Center of Excellence at Feinstein Institutes for Medical Research, Manhasset, N.Y.

Use of the combination of belimumab and rituximab was, however, associated with significant improvement over belimumab and placebo in several secondary efficacy endpoints.

Investigators in the randomized, controlled trial, dubbed BLISS-BELIEVE, had previously published a rationale for sequential therapy with belimumab, a human monoclonal antibody that binds to soluble B-lymphocyte stimulator, and rituximab, a B-cell–depleting anti-CD20 monoclonal antibody.

“These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE,” they wrote in an article published in 2019 in BMJ Open.
 

Three-arm trial

The investigators screened 396 patients, of whom 292 were randomly assigned in a 1:2:1 ratio to receive either subcutaneous belimumab 200 mg/wk plus intravenous placebo at weeks 4 and 6 (BEL/PBO, 72 patients), belimumab plus IV rituximab 1,000 mg at weeks 4 and 6 (BEL/RTX, 144 patients), or open-label belimumab plus standard therapy. Patients were allowed to continue taking antimalarial and nonsteroidal anti-inflammatory drugs throughout the study.

The primary disease-control endpoint was defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 2 or less, achieved without other immunosuppression, equivalent to that achieved with prednisone 5 mg/day or less.

As noted before, there were no significant differences between the BEL/RTX and BEL/PBO arms in either disease control at week 52 or in the secondary endpoints of clinical remission at week 64 (SLEDAI-2K score, 0) or in the proportion of patients with disease control at week 104.

However, use of BEL/RTX was associated with a significantly longer duration of disease control through 52 weeks than was BEL/PBO (mean, 105.4 days vs. 60.1 days; P = .0188) and with a large SLEDAI-2K mean change from baseline at week 104 (–7.2 vs 5.1; P = .0033).

In addition, there was a trend toward a shift in proteinuria from baseline high (>0.5 g/24 h) to normal in the BEL/RTX group at week 52 and a significantly greater shift at week 104 (P = .0085).

The overall adverse event profiles were generally consistent with those of the individual agents, although serious infections and infestations occurred more frequently with BEL/RTX than BEL/PBO.
 

Further analyses planned to look for subgroups that benefit

In a poster discussion session, Akshat Khanna, PhD, of Newtown, Pa., a consultant with Effimed Life Sciences Research, asked Dr. Aranow about the rationale for giving rituximab and belimumab concurrently and noted that, in the BEAT-LUPUS and CALIBRATE trials, anti-CD20 agents were given first, followed by belimumab, to prevent activation of humoral immunity.

“The two B-cell agents were given sequentially. Belimumab was given first to maximize the effect of peripheral B-cell depletion and [was] then continued after rituximab to suppress the elevation [of B-lymphocyte stimulator] that occurs after rituximab monotherapy. We used this approach (instead of that used in CALIBRATE and BEAT LUPUS), as we thought this might be more efficacious,” she explained.

When asked whether there were subgroups of patients who might still benefit from the combination, compared with belimumab alone, Dr. Aranow replied: “There may be individual patients in which it might be considered. Further analyses of the data are ongoing/planned.”

The study was supported by GlaxoSmithKline. Dr. Aranow has received grant/research support from GlaxoSmithKline and has consulted for Bristol-Myers Squibb. Dr. Khanna has disclosed no relevant financial relationships.

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

Adding a single cycle of rituximab to belimumab (Benlysta) did not improve disease control for patients with systemic lupus erythematosus (SLE) in comparison with belimumab alone in a phase 3, randomized, controlled trial.

Among patients with SLE who were randomly assigned to receive belimumab with either rituximab, placebo, or standard care, there were no statistically significant differences between the rituximab and placebo arms for the primary endpoint of the proportion of patients with disease control at week 52 or in the secondary endpoints of clinical remission at week 64 or disease control at week 104, Cynthia Aranow, MD, reported in a late-breaking poster session presented during the virtual annual meeting of the American College of Rheumatology.

“Using a new, clinically meaningful endpoint underscores the efficacy of belimumab for disease control, with some patients maintaining disease control with considerable reductions in steroids, and no immunosuppressants,” said Dr. Aranow, a rheumatologist specializing in SLE and RA in New York and director of the Clinical Autoimmunity Center of Excellence at Feinstein Institutes for Medical Research, Manhasset, N.Y.

Use of the combination of belimumab and rituximab was, however, associated with significant improvement over belimumab and placebo in several secondary efficacy endpoints.

Investigators in the randomized, controlled trial, dubbed BLISS-BELIEVE, had previously published a rationale for sequential therapy with belimumab, a human monoclonal antibody that binds to soluble B-lymphocyte stimulator, and rituximab, a B-cell–depleting anti-CD20 monoclonal antibody.

“These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE,” they wrote in an article published in 2019 in BMJ Open.
 

Three-arm trial

The investigators screened 396 patients, of whom 292 were randomly assigned in a 1:2:1 ratio to receive either subcutaneous belimumab 200 mg/wk plus intravenous placebo at weeks 4 and 6 (BEL/PBO, 72 patients), belimumab plus IV rituximab 1,000 mg at weeks 4 and 6 (BEL/RTX, 144 patients), or open-label belimumab plus standard therapy. Patients were allowed to continue taking antimalarial and nonsteroidal anti-inflammatory drugs throughout the study.

The primary disease-control endpoint was defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 2 or less, achieved without other immunosuppression, equivalent to that achieved with prednisone 5 mg/day or less.

As noted before, there were no significant differences between the BEL/RTX and BEL/PBO arms in either disease control at week 52 or in the secondary endpoints of clinical remission at week 64 (SLEDAI-2K score, 0) or in the proportion of patients with disease control at week 104.

However, use of BEL/RTX was associated with a significantly longer duration of disease control through 52 weeks than was BEL/PBO (mean, 105.4 days vs. 60.1 days; P = .0188) and with a large SLEDAI-2K mean change from baseline at week 104 (–7.2 vs 5.1; P = .0033).

In addition, there was a trend toward a shift in proteinuria from baseline high (>0.5 g/24 h) to normal in the BEL/RTX group at week 52 and a significantly greater shift at week 104 (P = .0085).

The overall adverse event profiles were generally consistent with those of the individual agents, although serious infections and infestations occurred more frequently with BEL/RTX than BEL/PBO.
 

Further analyses planned to look for subgroups that benefit

In a poster discussion session, Akshat Khanna, PhD, of Newtown, Pa., a consultant with Effimed Life Sciences Research, asked Dr. Aranow about the rationale for giving rituximab and belimumab concurrently and noted that, in the BEAT-LUPUS and CALIBRATE trials, anti-CD20 agents were given first, followed by belimumab, to prevent activation of humoral immunity.

“The two B-cell agents were given sequentially. Belimumab was given first to maximize the effect of peripheral B-cell depletion and [was] then continued after rituximab to suppress the elevation [of B-lymphocyte stimulator] that occurs after rituximab monotherapy. We used this approach (instead of that used in CALIBRATE and BEAT LUPUS), as we thought this might be more efficacious,” she explained.

When asked whether there were subgroups of patients who might still benefit from the combination, compared with belimumab alone, Dr. Aranow replied: “There may be individual patients in which it might be considered. Further analyses of the data are ongoing/planned.”

The study was supported by GlaxoSmithKline. Dr. Aranow has received grant/research support from GlaxoSmithKline and has consulted for Bristol-Myers Squibb. Dr. Khanna has disclosed no relevant financial relationships.

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

Adding a single cycle of rituximab to belimumab (Benlysta) did not improve disease control for patients with systemic lupus erythematosus (SLE) in comparison with belimumab alone in a phase 3, randomized, controlled trial.

Among patients with SLE who were randomly assigned to receive belimumab with either rituximab, placebo, or standard care, there were no statistically significant differences between the rituximab and placebo arms for the primary endpoint of the proportion of patients with disease control at week 52 or in the secondary endpoints of clinical remission at week 64 or disease control at week 104, Cynthia Aranow, MD, reported in a late-breaking poster session presented during the virtual annual meeting of the American College of Rheumatology.

“Using a new, clinically meaningful endpoint underscores the efficacy of belimumab for disease control, with some patients maintaining disease control with considerable reductions in steroids, and no immunosuppressants,” said Dr. Aranow, a rheumatologist specializing in SLE and RA in New York and director of the Clinical Autoimmunity Center of Excellence at Feinstein Institutes for Medical Research, Manhasset, N.Y.

Use of the combination of belimumab and rituximab was, however, associated with significant improvement over belimumab and placebo in several secondary efficacy endpoints.

Investigators in the randomized, controlled trial, dubbed BLISS-BELIEVE, had previously published a rationale for sequential therapy with belimumab, a human monoclonal antibody that binds to soluble B-lymphocyte stimulator, and rituximab, a B-cell–depleting anti-CD20 monoclonal antibody.

“These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE,” they wrote in an article published in 2019 in BMJ Open.
 

Three-arm trial

The investigators screened 396 patients, of whom 292 were randomly assigned in a 1:2:1 ratio to receive either subcutaneous belimumab 200 mg/wk plus intravenous placebo at weeks 4 and 6 (BEL/PBO, 72 patients), belimumab plus IV rituximab 1,000 mg at weeks 4 and 6 (BEL/RTX, 144 patients), or open-label belimumab plus standard therapy. Patients were allowed to continue taking antimalarial and nonsteroidal anti-inflammatory drugs throughout the study.

The primary disease-control endpoint was defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 2 or less, achieved without other immunosuppression, equivalent to that achieved with prednisone 5 mg/day or less.

As noted before, there were no significant differences between the BEL/RTX and BEL/PBO arms in either disease control at week 52 or in the secondary endpoints of clinical remission at week 64 (SLEDAI-2K score, 0) or in the proportion of patients with disease control at week 104.

However, use of BEL/RTX was associated with a significantly longer duration of disease control through 52 weeks than was BEL/PBO (mean, 105.4 days vs. 60.1 days; P = .0188) and with a large SLEDAI-2K mean change from baseline at week 104 (–7.2 vs 5.1; P = .0033).

In addition, there was a trend toward a shift in proteinuria from baseline high (>0.5 g/24 h) to normal in the BEL/RTX group at week 52 and a significantly greater shift at week 104 (P = .0085).

The overall adverse event profiles were generally consistent with those of the individual agents, although serious infections and infestations occurred more frequently with BEL/RTX than BEL/PBO.
 

Further analyses planned to look for subgroups that benefit

In a poster discussion session, Akshat Khanna, PhD, of Newtown, Pa., a consultant with Effimed Life Sciences Research, asked Dr. Aranow about the rationale for giving rituximab and belimumab concurrently and noted that, in the BEAT-LUPUS and CALIBRATE trials, anti-CD20 agents were given first, followed by belimumab, to prevent activation of humoral immunity.

“The two B-cell agents were given sequentially. Belimumab was given first to maximize the effect of peripheral B-cell depletion and [was] then continued after rituximab to suppress the elevation [of B-lymphocyte stimulator] that occurs after rituximab monotherapy. We used this approach (instead of that used in CALIBRATE and BEAT LUPUS), as we thought this might be more efficacious,” she explained.

When asked whether there were subgroups of patients who might still benefit from the combination, compared with belimumab alone, Dr. Aranow replied: “There may be individual patients in which it might be considered. Further analyses of the data are ongoing/planned.”

The study was supported by GlaxoSmithKline. Dr. Aranow has received grant/research support from GlaxoSmithKline and has consulted for Bristol-Myers Squibb. Dr. Khanna has disclosed no relevant financial relationships.

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

Additional analyses of a postmarketing trial that was required after the Food and Drug Administration’s approval of the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR) has identified characteristics of older patients with rheumatoid arthritis with at least one cardiovascular risk factor who may be at higher risk for major adverse cardiovascular events (MACE) when taking the drug.

Results from the phase 3b/4 ORAL Surveillance trial presented at the virtual annual meeting of the American College of Rheumatology show that people taking tofacitinib for RA with at least one cardiovascular (CV) risk factor had a nonsignificant higher risk for MACE than did people taking tumor necrosis factor inhibitors (TNFi), with the risk from tofacitinib more pronounced in current smokers, aspirin users, people older than 65 years, and men, compared with women.

“It is the first large, randomized safety study of active RA patients with increased CV risk comparing tofacitinib to TNF inhibition,” study author Christina Charles-Schoeman, MD, said in an interview. “These data emphasize the importance of assessing baseline CV risk when treating patients with RA.” Dr. Charles-Schoeman is chief of rheumatology at the University of California, Los Angeles.

The results shed further light on the trial’s findings, which the FDA used in September 2021 to mandate boxed warnings about the risk of MI or stroke, cancer, venous thromboembolism, and death, as well as updated indications, for tofacitinib and other JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq). The FDA limited all approved uses of these three medications to patients who have not responded well to TNFi to ensure their benefits outweigh their risks.

Tofacitinib is indicated for RA, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. Baricitinib and upadacitinib are approved only for RA.

While the overall results of the trial results show nonsignificant increased incidence rates for MACE in tofacitinib users versus TNFI users, Katherine Liao, MD, a rheumatologist at Brigham and Women’s Hospital in Boston, noted that more information is needed to determine who is at greatest risk. “Another thing to keep in mind is, while there was evidence of an elevated relative risk for MACE, compared to TNFi, the absolute risk, based on the numbers what we know so far, is small,” she said.

The trial compared two different doses of tofacitinib – 5 mg (1,455 patients) and 10 mg (n = 1,456) twice daily – and TNFi (n = 1,451) in people with moderate to severe RA over age 50. Patient characteristics were similar across all three treatment arms, Dr. Charles-Schoeman said. All patients had inadequate response to methotrexate, and about 57% in all three treatment groups were taking corticosteroids. The 10-mg tofacitinib patients switched to the 5-mg dose in February 2019 but represent the 10-mg group in the study analysis.

ORAL Surveillance demonstrated a 24% greater risk of MACE in the 5-mg tofacitinib patients and a 43% heightened risk the 10-mg group, compared with patients who received a TNFi.

The differentiating factor for MACE incidence was MI. The higher- and lower-dose tofacitinib groups had 69% and 80% greater risk for MI. While the risk for fatal MI were similar across all three treatment groups, the risk for nonfatal MI were more than doubled in the respective tofacitinib groups: hazard ratios of 2.32 and 2.08. The incidence of stroke was similar across all three arms, Dr. Charles-Schoeman said.

The study identified a number of baseline characteristics as independent overall risk factors for MACE across all treatment groups. Current smoking and aspirin use more than doubled the risk (HR, 2.18; P < .0001 and HR, 2.11; P = .004, respectively), while age greater than 65 years and male sex approached that level (HR, 1.81; P = .0011 and HR, 1.81; P = .0015) approached that level. Other factors that elevated the risk of MACE to a lesser extent were a history of diabetes, hypertension or coronary artery procedures, and a total cholesterol to HDL ratio greater than4.

Other ORAL Surveillance subanalyses and tofacitinib real-world data reported

This was one of several analyses presented at ACR 2021 that compared adverse event risks for tofacitinib versus TNFi drugs. A separate analysis of claims data from patients with RA in two U.S. insurance databases plus Medicare found a statistically nonsignificant increased risk of adverse CV outcomes (MI or stroke) with tofacitinib, compared with TNFi users, among patients who met the same inclusion and exclusion criteria of the ORAL Surveillance trial but not in a “real-world evidence” cohort of more than 102,000 patients with RA in routine care from the databases.

Two additional ORAL Surveillance analyses presented at ACR 2021 gave details about risk factors for higher rates of malignancies and venous thromboembolic events found in patients taking tofacitinib with at least one CV risk factor. As would be expected, older age (≥65 vs. 50-64 years) and current or past smoking (vs. never smoking) were independent risk factors for higher malignancy rates across all treatment arms. Pulmonary embolism events across treatment groups were independently associated with a history of venous thromboembolism, baseline use of oral contraceptives or hormone replacement therapy, baseline body mass index of at least 30 kg/m², age 65 or older, and history of hypertension.

The ORAL Surveillance findings are worth considering when determining treatments for RA patients with CV risk factors, Dr. Charles-Schoeman said. “Tofacitinib remains an effective RA treatment,” she said. “The choice of specific RA treatment for any patient remains an individual decision between the patient and physician, which is decided based on a number of different factors. This new study provides additional information regarding both tofacitinib as well as traditional CV risk factors for discussion with the patient.”

The ORAL Surveillance results may give rheumatologists reason to rethink use of tofacitinib in some patients with CV risk, said Dr. Liao of Brigham and Women’s Hospital in Boston. “Currently, we have limited data and are still awaiting a report of the full trial results,” she said in an interview. “Based on the data available, I can think of a few patients in my clinic where I would reconsider use of these drugs, i.e., history of heart attack with stable angina, especially if there are other options.” However, she noted that many patients on tofacitinib have already failed on older treatments.

These data emphasize the importance of addressing CV risk with patients, said Brittany N. Weber, MD, PhD, a cardio-rheumatologist at Brigham and Women’s Hospital who works with Dr. Liao. “It is also an opportunity to discuss modification of risk factors and to discuss primary prevention therapies, such as statin therapy, where appropriate,” she added. “Based on the individual’s cardiovascular risk, there may be a role for further risk stratification to further understand an individual’s risk, which can also inform primary prevention cardiovascular therapies and help guide these discussions.” Risk stratification could include cardiac CT for calcium scoring or cardiac coronary CT angiography for determining atherosclerotic burden.

The study was sponsored by Pfizer. Dr. Charles-Schoeman disclosed relationships with AbbVie, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Regeneron-Sanofi. Dr. Liao and Dr. Weber have no relevant disclosures.

Additional analyses of a postmarketing trial that was required after the Food and Drug Administration’s approval of the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR) has identified characteristics of older patients with rheumatoid arthritis with at least one cardiovascular risk factor who may be at higher risk for major adverse cardiovascular events (MACE) when taking the drug.

Results from the phase 3b/4 ORAL Surveillance trial presented at the virtual annual meeting of the American College of Rheumatology show that people taking tofacitinib for RA with at least one cardiovascular (CV) risk factor had a nonsignificant higher risk for MACE than did people taking tumor necrosis factor inhibitors (TNFi), with the risk from tofacitinib more pronounced in current smokers, aspirin users, people older than 65 years, and men, compared with women.

“It is the first large, randomized safety study of active RA patients with increased CV risk comparing tofacitinib to TNF inhibition,” study author Christina Charles-Schoeman, MD, said in an interview. “These data emphasize the importance of assessing baseline CV risk when treating patients with RA.” Dr. Charles-Schoeman is chief of rheumatology at the University of California, Los Angeles.

The results shed further light on the trial’s findings, which the FDA used in September 2021 to mandate boxed warnings about the risk of MI or stroke, cancer, venous thromboembolism, and death, as well as updated indications, for tofacitinib and other JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq). The FDA limited all approved uses of these three medications to patients who have not responded well to TNFi to ensure their benefits outweigh their risks.

Tofacitinib is indicated for RA, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. Baricitinib and upadacitinib are approved only for RA.

While the overall results of the trial results show nonsignificant increased incidence rates for MACE in tofacitinib users versus TNFI users, Katherine Liao, MD, a rheumatologist at Brigham and Women’s Hospital in Boston, noted that more information is needed to determine who is at greatest risk. “Another thing to keep in mind is, while there was evidence of an elevated relative risk for MACE, compared to TNFi, the absolute risk, based on the numbers what we know so far, is small,” she said.

The trial compared two different doses of tofacitinib – 5 mg (1,455 patients) and 10 mg (n = 1,456) twice daily – and TNFi (n = 1,451) in people with moderate to severe RA over age 50. Patient characteristics were similar across all three treatment arms, Dr. Charles-Schoeman said. All patients had inadequate response to methotrexate, and about 57% in all three treatment groups were taking corticosteroids. The 10-mg tofacitinib patients switched to the 5-mg dose in February 2019 but represent the 10-mg group in the study analysis.

ORAL Surveillance demonstrated a 24% greater risk of MACE in the 5-mg tofacitinib patients and a 43% heightened risk the 10-mg group, compared with patients who received a TNFi.

The differentiating factor for MACE incidence was MI. The higher- and lower-dose tofacitinib groups had 69% and 80% greater risk for MI. While the risk for fatal MI were similar across all three treatment groups, the risk for nonfatal MI were more than doubled in the respective tofacitinib groups: hazard ratios of 2.32 and 2.08. The incidence of stroke was similar across all three arms, Dr. Charles-Schoeman said.

The study identified a number of baseline characteristics as independent overall risk factors for MACE across all treatment groups. Current smoking and aspirin use more than doubled the risk (HR, 2.18; P < .0001 and HR, 2.11; P = .004, respectively), while age greater than 65 years and male sex approached that level (HR, 1.81; P = .0011 and HR, 1.81; P = .0015) approached that level. Other factors that elevated the risk of MACE to a lesser extent were a history of diabetes, hypertension or coronary artery procedures, and a total cholesterol to HDL ratio greater than4.

Other ORAL Surveillance subanalyses and tofacitinib real-world data reported

This was one of several analyses presented at ACR 2021 that compared adverse event risks for tofacitinib versus TNFi drugs. A separate analysis of claims data from patients with RA in two U.S. insurance databases plus Medicare found a statistically nonsignificant increased risk of adverse CV outcomes (MI or stroke) with tofacitinib, compared with TNFi users, among patients who met the same inclusion and exclusion criteria of the ORAL Surveillance trial but not in a “real-world evidence” cohort of more than 102,000 patients with RA in routine care from the databases.

Two additional ORAL Surveillance analyses presented at ACR 2021 gave details about risk factors for higher rates of malignancies and venous thromboembolic events found in patients taking tofacitinib with at least one CV risk factor. As would be expected, older age (≥65 vs. 50-64 years) and current or past smoking (vs. never smoking) were independent risk factors for higher malignancy rates across all treatment arms. Pulmonary embolism events across treatment groups were independently associated with a history of venous thromboembolism, baseline use of oral contraceptives or hormone replacement therapy, baseline body mass index of at least 30 kg/m², age 65 or older, and history of hypertension.

The ORAL Surveillance findings are worth considering when determining treatments for RA patients with CV risk factors, Dr. Charles-Schoeman said. “Tofacitinib remains an effective RA treatment,” she said. “The choice of specific RA treatment for any patient remains an individual decision between the patient and physician, which is decided based on a number of different factors. This new study provides additional information regarding both tofacitinib as well as traditional CV risk factors for discussion with the patient.”

The ORAL Surveillance results may give rheumatologists reason to rethink use of tofacitinib in some patients with CV risk, said Dr. Liao of Brigham and Women’s Hospital in Boston. “Currently, we have limited data and are still awaiting a report of the full trial results,” she said in an interview. “Based on the data available, I can think of a few patients in my clinic where I would reconsider use of these drugs, i.e., history of heart attack with stable angina, especially if there are other options.” However, she noted that many patients on tofacitinib have already failed on older treatments.

These data emphasize the importance of addressing CV risk with patients, said Brittany N. Weber, MD, PhD, a cardio-rheumatologist at Brigham and Women’s Hospital who works with Dr. Liao. “It is also an opportunity to discuss modification of risk factors and to discuss primary prevention therapies, such as statin therapy, where appropriate,” she added. “Based on the individual’s cardiovascular risk, there may be a role for further risk stratification to further understand an individual’s risk, which can also inform primary prevention cardiovascular therapies and help guide these discussions.” Risk stratification could include cardiac CT for calcium scoring or cardiac coronary CT angiography for determining atherosclerotic burden.

The study was sponsored by Pfizer. Dr. Charles-Schoeman disclosed relationships with AbbVie, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Regeneron-Sanofi. Dr. Liao and Dr. Weber have no relevant disclosures.

Additional analyses of a postmarketing trial that was required after the Food and Drug Administration’s approval of the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR) has identified characteristics of older patients with rheumatoid arthritis with at least one cardiovascular risk factor who may be at higher risk for major adverse cardiovascular events (MACE) when taking the drug.

Results from the phase 3b/4 ORAL Surveillance trial presented at the virtual annual meeting of the American College of Rheumatology show that people taking tofacitinib for RA with at least one cardiovascular (CV) risk factor had a nonsignificant higher risk for MACE than did people taking tumor necrosis factor inhibitors (TNFi), with the risk from tofacitinib more pronounced in current smokers, aspirin users, people older than 65 years, and men, compared with women.

“It is the first large, randomized safety study of active RA patients with increased CV risk comparing tofacitinib to TNF inhibition,” study author Christina Charles-Schoeman, MD, said in an interview. “These data emphasize the importance of assessing baseline CV risk when treating patients with RA.” Dr. Charles-Schoeman is chief of rheumatology at the University of California, Los Angeles.

The results shed further light on the trial’s findings, which the FDA used in September 2021 to mandate boxed warnings about the risk of MI or stroke, cancer, venous thromboembolism, and death, as well as updated indications, for tofacitinib and other JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq). The FDA limited all approved uses of these three medications to patients who have not responded well to TNFi to ensure their benefits outweigh their risks.

Tofacitinib is indicated for RA, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. Baricitinib and upadacitinib are approved only for RA.

While the overall results of the trial results show nonsignificant increased incidence rates for MACE in tofacitinib users versus TNFI users, Katherine Liao, MD, a rheumatologist at Brigham and Women’s Hospital in Boston, noted that more information is needed to determine who is at greatest risk. “Another thing to keep in mind is, while there was evidence of an elevated relative risk for MACE, compared to TNFi, the absolute risk, based on the numbers what we know so far, is small,” she said.

The trial compared two different doses of tofacitinib – 5 mg (1,455 patients) and 10 mg (n = 1,456) twice daily – and TNFi (n = 1,451) in people with moderate to severe RA over age 50. Patient characteristics were similar across all three treatment arms, Dr. Charles-Schoeman said. All patients had inadequate response to methotrexate, and about 57% in all three treatment groups were taking corticosteroids. The 10-mg tofacitinib patients switched to the 5-mg dose in February 2019 but represent the 10-mg group in the study analysis.

ORAL Surveillance demonstrated a 24% greater risk of MACE in the 5-mg tofacitinib patients and a 43% heightened risk the 10-mg group, compared with patients who received a TNFi.

The differentiating factor for MACE incidence was MI. The higher- and lower-dose tofacitinib groups had 69% and 80% greater risk for MI. While the risk for fatal MI were similar across all three treatment groups, the risk for nonfatal MI were more than doubled in the respective tofacitinib groups: hazard ratios of 2.32 and 2.08. The incidence of stroke was similar across all three arms, Dr. Charles-Schoeman said.

The study identified a number of baseline characteristics as independent overall risk factors for MACE across all treatment groups. Current smoking and aspirin use more than doubled the risk (HR, 2.18; P < .0001 and HR, 2.11; P = .004, respectively), while age greater than 65 years and male sex approached that level (HR, 1.81; P = .0011 and HR, 1.81; P = .0015) approached that level. Other factors that elevated the risk of MACE to a lesser extent were a history of diabetes, hypertension or coronary artery procedures, and a total cholesterol to HDL ratio greater than4.

Other ORAL Surveillance subanalyses and tofacitinib real-world data reported

This was one of several analyses presented at ACR 2021 that compared adverse event risks for tofacitinib versus TNFi drugs. A separate analysis of claims data from patients with RA in two U.S. insurance databases plus Medicare found a statistically nonsignificant increased risk of adverse CV outcomes (MI or stroke) with tofacitinib, compared with TNFi users, among patients who met the same inclusion and exclusion criteria of the ORAL Surveillance trial but not in a “real-world evidence” cohort of more than 102,000 patients with RA in routine care from the databases.

Two additional ORAL Surveillance analyses presented at ACR 2021 gave details about risk factors for higher rates of malignancies and venous thromboembolic events found in patients taking tofacitinib with at least one CV risk factor. As would be expected, older age (≥65 vs. 50-64 years) and current or past smoking (vs. never smoking) were independent risk factors for higher malignancy rates across all treatment arms. Pulmonary embolism events across treatment groups were independently associated with a history of venous thromboembolism, baseline use of oral contraceptives or hormone replacement therapy, baseline body mass index of at least 30 kg/m², age 65 or older, and history of hypertension.

The ORAL Surveillance findings are worth considering when determining treatments for RA patients with CV risk factors, Dr. Charles-Schoeman said. “Tofacitinib remains an effective RA treatment,” she said. “The choice of specific RA treatment for any patient remains an individual decision between the patient and physician, which is decided based on a number of different factors. This new study provides additional information regarding both tofacitinib as well as traditional CV risk factors for discussion with the patient.”

The ORAL Surveillance results may give rheumatologists reason to rethink use of tofacitinib in some patients with CV risk, said Dr. Liao of Brigham and Women’s Hospital in Boston. “Currently, we have limited data and are still awaiting a report of the full trial results,” she said in an interview. “Based on the data available, I can think of a few patients in my clinic where I would reconsider use of these drugs, i.e., history of heart attack with stable angina, especially if there are other options.” However, she noted that many patients on tofacitinib have already failed on older treatments.

These data emphasize the importance of addressing CV risk with patients, said Brittany N. Weber, MD, PhD, a cardio-rheumatologist at Brigham and Women’s Hospital who works with Dr. Liao. “It is also an opportunity to discuss modification of risk factors and to discuss primary prevention therapies, such as statin therapy, where appropriate,” she added. “Based on the individual’s cardiovascular risk, there may be a role for further risk stratification to further understand an individual’s risk, which can also inform primary prevention cardiovascular therapies and help guide these discussions.” Risk stratification could include cardiac CT for calcium scoring or cardiac coronary CT angiography for determining atherosclerotic burden.

The study was sponsored by Pfizer. Dr. Charles-Schoeman disclosed relationships with AbbVie, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Regeneron-Sanofi. Dr. Liao and Dr. Weber have no relevant disclosures.

In November, the office manager of a San Antonio dermatology practice was sentenced to 46 months in prison for defrauding the practice of nearly $350,000 from patient billings and employee profit sharing accounts.

Per the indictment, the practice conducted a nonprofit educational symposium in 2012. A bank account was established to collect contributions for that event, which was supposed to be closed at its conclusion; but the office manager kept it open, and deposited practice receipts into it. She then used the account as her slush fund for travel, property payments, meal purchases, and other personal expenses on credit cards she fraudulently opened in the practice’s name. This continued for several years.

Because this case has received national attention, I am republishing my column on embezzlement, which includes recommendations that could prevent such unfortunate situations from occurring.

Few crimes are more easily overlooked than theft from within. Embezzlement remains far more common in medical offices than generally assumed – and it often occurs in full view of physicians who think everything is fine. Most embezzlers are not skillful or discreet; but their transgressions may go undetected for years, simply because no one suspects it is happening.

Detecting fraud is an inexact science. There is no textbook approach that one can follow, but a few simple measures will prevent or expose the most common forms:

Make it more difficult. Theft and embezzlement are usually products of opportunity, so minimize those opportunities. No one person should be in charge of the entire bookkeeping process: the person who enters charges should be different from the one who enters payments. The one who writes checks or makes electronic fund transfers should not balance the books, and so on. Internal audits should be done on a regular basis, and all employees should know that. Your accountant can help.

Reconcile cash receipts daily. Embezzlement does not require sophisticated technology; the most common form is simply taking cash out of the till. In a typical scenario, a patient pays a copay of $15 in cash; the receptionist records the payment as $5, and pockets the rest. Make sure a receipt is generated for every cash transaction, and that someone other than the person accepting cash reconciles the charges, receipts, and cash totals daily.

Inventory your stock. Cash isn’t the only susceptible commodity. If you sell cosmetics or other products, inventory your stock frequently. And office personnel are not the only potential thieves: Over a year ago, a locum tenens physician down the street conspired with a receptionist to take cash transactions for cosmetic neurotoxins and fillers “off the books” and split the spoils. That office was being ripped off twice; first for the neurotoxin and filler materials themselves, and then for the cash proceeds.

Separate all accounting duties. Another popular ploy is false invoicing for imaginary supplies. A friend’s experience provides a good example (retold with his permission): His bookkeeper wrote sizable checks to herself, disguising them in the ledger as payments to vendors commonly used by his practice. Since the same employee also balanced the checkbook, she got away with it for years. “It wasn’t at all clever,” he told me, “and I’m embarrassed to admit that it happened to me.”

Once again, separation of duties is the key to prevention. One employee should enter invoices into the data system, another should issue the check or make the electronic transfer, and a third should match invoices to goods and services received.

Verify expense reports. False expense reporting is a subset of the fake invoice scam. When an employee asks for reimbursement of expenses, make sure those expenses are real.

Ask about computer safeguards. Computers facilitate a lot of financial chores, but they also consolidate financial data in one place, where it is potentially accessible to anybody, anywhere. Your computer vendor should be aware of this, and should have safeguards built into your system. Ask about them. If they aren’t there, ask why.

Hire honest employees. All applicants look great on paper, so check their references; and with their permission, you can run background checks for a few dollars on any of several public information websites. (See my previous columns on hiring at http://www.mdedge.com/dermatology/managing-your-practice.)

Look for “red flags.” Examples are employees who refuse to take vacations, because someone else will have do their work; or who insist on posting expenses that are a coworker’s responsibility, “just to be nice.” Anyone obviously living beyond his or her means merits suspicion as well.

Consider bonding your employees. Dishonesty bonds are relatively inexpensive, and you will be assured of some measure of recovery should your safeguards fail. In addition, the mere knowledge that your staff is bonded will frighten off most dishonest applicants. One effective screen is a question on your employment application: “Would you object to being bonded?”

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

In November, the office manager of a San Antonio dermatology practice was sentenced to 46 months in prison for defrauding the practice of nearly $350,000 from patient billings and employee profit sharing accounts.

Per the indictment, the practice conducted a nonprofit educational symposium in 2012. A bank account was established to collect contributions for that event, which was supposed to be closed at its conclusion; but the office manager kept it open, and deposited practice receipts into it. She then used the account as her slush fund for travel, property payments, meal purchases, and other personal expenses on credit cards she fraudulently opened in the practice’s name. This continued for several years.

Because this case has received national attention, I am republishing my column on embezzlement, which includes recommendations that could prevent such unfortunate situations from occurring.

Few crimes are more easily overlooked than theft from within. Embezzlement remains far more common in medical offices than generally assumed – and it often occurs in full view of physicians who think everything is fine. Most embezzlers are not skillful or discreet; but their transgressions may go undetected for years, simply because no one suspects it is happening.

Detecting fraud is an inexact science. There is no textbook approach that one can follow, but a few simple measures will prevent or expose the most common forms:

Make it more difficult. Theft and embezzlement are usually products of opportunity, so minimize those opportunities. No one person should be in charge of the entire bookkeeping process: the person who enters charges should be different from the one who enters payments. The one who writes checks or makes electronic fund transfers should not balance the books, and so on. Internal audits should be done on a regular basis, and all employees should know that. Your accountant can help.

Reconcile cash receipts daily. Embezzlement does not require sophisticated technology; the most common form is simply taking cash out of the till. In a typical scenario, a patient pays a copay of $15 in cash; the receptionist records the payment as $5, and pockets the rest. Make sure a receipt is generated for every cash transaction, and that someone other than the person accepting cash reconciles the charges, receipts, and cash totals daily.

Inventory your stock. Cash isn’t the only susceptible commodity. If you sell cosmetics or other products, inventory your stock frequently. And office personnel are not the only potential thieves: Over a year ago, a locum tenens physician down the street conspired with a receptionist to take cash transactions for cosmetic neurotoxins and fillers “off the books” and split the spoils. That office was being ripped off twice; first for the neurotoxin and filler materials themselves, and then for the cash proceeds.

Separate all accounting duties. Another popular ploy is false invoicing for imaginary supplies. A friend’s experience provides a good example (retold with his permission): His bookkeeper wrote sizable checks to herself, disguising them in the ledger as payments to vendors commonly used by his practice. Since the same employee also balanced the checkbook, she got away with it for years. “It wasn’t at all clever,” he told me, “and I’m embarrassed to admit that it happened to me.”

Once again, separation of duties is the key to prevention. One employee should enter invoices into the data system, another should issue the check or make the electronic transfer, and a third should match invoices to goods and services received.

Verify expense reports. False expense reporting is a subset of the fake invoice scam. When an employee asks for reimbursement of expenses, make sure those expenses are real.

Ask about computer safeguards. Computers facilitate a lot of financial chores, but they also consolidate financial data in one place, where it is potentially accessible to anybody, anywhere. Your computer vendor should be aware of this, and should have safeguards built into your system. Ask about them. If they aren’t there, ask why.

Hire honest employees. All applicants look great on paper, so check their references; and with their permission, you can run background checks for a few dollars on any of several public information websites. (See my previous columns on hiring at http://www.mdedge.com/dermatology/managing-your-practice.)

Look for “red flags.” Examples are employees who refuse to take vacations, because someone else will have do their work; or who insist on posting expenses that are a coworker’s responsibility, “just to be nice.” Anyone obviously living beyond his or her means merits suspicion as well.

Consider bonding your employees. Dishonesty bonds are relatively inexpensive, and you will be assured of some measure of recovery should your safeguards fail. In addition, the mere knowledge that your staff is bonded will frighten off most dishonest applicants. One effective screen is a question on your employment application: “Would you object to being bonded?”

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

In November, the office manager of a San Antonio dermatology practice was sentenced to 46 months in prison for defrauding the practice of nearly $350,000 from patient billings and employee profit sharing accounts.

Per the indictment, the practice conducted a nonprofit educational symposium in 2012. A bank account was established to collect contributions for that event, which was supposed to be closed at its conclusion; but the office manager kept it open, and deposited practice receipts into it. She then used the account as her slush fund for travel, property payments, meal purchases, and other personal expenses on credit cards she fraudulently opened in the practice’s name. This continued for several years.

Because this case has received national attention, I am republishing my column on embezzlement, which includes recommendations that could prevent such unfortunate situations from occurring.

Few crimes are more easily overlooked than theft from within. Embezzlement remains far more common in medical offices than generally assumed – and it often occurs in full view of physicians who think everything is fine. Most embezzlers are not skillful or discreet; but their transgressions may go undetected for years, simply because no one suspects it is happening.

Detecting fraud is an inexact science. There is no textbook approach that one can follow, but a few simple measures will prevent or expose the most common forms:

Make it more difficult. Theft and embezzlement are usually products of opportunity, so minimize those opportunities. No one person should be in charge of the entire bookkeeping process: the person who enters charges should be different from the one who enters payments. The one who writes checks or makes electronic fund transfers should not balance the books, and so on. Internal audits should be done on a regular basis, and all employees should know that. Your accountant can help.

Reconcile cash receipts daily. Embezzlement does not require sophisticated technology; the most common form is simply taking cash out of the till. In a typical scenario, a patient pays a copay of $15 in cash; the receptionist records the payment as $5, and pockets the rest. Make sure a receipt is generated for every cash transaction, and that someone other than the person accepting cash reconciles the charges, receipts, and cash totals daily.

Inventory your stock. Cash isn’t the only susceptible commodity. If you sell cosmetics or other products, inventory your stock frequently. And office personnel are not the only potential thieves: Over a year ago, a locum tenens physician down the street conspired with a receptionist to take cash transactions for cosmetic neurotoxins and fillers “off the books” and split the spoils. That office was being ripped off twice; first for the neurotoxin and filler materials themselves, and then for the cash proceeds.

Separate all accounting duties. Another popular ploy is false invoicing for imaginary supplies. A friend’s experience provides a good example (retold with his permission): His bookkeeper wrote sizable checks to herself, disguising them in the ledger as payments to vendors commonly used by his practice. Since the same employee also balanced the checkbook, she got away with it for years. “It wasn’t at all clever,” he told me, “and I’m embarrassed to admit that it happened to me.”

Once again, separation of duties is the key to prevention. One employee should enter invoices into the data system, another should issue the check or make the electronic transfer, and a third should match invoices to goods and services received.

Verify expense reports. False expense reporting is a subset of the fake invoice scam. When an employee asks for reimbursement of expenses, make sure those expenses are real.

Ask about computer safeguards. Computers facilitate a lot of financial chores, but they also consolidate financial data in one place, where it is potentially accessible to anybody, anywhere. Your computer vendor should be aware of this, and should have safeguards built into your system. Ask about them. If they aren’t there, ask why.

Hire honest employees. All applicants look great on paper, so check their references; and with their permission, you can run background checks for a few dollars on any of several public information websites. (See my previous columns on hiring at http://www.mdedge.com/dermatology/managing-your-practice.)

Look for “red flags.” Examples are employees who refuse to take vacations, because someone else will have do their work; or who insist on posting expenses that are a coworker’s responsibility, “just to be nice.” Anyone obviously living beyond his or her means merits suspicion as well.

Consider bonding your employees. Dishonesty bonds are relatively inexpensive, and you will be assured of some measure of recovery should your safeguards fail. In addition, the mere knowledge that your staff is bonded will frighten off most dishonest applicants. One effective screen is a question on your employment application: “Would you object to being bonded?”

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

Rituximab didn’t perform any worse or better at inducing remission after a year in patients with eosinophilic granulomatosis with polyangiitis (EGPA) than did conventional treatment with cyclophosphamide in the phase 3 REOVAS trial conducted in France.

The B-cell–depleting agent also had a safety profile similar to cyclophosphamide during that window of time, Benjamin Terrier, MD, PhD, said in presenting results of the trial at the virtual annual meeting of the American College of Rheumatology. He is a professor of rheumatology at Cochin Hospital in Paris, the University of Paris, and vice president of the French Vasculitis Study Group.

“So some of the major adverse events that we can consider with this treatment, especially with cyclophosphamide and specifically the fertility issues and the cancer issues, the follow-up of this study does not allow us to evaluate the potential benefit of rituximab over cyclophosphamide,” Dr. Terrier said in an interview.

“But on the short-term study of 1 year, for which the major adverse events are infections, there is almost no difference between the two treatments,” he said. A total of 11 patients taking rituximab and 9 patients taking cyclophosphamide had infections in the study period.

The REOVAS trial randomly assigned 105 adult patients with EPGA, otherwise known as Churg-Strauss syndrome, to either rituximab (52 patients) or the conventional strategy using cyclophosphamide (53). The patients had either newly diagnosed or relapsing disease. There was no significant differences in average daily glucocorticoid use between the two arms.

Patient characteristics were similar in both arms, including the percentages of patients with severe disease. Overall, 60% in each group had a Five-Factor Score (FFS) of 0, while the remainder had an FFS greater than 1. The FFS is calculated by giving 1 point for the presence of each of the following: proteinuria greater than 1 g/day, serum creatinine greater than 140 micromol/L, GI involvement, cardiomyopathy, and CNS involvement. The presence of each FFS component was similar between the groups at baseline, although 25% of the rituximab group and 30.2% of the conventional arm had myeloperoxidase-positive antineutrophilic cytoplasmic antibodies, and the absolute eosinophil count was 180 per mm³ in the former and 300 per mm³ in the latter.

Treatment outcomes at 6 months and 1 year were similar in both groups. At 1 year, remission occurred in 59.6% with rituximab and 64.2% with cyclophosphamide, Birmingham Vasculitis Activity Score equaled 0 in 85.7% with rituximab and 86.5% with cyclophosphamide, and prednisone dose was less than 7.5 mg/day in 77.1% with rituximab and 71.2% with cyclophosphamide.

The cumulative total weeks of complete remission was about 16 weeks in each group. Relapse-free survival, prednisone dosage, quality of life, and disease sequelae patterns also were similar.

Tailor treatment choice to the patient

Despite the equivocal findings between the two treatments, Dr. Terrier said there may be individual patients for whom rituximab would be preferred to cyclophosphamide. “It’s not dependent on the disease by itself but more on the patients we want to treat,” he said. “And clearly if there is a young female patient who wants to get pregnant, knowing that rituximab is not superior but does not appear to be inferior to cyclophosphamide can be interesting.”

The researchers opted to test the superiority rather than noninferiority of rituximab versus cyclophosphamide because a noninferiority design would have required a larger patient population, “which is not possible for a disease like this one,” he said.

“Ostensibly, [the trial] failed to show superiority, but given its favorable side-effect profile, it may be sufficient to show it’s more or less the same,” Michael Putman, MD, MSc, an associate professor and director of the vasculitis program at the Medical College of Wisconsin, Milwaukee, said in an interview. However, he noted that the study didn’t include some phenotypes seen in patients with EGPA, “in particular patients with neurological involvement.”

Dr. Putman added that the French REOVAS findings support recommendations in the 2021 ACR/Vasculitis Foundation guideline for using rituximab as a possible first-line agent to induce remission in severe granulomatosis with polyangiitis and microscopic polyangiitis. “I was somewhat surprised by that,” he said of the ACR/VF recommendation. “These are the best data to date comparing rituximab to cyclophosphamide in EGPA. I would feel more comfortable using rituximab in cases where previously I would have reached for cyclophosphamide.”

He also concurred with Dr. Terrier’s comment that rituximab may be preferred in people of child-bearing age, even extending that to men. “Cyclophosphamide can be quite toxic in terms of ovarian toxicity and premature ovarian failure,” he said. “Young men or women of child-bearing age are a group in whom I would strongly consider using rituximab.”

The French REOVAS investigators’ future research into rituximab for EGPA will include long-term follow-up for relapse and the induction of remission, Dr. Terrier said.

Dr. Terrier disclosed relationships with Roche, Chugai, Vifor, LFB, Grifols, GlaxoSmithKline, AstraZeneca, Bristol-Myers Squibb, Octapharma, and Janssen. Dr. Putnam has no relevant relationships to disclose

Rituximab didn’t perform any worse or better at inducing remission after a year in patients with eosinophilic granulomatosis with polyangiitis (EGPA) than did conventional treatment with cyclophosphamide in the phase 3 REOVAS trial conducted in France.

The B-cell–depleting agent also had a safety profile similar to cyclophosphamide during that window of time, Benjamin Terrier, MD, PhD, said in presenting results of the trial at the virtual annual meeting of the American College of Rheumatology. He is a professor of rheumatology at Cochin Hospital in Paris, the University of Paris, and vice president of the French Vasculitis Study Group.

“So some of the major adverse events that we can consider with this treatment, especially with cyclophosphamide and specifically the fertility issues and the cancer issues, the follow-up of this study does not allow us to evaluate the potential benefit of rituximab over cyclophosphamide,” Dr. Terrier said in an interview.

“But on the short-term study of 1 year, for which the major adverse events are infections, there is almost no difference between the two treatments,” he said. A total of 11 patients taking rituximab and 9 patients taking cyclophosphamide had infections in the study period.

The REOVAS trial randomly assigned 105 adult patients with EPGA, otherwise known as Churg-Strauss syndrome, to either rituximab (52 patients) or the conventional strategy using cyclophosphamide (53). The patients had either newly diagnosed or relapsing disease. There was no significant differences in average daily glucocorticoid use between the two arms.

Patient characteristics were similar in both arms, including the percentages of patients with severe disease. Overall, 60% in each group had a Five-Factor Score (FFS) of 0, while the remainder had an FFS greater than 1. The FFS is calculated by giving 1 point for the presence of each of the following: proteinuria greater than 1 g/day, serum creatinine greater than 140 micromol/L, GI involvement, cardiomyopathy, and CNS involvement. The presence of each FFS component was similar between the groups at baseline, although 25% of the rituximab group and 30.2% of the conventional arm had myeloperoxidase-positive antineutrophilic cytoplasmic antibodies, and the absolute eosinophil count was 180 per mm³ in the former and 300 per mm³ in the latter.

Treatment outcomes at 6 months and 1 year were similar in both groups. At 1 year, remission occurred in 59.6% with rituximab and 64.2% with cyclophosphamide, Birmingham Vasculitis Activity Score equaled 0 in 85.7% with rituximab and 86.5% with cyclophosphamide, and prednisone dose was less than 7.5 mg/day in 77.1% with rituximab and 71.2% with cyclophosphamide.

The cumulative total weeks of complete remission was about 16 weeks in each group. Relapse-free survival, prednisone dosage, quality of life, and disease sequelae patterns also were similar.

Tailor treatment choice to the patient

Despite the equivocal findings between the two treatments, Dr. Terrier said there may be individual patients for whom rituximab would be preferred to cyclophosphamide. “It’s not dependent on the disease by itself but more on the patients we want to treat,” he said. “And clearly if there is a young female patient who wants to get pregnant, knowing that rituximab is not superior but does not appear to be inferior to cyclophosphamide can be interesting.”

The researchers opted to test the superiority rather than noninferiority of rituximab versus cyclophosphamide because a noninferiority design would have required a larger patient population, “which is not possible for a disease like this one,” he said.

“Ostensibly, [the trial] failed to show superiority, but given its favorable side-effect profile, it may be sufficient to show it’s more or less the same,” Michael Putman, MD, MSc, an associate professor and director of the vasculitis program at the Medical College of Wisconsin, Milwaukee, said in an interview. However, he noted that the study didn’t include some phenotypes seen in patients with EGPA, “in particular patients with neurological involvement.”

Dr. Putman added that the French REOVAS findings support recommendations in the 2021 ACR/Vasculitis Foundation guideline for using rituximab as a possible first-line agent to induce remission in severe granulomatosis with polyangiitis and microscopic polyangiitis. “I was somewhat surprised by that,” he said of the ACR/VF recommendation. “These are the best data to date comparing rituximab to cyclophosphamide in EGPA. I would feel more comfortable using rituximab in cases where previously I would have reached for cyclophosphamide.”

He also concurred with Dr. Terrier’s comment that rituximab may be preferred in people of child-bearing age, even extending that to men. “Cyclophosphamide can be quite toxic in terms of ovarian toxicity and premature ovarian failure,” he said. “Young men or women of child-bearing age are a group in whom I would strongly consider using rituximab.”

The French REOVAS investigators’ future research into rituximab for EGPA will include long-term follow-up for relapse and the induction of remission, Dr. Terrier said.

Dr. Terrier disclosed relationships with Roche, Chugai, Vifor, LFB, Grifols, GlaxoSmithKline, AstraZeneca, Bristol-Myers Squibb, Octapharma, and Janssen. Dr. Putnam has no relevant relationships to disclose

Rituximab didn’t perform any worse or better at inducing remission after a year in patients with eosinophilic granulomatosis with polyangiitis (EGPA) than did conventional treatment with cyclophosphamide in the phase 3 REOVAS trial conducted in France.

The B-cell–depleting agent also had a safety profile similar to cyclophosphamide during that window of time, Benjamin Terrier, MD, PhD, said in presenting results of the trial at the virtual annual meeting of the American College of Rheumatology. He is a professor of rheumatology at Cochin Hospital in Paris, the University of Paris, and vice president of the French Vasculitis Study Group.

“So some of the major adverse events that we can consider with this treatment, especially with cyclophosphamide and specifically the fertility issues and the cancer issues, the follow-up of this study does not allow us to evaluate the potential benefit of rituximab over cyclophosphamide,” Dr. Terrier said in an interview.

“But on the short-term study of 1 year, for which the major adverse events are infections, there is almost no difference between the two treatments,” he said. A total of 11 patients taking rituximab and 9 patients taking cyclophosphamide had infections in the study period.

The REOVAS trial randomly assigned 105 adult patients with EPGA, otherwise known as Churg-Strauss syndrome, to either rituximab (52 patients) or the conventional strategy using cyclophosphamide (53). The patients had either newly diagnosed or relapsing disease. There was no significant differences in average daily glucocorticoid use between the two arms.

Patient characteristics were similar in both arms, including the percentages of patients with severe disease. Overall, 60% in each group had a Five-Factor Score (FFS) of 0, while the remainder had an FFS greater than 1. The FFS is calculated by giving 1 point for the presence of each of the following: proteinuria greater than 1 g/day, serum creatinine greater than 140 micromol/L, GI involvement, cardiomyopathy, and CNS involvement. The presence of each FFS component was similar between the groups at baseline, although 25% of the rituximab group and 30.2% of the conventional arm had myeloperoxidase-positive antineutrophilic cytoplasmic antibodies, and the absolute eosinophil count was 180 per mm³ in the former and 300 per mm³ in the latter.

Treatment outcomes at 6 months and 1 year were similar in both groups. At 1 year, remission occurred in 59.6% with rituximab and 64.2% with cyclophosphamide, Birmingham Vasculitis Activity Score equaled 0 in 85.7% with rituximab and 86.5% with cyclophosphamide, and prednisone dose was less than 7.5 mg/day in 77.1% with rituximab and 71.2% with cyclophosphamide.

The cumulative total weeks of complete remission was about 16 weeks in each group. Relapse-free survival, prednisone dosage, quality of life, and disease sequelae patterns also were similar.

Tailor treatment choice to the patient

Despite the equivocal findings between the two treatments, Dr. Terrier said there may be individual patients for whom rituximab would be preferred to cyclophosphamide. “It’s not dependent on the disease by itself but more on the patients we want to treat,” he said. “And clearly if there is a young female patient who wants to get pregnant, knowing that rituximab is not superior but does not appear to be inferior to cyclophosphamide can be interesting.”

The researchers opted to test the superiority rather than noninferiority of rituximab versus cyclophosphamide because a noninferiority design would have required a larger patient population, “which is not possible for a disease like this one,” he said.

“Ostensibly, [the trial] failed to show superiority, but given its favorable side-effect profile, it may be sufficient to show it’s more or less the same,” Michael Putman, MD, MSc, an associate professor and director of the vasculitis program at the Medical College of Wisconsin, Milwaukee, said in an interview. However, he noted that the study didn’t include some phenotypes seen in patients with EGPA, “in particular patients with neurological involvement.”

Dr. Putman added that the French REOVAS findings support recommendations in the 2021 ACR/Vasculitis Foundation guideline for using rituximab as a possible first-line agent to induce remission in severe granulomatosis with polyangiitis and microscopic polyangiitis. “I was somewhat surprised by that,” he said of the ACR/VF recommendation. “These are the best data to date comparing rituximab to cyclophosphamide in EGPA. I would feel more comfortable using rituximab in cases where previously I would have reached for cyclophosphamide.”

He also concurred with Dr. Terrier’s comment that rituximab may be preferred in people of child-bearing age, even extending that to men. “Cyclophosphamide can be quite toxic in terms of ovarian toxicity and premature ovarian failure,” he said. “Young men or women of child-bearing age are a group in whom I would strongly consider using rituximab.”

The French REOVAS investigators’ future research into rituximab for EGPA will include long-term follow-up for relapse and the induction of remission, Dr. Terrier said.

Dr. Terrier disclosed relationships with Roche, Chugai, Vifor, LFB, Grifols, GlaxoSmithKline, AstraZeneca, Bristol-Myers Squibb, Octapharma, and Janssen. Dr. Putnam has no relevant relationships to disclose

People with paroxysmal atrial fibrillation who explored potential triggers of their arrhythmia, and used them to make lifestyle changes, went on to show a 40% decline in subjectively experienced bouts of AFib in a randomized trial with an unusual design.

American Heart Association

But the study didn’t provide evidence that the drop in self-reported AFib necessarily improved their quality of life, its primary endpoint. Nor was there any apparent relationship between potential triggers and AFib episodes detected less subjectively using a handheld electrocardiography monitor.

Although the study – called I-STOP-AFib – has limitations, its results jibe with alcohol intake’s increasingly appreciated status as a potential AFib trigger. It was alone among many possible triggers tested in showing a consistent association with self-reported AFib.

As a result, the study offers no support for such a link between the arrhythmia and caffeine intake, sleep deprivation, dehydration, exercise, or other conditions sometimes perceived as triggers, observed principal investigator Gregory M. Marcus, MD, MAS, University of California, San Francisco, when presenting results at the American Heart Association scientific sessions. He is also lead author on the study’s simultaneous publication in JAMA Cardiology.

The I-STOP-AFib trial was unusual in part for its virtual design, in which participants followed instructions and tracked AFib episodes – both perceived and detected by the handheld ECG device – through a smartphone application. It also featured an N-of-1 randomized comparisons of different weeks in which individuals were or were not exposed to their self-selected trigger.

Such patients following their own weekly personalized randomization were compared to an entirely separate randomized control arm of the trial, in which patients simply tracked any ECG-monitored and self-perceived AFib episodes.
 

Current use in patients

Although wearable and smartphone-based ECG recorders are increasingly popular for AFib screening, Dr. Marcus said the devices may be especially helpful for validating whether a person’s symptoms are actually caused by AFib.

“I have actually suggested to some of my patients that they run some of these experiments,” he said at a media briefing on I-STOP-AFib before his main presentation of the trial. The demonstration might help patients recognize that some perceived triggers actually do not induce AFib.

Allowing patients to determine on their own whether a substance indeed triggers their AFib “is an efficient use of these devices,” Dr. Marcus said. Such N-of-1 exploration of possible triggers “might help free patients up to enjoy substances – caffeine or coffee is one example – that they otherwise might not, and may help actually reassure them that certain exposures –like certain exercises, which can also be beneficial – might actually not be harmful.”

Dr. Marcus and the other authors on the report noted – as he did at the AHA sessions – that the study has several limitations, such as the subjectivity of self-reported AFib, dropouts from the trial that shrank the randomization arms, and a population that may not be very representative.

There is also the potential for detection bias in the group assigned to track their selected triggers, as Dr. Marcus and some observers have noted.

It follows that conscious avoidance of a potential AFib trigger might well lead to a reduction in AFib subjectively identified by symptoms, proposed David Conen, MD, MPH, Population Health Research Institute, McMaster University, Hamilton, Ont. But perhaps there would have been no reduction in AFib had it been objectively documented with the handheld ECG device, he said in an interview.

“If I were to redesign the study,” he said, “I think the primary endpoint should be confirmed atrial fibrillation, because we would have to show first that the specific trigger actually reduced objective AFib events before we then try to address the question whether reducing that trigger improves quality of life.”
 

Unrepresentative sample

The trial entered 446 overwhelmingly White and college-educated adults known to have symptomatic paroxysmal AFib who were “interested in testing a presumed AFib trigger they could readily introduce or withhold” and who owned a smartphone; the average age was 58 years, and 58% were men. The cohort was randomly assigned to the trigger-testing group or the control group, charged only with tracking their AFib.

Of the total, 320, or about 72%, completed the study; those who did not were mostly from the trigger-testing arm, leaving 136 in that group versus 184 patients in the control group.

Potential triggers that participants selected for tracking included, foremost, caffeine, alcohol, reduced sleep, and exercise, followed by lying on the left side, dehydration, large meals, and cold food or drink, the report noted.

Patients in the control group used the smartphone app and handheld ECG monitor (KardiaMobile, AliveCor) to document the duration and severity of AFib episodes daily and received data summary reports through the app weekly for 10 weeks. They then had the option to follow the trigger-testing protocol at least once.

Those in the trigger-testing group conducted their N-of-1 trials by exposing themselves to their chosen potential trigger during 3 separate weeks and avoiding the trigger during 3 other weeks, alternating each of the 6 weeks of trigger exposure or avoidance. They were instructed through the app to start the 6-week sequence with one or the other strategy randomly and to regularly track their AFib.

At the end of 6 weeks, each participant in the trigger-testing group had the opportunity to review their data for any potential trigger-AFib associations. They were then to use the next 4 weeks to enact lifestyle changes based on what they learned – as described in the report and on clinicaltrials.gov. They had the option of repeating the entire N-of-1 sequence at least one more time.

Participants in both the trigger-tracking and control arms were tested at baseline and at 10 weeks using the validated Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire.

AFEQT scores didn’t change significantly over the 10 weeks in either arm, nor were they significantly different in one arm, compared with the other.

On the other hand, patients in the trigger-tracking arm reported significantly fewer daily AFib episodes during the final 4-week period of lifestyle changes based on their N-of-1 trial results, compared to the monitoring-only control group’s final 4 weeks.

The adjusted relative risk in the trigger-tracking arm was 0.60 (95% confidence interval, 0.43-0.83; P < .001), the difference driven by patients who selected alcohol, dehydration, or exercise for their trigger, Dr. Marcus reported.

Only alcohol intake emerged consistently as a significant predictor of risk for self-reported AFib episodes in a series of meta-analyses conducted using all of the individual N-of-1 trials that provided per-protocol data. The odds ratio was 1.77 (95% CI, 1.20-2.69).

I-STOP-AFib explored an important subject “that has been understudied,” Dr. Conen said. “The trial has some limitations that the authors address themselves, but hopefully it opens the path to future studies that can build upon this experience.”

Dr. Marcus reported receiving personal fees and equity interest from InCarda Therapeutics; personal fees from Johnson & Johnson; and grants from Baylis Medical, Medtronic, the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and the California Tobacco-Related Disease Research Program.

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

People with paroxysmal atrial fibrillation who explored potential triggers of their arrhythmia, and used them to make lifestyle changes, went on to show a 40% decline in subjectively experienced bouts of AFib in a randomized trial with an unusual design.

American Heart Association

But the study didn’t provide evidence that the drop in self-reported AFib necessarily improved their quality of life, its primary endpoint. Nor was there any apparent relationship between potential triggers and AFib episodes detected less subjectively using a handheld electrocardiography monitor.

Although the study – called I-STOP-AFib – has limitations, its results jibe with alcohol intake’s increasingly appreciated status as a potential AFib trigger. It was alone among many possible triggers tested in showing a consistent association with self-reported AFib.

As a result, the study offers no support for such a link between the arrhythmia and caffeine intake, sleep deprivation, dehydration, exercise, or other conditions sometimes perceived as triggers, observed principal investigator Gregory M. Marcus, MD, MAS, University of California, San Francisco, when presenting results at the American Heart Association scientific sessions. He is also lead author on the study’s simultaneous publication in JAMA Cardiology.

The I-STOP-AFib trial was unusual in part for its virtual design, in which participants followed instructions and tracked AFib episodes – both perceived and detected by the handheld ECG device – through a smartphone application. It also featured an N-of-1 randomized comparisons of different weeks in which individuals were or were not exposed to their self-selected trigger.

Such patients following their own weekly personalized randomization were compared to an entirely separate randomized control arm of the trial, in which patients simply tracked any ECG-monitored and self-perceived AFib episodes.
 

Current use in patients

Although wearable and smartphone-based ECG recorders are increasingly popular for AFib screening, Dr. Marcus said the devices may be especially helpful for validating whether a person’s symptoms are actually caused by AFib.

“I have actually suggested to some of my patients that they run some of these experiments,” he said at a media briefing on I-STOP-AFib before his main presentation of the trial. The demonstration might help patients recognize that some perceived triggers actually do not induce AFib.

Allowing patients to determine on their own whether a substance indeed triggers their AFib “is an efficient use of these devices,” Dr. Marcus said. Such N-of-1 exploration of possible triggers “might help free patients up to enjoy substances – caffeine or coffee is one example – that they otherwise might not, and may help actually reassure them that certain exposures –like certain exercises, which can also be beneficial – might actually not be harmful.”

Dr. Marcus and the other authors on the report noted – as he did at the AHA sessions – that the study has several limitations, such as the subjectivity of self-reported AFib, dropouts from the trial that shrank the randomization arms, and a population that may not be very representative.

There is also the potential for detection bias in the group assigned to track their selected triggers, as Dr. Marcus and some observers have noted.

It follows that conscious avoidance of a potential AFib trigger might well lead to a reduction in AFib subjectively identified by symptoms, proposed David Conen, MD, MPH, Population Health Research Institute, McMaster University, Hamilton, Ont. But perhaps there would have been no reduction in AFib had it been objectively documented with the handheld ECG device, he said in an interview.

“If I were to redesign the study,” he said, “I think the primary endpoint should be confirmed atrial fibrillation, because we would have to show first that the specific trigger actually reduced objective AFib events before we then try to address the question whether reducing that trigger improves quality of life.”
 

Unrepresentative sample

The trial entered 446 overwhelmingly White and college-educated adults known to have symptomatic paroxysmal AFib who were “interested in testing a presumed AFib trigger they could readily introduce or withhold” and who owned a smartphone; the average age was 58 years, and 58% were men. The cohort was randomly assigned to the trigger-testing group or the control group, charged only with tracking their AFib.

Of the total, 320, or about 72%, completed the study; those who did not were mostly from the trigger-testing arm, leaving 136 in that group versus 184 patients in the control group.

Potential triggers that participants selected for tracking included, foremost, caffeine, alcohol, reduced sleep, and exercise, followed by lying on the left side, dehydration, large meals, and cold food or drink, the report noted.

Patients in the control group used the smartphone app and handheld ECG monitor (KardiaMobile, AliveCor) to document the duration and severity of AFib episodes daily and received data summary reports through the app weekly for 10 weeks. They then had the option to follow the trigger-testing protocol at least once.

Those in the trigger-testing group conducted their N-of-1 trials by exposing themselves to their chosen potential trigger during 3 separate weeks and avoiding the trigger during 3 other weeks, alternating each of the 6 weeks of trigger exposure or avoidance. They were instructed through the app to start the 6-week sequence with one or the other strategy randomly and to regularly track their AFib.

At the end of 6 weeks, each participant in the trigger-testing group had the opportunity to review their data for any potential trigger-AFib associations. They were then to use the next 4 weeks to enact lifestyle changes based on what they learned – as described in the report and on clinicaltrials.gov. They had the option of repeating the entire N-of-1 sequence at least one more time.

Participants in both the trigger-tracking and control arms were tested at baseline and at 10 weeks using the validated Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire.

AFEQT scores didn’t change significantly over the 10 weeks in either arm, nor were they significantly different in one arm, compared with the other.

On the other hand, patients in the trigger-tracking arm reported significantly fewer daily AFib episodes during the final 4-week period of lifestyle changes based on their N-of-1 trial results, compared to the monitoring-only control group’s final 4 weeks.

The adjusted relative risk in the trigger-tracking arm was 0.60 (95% confidence interval, 0.43-0.83; P < .001), the difference driven by patients who selected alcohol, dehydration, or exercise for their trigger, Dr. Marcus reported.

Only alcohol intake emerged consistently as a significant predictor of risk for self-reported AFib episodes in a series of meta-analyses conducted using all of the individual N-of-1 trials that provided per-protocol data. The odds ratio was 1.77 (95% CI, 1.20-2.69).

I-STOP-AFib explored an important subject “that has been understudied,” Dr. Conen said. “The trial has some limitations that the authors address themselves, but hopefully it opens the path to future studies that can build upon this experience.”

Dr. Marcus reported receiving personal fees and equity interest from InCarda Therapeutics; personal fees from Johnson & Johnson; and grants from Baylis Medical, Medtronic, the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and the California Tobacco-Related Disease Research Program.

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

People with paroxysmal atrial fibrillation who explored potential triggers of their arrhythmia, and used them to make lifestyle changes, went on to show a 40% decline in subjectively experienced bouts of AFib in a randomized trial with an unusual design.

American Heart Association

But the study didn’t provide evidence that the drop in self-reported AFib necessarily improved their quality of life, its primary endpoint. Nor was there any apparent relationship between potential triggers and AFib episodes detected less subjectively using a handheld electrocardiography monitor.

Although the study – called I-STOP-AFib – has limitations, its results jibe with alcohol intake’s increasingly appreciated status as a potential AFib trigger. It was alone among many possible triggers tested in showing a consistent association with self-reported AFib.

As a result, the study offers no support for such a link between the arrhythmia and caffeine intake, sleep deprivation, dehydration, exercise, or other conditions sometimes perceived as triggers, observed principal investigator Gregory M. Marcus, MD, MAS, University of California, San Francisco, when presenting results at the American Heart Association scientific sessions. He is also lead author on the study’s simultaneous publication in JAMA Cardiology.

The I-STOP-AFib trial was unusual in part for its virtual design, in which participants followed instructions and tracked AFib episodes – both perceived and detected by the handheld ECG device – through a smartphone application. It also featured an N-of-1 randomized comparisons of different weeks in which individuals were or were not exposed to their self-selected trigger.

Such patients following their own weekly personalized randomization were compared to an entirely separate randomized control arm of the trial, in which patients simply tracked any ECG-monitored and self-perceived AFib episodes.
 

Current use in patients

Although wearable and smartphone-based ECG recorders are increasingly popular for AFib screening, Dr. Marcus said the devices may be especially helpful for validating whether a person’s symptoms are actually caused by AFib.

“I have actually suggested to some of my patients that they run some of these experiments,” he said at a media briefing on I-STOP-AFib before his main presentation of the trial. The demonstration might help patients recognize that some perceived triggers actually do not induce AFib.

Allowing patients to determine on their own whether a substance indeed triggers their AFib “is an efficient use of these devices,” Dr. Marcus said. Such N-of-1 exploration of possible triggers “might help free patients up to enjoy substances – caffeine or coffee is one example – that they otherwise might not, and may help actually reassure them that certain exposures –like certain exercises, which can also be beneficial – might actually not be harmful.”

Dr. Marcus and the other authors on the report noted – as he did at the AHA sessions – that the study has several limitations, such as the subjectivity of self-reported AFib, dropouts from the trial that shrank the randomization arms, and a population that may not be very representative.

There is also the potential for detection bias in the group assigned to track their selected triggers, as Dr. Marcus and some observers have noted.

It follows that conscious avoidance of a potential AFib trigger might well lead to a reduction in AFib subjectively identified by symptoms, proposed David Conen, MD, MPH, Population Health Research Institute, McMaster University, Hamilton, Ont. But perhaps there would have been no reduction in AFib had it been objectively documented with the handheld ECG device, he said in an interview.

“If I were to redesign the study,” he said, “I think the primary endpoint should be confirmed atrial fibrillation, because we would have to show first that the specific trigger actually reduced objective AFib events before we then try to address the question whether reducing that trigger improves quality of life.”
 

Unrepresentative sample

The trial entered 446 overwhelmingly White and college-educated adults known to have symptomatic paroxysmal AFib who were “interested in testing a presumed AFib trigger they could readily introduce or withhold” and who owned a smartphone; the average age was 58 years, and 58% were men. The cohort was randomly assigned to the trigger-testing group or the control group, charged only with tracking their AFib.

Of the total, 320, or about 72%, completed the study; those who did not were mostly from the trigger-testing arm, leaving 136 in that group versus 184 patients in the control group.

Potential triggers that participants selected for tracking included, foremost, caffeine, alcohol, reduced sleep, and exercise, followed by lying on the left side, dehydration, large meals, and cold food or drink, the report noted.

Patients in the control group used the smartphone app and handheld ECG monitor (KardiaMobile, AliveCor) to document the duration and severity of AFib episodes daily and received data summary reports through the app weekly for 10 weeks. They then had the option to follow the trigger-testing protocol at least once.

Those in the trigger-testing group conducted their N-of-1 trials by exposing themselves to their chosen potential trigger during 3 separate weeks and avoiding the trigger during 3 other weeks, alternating each of the 6 weeks of trigger exposure or avoidance. They were instructed through the app to start the 6-week sequence with one or the other strategy randomly and to regularly track their AFib.

At the end of 6 weeks, each participant in the trigger-testing group had the opportunity to review their data for any potential trigger-AFib associations. They were then to use the next 4 weeks to enact lifestyle changes based on what they learned – as described in the report and on clinicaltrials.gov. They had the option of repeating the entire N-of-1 sequence at least one more time.

Participants in both the trigger-tracking and control arms were tested at baseline and at 10 weeks using the validated Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire.

AFEQT scores didn’t change significantly over the 10 weeks in either arm, nor were they significantly different in one arm, compared with the other.

On the other hand, patients in the trigger-tracking arm reported significantly fewer daily AFib episodes during the final 4-week period of lifestyle changes based on their N-of-1 trial results, compared to the monitoring-only control group’s final 4 weeks.

The adjusted relative risk in the trigger-tracking arm was 0.60 (95% confidence interval, 0.43-0.83; P < .001), the difference driven by patients who selected alcohol, dehydration, or exercise for their trigger, Dr. Marcus reported.

Only alcohol intake emerged consistently as a significant predictor of risk for self-reported AFib episodes in a series of meta-analyses conducted using all of the individual N-of-1 trials that provided per-protocol data. The odds ratio was 1.77 (95% CI, 1.20-2.69).

I-STOP-AFib explored an important subject “that has been understudied,” Dr. Conen said. “The trial has some limitations that the authors address themselves, but hopefully it opens the path to future studies that can build upon this experience.”

Dr. Marcus reported receiving personal fees and equity interest from InCarda Therapeutics; personal fees from Johnson & Johnson; and grants from Baylis Medical, Medtronic, the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and the California Tobacco-Related Disease Research Program.

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

Allopurinol may finally start to get the respect that many rheumatologists feel it deserves as a first-line urate-lowering treatment for gout, following results of a randomized trial showing that it was noninferior to febuxostat both in the overall trial population and in patients with stage 3 chronic kidney disease (CKD).

Sirisak Boakaew/Getty Images

In the multicenter, randomized, double-blinded comparison trial that used a treat-to-target strategy, allopurinol met the primary outcome of noninferiority to febuxostat for preventing gout flare during the observation phase of therapy, reported James O’Dell, MD, chief of the division of rheumatology and vice chair for education in the department of internal medicine at the University of Nebraska Medical Center in Omaha.

“Both agents were well tolerated, with or without CKD. Most importantly, both agents were highly effective when used in a treat-to-target protocol in getting patients to target urate levels,” he said in an oral abstract presentation during the American College of Rheumatology (ACR) 2021 Annual Meeting, which was held online.

And although febuxostat contains a boxed warning about the risks of cardiovascular adverse events with its use, there were no signals for increased cardiovascular toxicity with febuxostat compared with allopurinol, the investigators found.

The trial is the first to compare allopurinol, a decades-old drug, with febuxostat, approved in 2009, in a treat-to-target approach, Dr. O’Dell said.
 

American College of Physicians’ guideline ‘antiquated’

The results of the study “will hopefully teach doctors how to treat gout better by encouraging them to use higher doses of gout medications safely than they’re actually using at this time,” said Donald Thomas Jr., MD, in private practice in Greenbelt, Md., and associate professor of medicine at the Uniformed Services University of the Health Sciences in Bethesda, Md.

Dr. Thomas, who moderated a media briefing where Dr. O’Dell discussed the results of the trial, said that he had recently read the 2017 gout guideline by the American College of Physicians (ACP), which he called “antiquated.”

The ACP recommends the use of corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or low-dose colchicine to treat patients with acute gout. The ACP also recommends “against initiating long-term urate-lowering therapy in most patients after a first gout attack or in patients with infrequent attacks.”

The guideline recommends that clinicians discuss potential benefits, risks, costs, and personal preferences before starting patients on urate-lowering therapy in patients with recurrent gout attacks.

The 2017 guidelines also state, however, that “[e]vidence was insufficient to conclude whether the benefits of escalating urate-lowering therapy to reach a serum urate target (‘treat to target’) outweigh the harms associated with repeated monitoring and medication escalation.”

“I’ve been a proud member of the American College of Physicians for years, I’m a master of the ACP, and they do a lot of great things, but this is one case where their insistence that they’re not going to have a guideline that isn’t completely based in evidence from studies is getting in the way of common sense,” Dr. O’Dell said.

“Their contention is that what matters to a gout patient is a gout flare, and how do we know that gout flares are less if you treat to target or not – and that’s a fair question,” he continued, “except for the fact that in uric acid metabolism we know physiologically that there’s a magic number and that’s 6.8 mg/dL, and anything above that, every day uric acid is above 6.8, you are literally putting crystal out into all places in your body.”

In contrast, the ACR’s 2020 guideline for the management of gout strongly recommends starting urate-lowering therapy for all patients with tophaceous gout, radiographic damage because of gout, or frequent gout flares. It also advises using allopurinol as the preferred first-line urate-lowering therapy, including for those with stage 3 or greater CKD, and using a low starting dose of allopurinol of 100 mg/day or less (lower in CKD) or febuxostat at 40 mg/day or less. It endorses a treat-to-target management strategy that aims for serum urate < 6 mg/dL with dose titration of urate-lowering agents guided by serial serum urate measurements.

Dr. Thomas and Dr. O’Dell expressed hope that the results of this clinical trial will put the issue to rest, and that the ACP will update its guideline accordingly.

VA-sponsored trial

The study was conducted at 19 Veterans Affairs medical centers and two non-VA sites. The trial was divided into dose-titration, maintenance, and observation phases, each lasting 24 weeks.

A total of 950 participants with gout and a serum urate concentration 6.8 mg/dL or greater were randomly assigned on a 1:1 basis to receive allopurinol 100-800 mg or febuxostat 40 mg to 80/120 mg daily. In 2019, the Food and Drug Administration requested that the maximum titrated dose of febuxostat in the trial be capped at 80 mg daily. All patients stopped prophylaxis with NSAIDs, colchicine, or prednisone before the observation phase.

Patients with persistent hyperuricemia despite treatment with allopurinol were eligible, and these patients were started in the titration phase at their current dose.

The mean patient age was 62.9 years in the allopurinol arm and 61.3 years in the febuxostat arm. Men comprised 98% of patients in each study arm.

The racial/ethnic distribution of patients was similar between the groups. In all, 38.7% of patients assigned to allopurinol and 36% assigned to febuxostat had CKD stages 1-3. (Patients with stage 4 or 5 CKD were excluded from the study.)

A gout flare occurred if a participants reported three or more symptoms of tender, warm, swollen joints, or gout flare, or if the participant reported use of medication for gout flare in the observation phase during weeks 49-72.

As noted before, the trial met its primary endpoint, with 36.5% of patients on allopurinol reporting gout flare in the observation phase, compared with 43.5% on febuxostat (P for noninferiority < .001).

Among patients with CKD stage 3, the respective percentages of patients reporting at least one gout flare in the observation phase were 31.9% and 45.3% (P for noninferiority < .001).

Approximately 80% of patients in each arm had mean serum urate concentrations less than 6.0 mg/dL during the maintenance phase (weeks 36, 42, and 48).

In each arm, about 20% of patients left the study before completing 72 weeks of follow-up. Serious adverse events occurred in 26.7% of patients assigned to allopurinol and 26.1% of patients assigned to febuxostat.

Cardiovascular adverse events occurred in 8.1% and 6.8%, respectively. There were three cases of cardiovascular death in the allopurinol arm and one in the febuxostat arm. Nonfatal myocardial infarction occurred in two and four patients, respectively, stroke in one and two, and unstable angina requiring urgent revascularization in four and three patients.

In the question-and-answer session of the briefing, this news organization asked Dr. Thomas whether he would use the agents interchangeably in his practice. He replied “no, I start off with allopurinol in all of my patients, even those with chronic kidney disease, because it has been shown to be safe. I start off at a very low dose, go up slowly, [and] if they have a reaction, I change it to febuxostat.”

The study was supported by the U.S. Department of Veterans Affairs. Dr. O’Dell and Dr. Thomas have disclosed no relevant financial relationships.

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

Allopurinol may finally start to get the respect that many rheumatologists feel it deserves as a first-line urate-lowering treatment for gout, following results of a randomized trial showing that it was noninferior to febuxostat both in the overall trial population and in patients with stage 3 chronic kidney disease (CKD).

Sirisak Boakaew/Getty Images

In the multicenter, randomized, double-blinded comparison trial that used a treat-to-target strategy, allopurinol met the primary outcome of noninferiority to febuxostat for preventing gout flare during the observation phase of therapy, reported James O’Dell, MD, chief of the division of rheumatology and vice chair for education in the department of internal medicine at the University of Nebraska Medical Center in Omaha.

“Both agents were well tolerated, with or without CKD. Most importantly, both agents were highly effective when used in a treat-to-target protocol in getting patients to target urate levels,” he said in an oral abstract presentation during the American College of Rheumatology (ACR) 2021 Annual Meeting, which was held online.

And although febuxostat contains a boxed warning about the risks of cardiovascular adverse events with its use, there were no signals for increased cardiovascular toxicity with febuxostat compared with allopurinol, the investigators found.

The trial is the first to compare allopurinol, a decades-old drug, with febuxostat, approved in 2009, in a treat-to-target approach, Dr. O’Dell said.
 

American College of Physicians’ guideline ‘antiquated’

The results of the study “will hopefully teach doctors how to treat gout better by encouraging them to use higher doses of gout medications safely than they’re actually using at this time,” said Donald Thomas Jr., MD, in private practice in Greenbelt, Md., and associate professor of medicine at the Uniformed Services University of the Health Sciences in Bethesda, Md.

Dr. Thomas, who moderated a media briefing where Dr. O’Dell discussed the results of the trial, said that he had recently read the 2017 gout guideline by the American College of Physicians (ACP), which he called “antiquated.”

The ACP recommends the use of corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or low-dose colchicine to treat patients with acute gout. The ACP also recommends “against initiating long-term urate-lowering therapy in most patients after a first gout attack or in patients with infrequent attacks.”

The guideline recommends that clinicians discuss potential benefits, risks, costs, and personal preferences before starting patients on urate-lowering therapy in patients with recurrent gout attacks.

The 2017 guidelines also state, however, that “[e]vidence was insufficient to conclude whether the benefits of escalating urate-lowering therapy to reach a serum urate target (‘treat to target’) outweigh the harms associated with repeated monitoring and medication escalation.”

“I’ve been a proud member of the American College of Physicians for years, I’m a master of the ACP, and they do a lot of great things, but this is one case where their insistence that they’re not going to have a guideline that isn’t completely based in evidence from studies is getting in the way of common sense,” Dr. O’Dell said.

“Their contention is that what matters to a gout patient is a gout flare, and how do we know that gout flares are less if you treat to target or not – and that’s a fair question,” he continued, “except for the fact that in uric acid metabolism we know physiologically that there’s a magic number and that’s 6.8 mg/dL, and anything above that, every day uric acid is above 6.8, you are literally putting crystal out into all places in your body.”

In contrast, the ACR’s 2020 guideline for the management of gout strongly recommends starting urate-lowering therapy for all patients with tophaceous gout, radiographic damage because of gout, or frequent gout flares. It also advises using allopurinol as the preferred first-line urate-lowering therapy, including for those with stage 3 or greater CKD, and using a low starting dose of allopurinol of 100 mg/day or less (lower in CKD) or febuxostat at 40 mg/day or less. It endorses a treat-to-target management strategy that aims for serum urate < 6 mg/dL with dose titration of urate-lowering agents guided by serial serum urate measurements.

Dr. Thomas and Dr. O’Dell expressed hope that the results of this clinical trial will put the issue to rest, and that the ACP will update its guideline accordingly.

VA-sponsored trial

The study was conducted at 19 Veterans Affairs medical centers and two non-VA sites. The trial was divided into dose-titration, maintenance, and observation phases, each lasting 24 weeks.

A total of 950 participants with gout and a serum urate concentration 6.8 mg/dL or greater were randomly assigned on a 1:1 basis to receive allopurinol 100-800 mg or febuxostat 40 mg to 80/120 mg daily. In 2019, the Food and Drug Administration requested that the maximum titrated dose of febuxostat in the trial be capped at 80 mg daily. All patients stopped prophylaxis with NSAIDs, colchicine, or prednisone before the observation phase.

Patients with persistent hyperuricemia despite treatment with allopurinol were eligible, and these patients were started in the titration phase at their current dose.

The mean patient age was 62.9 years in the allopurinol arm and 61.3 years in the febuxostat arm. Men comprised 98% of patients in each study arm.

The racial/ethnic distribution of patients was similar between the groups. In all, 38.7% of patients assigned to allopurinol and 36% assigned to febuxostat had CKD stages 1-3. (Patients with stage 4 or 5 CKD were excluded from the study.)

A gout flare occurred if a participants reported three or more symptoms of tender, warm, swollen joints, or gout flare, or if the participant reported use of medication for gout flare in the observation phase during weeks 49-72.

As noted before, the trial met its primary endpoint, with 36.5% of patients on allopurinol reporting gout flare in the observation phase, compared with 43.5% on febuxostat (P for noninferiority < .001).

Among patients with CKD stage 3, the respective percentages of patients reporting at least one gout flare in the observation phase were 31.9% and 45.3% (P for noninferiority < .001).

Approximately 80% of patients in each arm had mean serum urate concentrations less than 6.0 mg/dL during the maintenance phase (weeks 36, 42, and 48).

In each arm, about 20% of patients left the study before completing 72 weeks of follow-up. Serious adverse events occurred in 26.7% of patients assigned to allopurinol and 26.1% of patients assigned to febuxostat.

Cardiovascular adverse events occurred in 8.1% and 6.8%, respectively. There were three cases of cardiovascular death in the allopurinol arm and one in the febuxostat arm. Nonfatal myocardial infarction occurred in two and four patients, respectively, stroke in one and two, and unstable angina requiring urgent revascularization in four and three patients.

In the question-and-answer session of the briefing, this news organization asked Dr. Thomas whether he would use the agents interchangeably in his practice. He replied “no, I start off with allopurinol in all of my patients, even those with chronic kidney disease, because it has been shown to be safe. I start off at a very low dose, go up slowly, [and] if they have a reaction, I change it to febuxostat.”

The study was supported by the U.S. Department of Veterans Affairs. Dr. O’Dell and Dr. Thomas have disclosed no relevant financial relationships.

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

Allopurinol may finally start to get the respect that many rheumatologists feel it deserves as a first-line urate-lowering treatment for gout, following results of a randomized trial showing that it was noninferior to febuxostat both in the overall trial population and in patients with stage 3 chronic kidney disease (CKD).

Sirisak Boakaew/Getty Images

In the multicenter, randomized, double-blinded comparison trial that used a treat-to-target strategy, allopurinol met the primary outcome of noninferiority to febuxostat for preventing gout flare during the observation phase of therapy, reported James O’Dell, MD, chief of the division of rheumatology and vice chair for education in the department of internal medicine at the University of Nebraska Medical Center in Omaha.

“Both agents were well tolerated, with or without CKD. Most importantly, both agents were highly effective when used in a treat-to-target protocol in getting patients to target urate levels,” he said in an oral abstract presentation during the American College of Rheumatology (ACR) 2021 Annual Meeting, which was held online.

And although febuxostat contains a boxed warning about the risks of cardiovascular adverse events with its use, there were no signals for increased cardiovascular toxicity with febuxostat compared with allopurinol, the investigators found.

The trial is the first to compare allopurinol, a decades-old drug, with febuxostat, approved in 2009, in a treat-to-target approach, Dr. O’Dell said.
 

American College of Physicians’ guideline ‘antiquated’

The results of the study “will hopefully teach doctors how to treat gout better by encouraging them to use higher doses of gout medications safely than they’re actually using at this time,” said Donald Thomas Jr., MD, in private practice in Greenbelt, Md., and associate professor of medicine at the Uniformed Services University of the Health Sciences in Bethesda, Md.

Dr. Thomas, who moderated a media briefing where Dr. O’Dell discussed the results of the trial, said that he had recently read the 2017 gout guideline by the American College of Physicians (ACP), which he called “antiquated.”

The ACP recommends the use of corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or low-dose colchicine to treat patients with acute gout. The ACP also recommends “against initiating long-term urate-lowering therapy in most patients after a first gout attack or in patients with infrequent attacks.”

The guideline recommends that clinicians discuss potential benefits, risks, costs, and personal preferences before starting patients on urate-lowering therapy in patients with recurrent gout attacks.

The 2017 guidelines also state, however, that “[e]vidence was insufficient to conclude whether the benefits of escalating urate-lowering therapy to reach a serum urate target (‘treat to target’) outweigh the harms associated with repeated monitoring and medication escalation.”

“I’ve been a proud member of the American College of Physicians for years, I’m a master of the ACP, and they do a lot of great things, but this is one case where their insistence that they’re not going to have a guideline that isn’t completely based in evidence from studies is getting in the way of common sense,” Dr. O’Dell said.

“Their contention is that what matters to a gout patient is a gout flare, and how do we know that gout flares are less if you treat to target or not – and that’s a fair question,” he continued, “except for the fact that in uric acid metabolism we know physiologically that there’s a magic number and that’s 6.8 mg/dL, and anything above that, every day uric acid is above 6.8, you are literally putting crystal out into all places in your body.”

In contrast, the ACR’s 2020 guideline for the management of gout strongly recommends starting urate-lowering therapy for all patients with tophaceous gout, radiographic damage because of gout, or frequent gout flares. It also advises using allopurinol as the preferred first-line urate-lowering therapy, including for those with stage 3 or greater CKD, and using a low starting dose of allopurinol of 100 mg/day or less (lower in CKD) or febuxostat at 40 mg/day or less. It endorses a treat-to-target management strategy that aims for serum urate < 6 mg/dL with dose titration of urate-lowering agents guided by serial serum urate measurements.

Dr. Thomas and Dr. O’Dell expressed hope that the results of this clinical trial will put the issue to rest, and that the ACP will update its guideline accordingly.

VA-sponsored trial

The study was conducted at 19 Veterans Affairs medical centers and two non-VA sites. The trial was divided into dose-titration, maintenance, and observation phases, each lasting 24 weeks.

A total of 950 participants with gout and a serum urate concentration 6.8 mg/dL or greater were randomly assigned on a 1:1 basis to receive allopurinol 100-800 mg or febuxostat 40 mg to 80/120 mg daily. In 2019, the Food and Drug Administration requested that the maximum titrated dose of febuxostat in the trial be capped at 80 mg daily. All patients stopped prophylaxis with NSAIDs, colchicine, or prednisone before the observation phase.

Patients with persistent hyperuricemia despite treatment with allopurinol were eligible, and these patients were started in the titration phase at their current dose.

The mean patient age was 62.9 years in the allopurinol arm and 61.3 years in the febuxostat arm. Men comprised 98% of patients in each study arm.

The racial/ethnic distribution of patients was similar between the groups. In all, 38.7% of patients assigned to allopurinol and 36% assigned to febuxostat had CKD stages 1-3. (Patients with stage 4 or 5 CKD were excluded from the study.)

A gout flare occurred if a participants reported three or more symptoms of tender, warm, swollen joints, or gout flare, or if the participant reported use of medication for gout flare in the observation phase during weeks 49-72.

As noted before, the trial met its primary endpoint, with 36.5% of patients on allopurinol reporting gout flare in the observation phase, compared with 43.5% on febuxostat (P for noninferiority < .001).

Among patients with CKD stage 3, the respective percentages of patients reporting at least one gout flare in the observation phase were 31.9% and 45.3% (P for noninferiority < .001).

Approximately 80% of patients in each arm had mean serum urate concentrations less than 6.0 mg/dL during the maintenance phase (weeks 36, 42, and 48).

In each arm, about 20% of patients left the study before completing 72 weeks of follow-up. Serious adverse events occurred in 26.7% of patients assigned to allopurinol and 26.1% of patients assigned to febuxostat.

Cardiovascular adverse events occurred in 8.1% and 6.8%, respectively. There were three cases of cardiovascular death in the allopurinol arm and one in the febuxostat arm. Nonfatal myocardial infarction occurred in two and four patients, respectively, stroke in one and two, and unstable angina requiring urgent revascularization in four and three patients.

In the question-and-answer session of the briefing, this news organization asked Dr. Thomas whether he would use the agents interchangeably in his practice. He replied “no, I start off with allopurinol in all of my patients, even those with chronic kidney disease, because it has been shown to be safe. I start off at a very low dose, go up slowly, [and] if they have a reaction, I change it to febuxostat.”

The study was supported by the U.S. Department of Veterans Affairs. Dr. O’Dell and Dr. Thomas have disclosed no relevant financial relationships.

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

COVID-19 has been difficult for parents trying to balance careers, home life, and keeping their loved ones safe. A new study indicates that, not only are physicians not immune to these stressors, but the long-term effects could be devastating for health care overall.

Juanmonino/Getty Images

In a study published Nov. 11, 2021, in JAMA Network Open , researchers found that stresses to work/life balance and family life caused by the pandemic have differed among men and women physicians. Women physicians have borne more of the burden, and the consequences could reach far beyond home.

Physicians and other health care workers have been at the front lines of the COVID-19 pandemic, and their work lives have been the focus of a lot of attention in the media and by researchers. Their family lives, not so much. But physicians have families, and the pandemic has upended almost everything about their lives, particularly where work life and home life intersect. School and day care closures, working from home, working extra hours, or working less – all of these changes have consequences on family life and the mental health of parents who are also physicians.

Findings from a Medscape survey published in early 2021 indicate that more female physicians than male physicians were either “conflicted” or “very conflicted” as parents because of work demands (42% vs. 23%) nearly 6 months into the pandemic.

In the current study, researchers from the University of Michigan, Harvard University, and the Medical University of South Carolina teamed up to investigate gender differences in how work/family factors affected the mental health of early-career physician parents in the United States during the first year of the COVID-19 pandemic. The results suggest that the pandemic has increased gender disparity and added disproportionately to the burden of female physicians.
 

Managing the household falls mostly on moms

Participants were physicians enrolled in the Intern Health Study, a longitudinal study that regularly surveys medical interns in the United States to assess stress and mood. When researchers compared survey results from before the onset of the pandemic (2018) with later results (2020), they found a striking gender difference in how the pandemic has changed family and work duties for physicians.

The authors of the study pointed out that previous research had found that female physicians take on a greater share of household and childcare duties than male physicians. The current study found that their share had increased with the pandemic. Physician moms are now 30 times more likely to be in charge of these tasks than physician dads.

In families in which both parents were physicians, none of the men said they took the primary role in managing the extra demands caused by the pandemic. In addition, women were twice as likely as men to work primarily from home and to work reduced hours.

The extra stress seems to be taking a toll on women physicians. In the 2020 survey, physician mothers had higher scores for anxiety and depression symptoms, compared with men. Notably, the 2018 survey did not show a significant difference in depression scores between men and women. Nor were there significant differences in depression and anxiety scores between women and men who were not parents or in reports of work/family conflict before and after the pandemic.

In general, the results indicate that the pandemic has only widened the gender gap between women and men physicians when it comes to managing family life and dealing with the stresses of maintaining a suitable work-life balance.
 

‘Long-term repercussions’ for gender equity in medicine

Although these are serious problems for women physicians and their families, the effects go beyond the home and beyond individuals. Even before the pandemic, women in medicine struggled for parity in career advancement and opportunities as well as in pay, and this new setback could make those challenges even greater.

“Even short-term adjustments can have serious long-term repercussions as they may lead to lower earnings and negatively impact opportunities for promotion, further exacerbating gender inequalities in compensation and advancement,” the study’s authors wrote.

The potential damage extends to the entire profession and the health care system itself. The profession is already struggling to retain young female physicians, and this situation is likely to make that problem worse and have long-term consequences. Citing data showing that female physicians spend more time with patients and that their patients may have better outcomes, the authors wrote that the consequences of losing more early-career female physicians “could be devastating to the U.S. health care system, particularly in the context of a global pandemic and an impending physician shortage.”

The sample size was small (276 U.S. physicians), and the study relied on self-reported data. The findings suggest that more research on this topic is needed, especially research that includes other demographic factors, such as sexual orientation and ethnicity. The authors recommend that institutional and public policymakers take into account the effects of the pandemic on physician mothers to ensure that recent gains in gender equity for women physicians do not fall victim to COVID-19.

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

COVID-19 has been difficult for parents trying to balance careers, home life, and keeping their loved ones safe. A new study indicates that, not only are physicians not immune to these stressors, but the long-term effects could be devastating for health care overall.

Juanmonino/Getty Images

In a study published Nov. 11, 2021, in JAMA Network Open , researchers found that stresses to work/life balance and family life caused by the pandemic have differed among men and women physicians. Women physicians have borne more of the burden, and the consequences could reach far beyond home.

Physicians and other health care workers have been at the front lines of the COVID-19 pandemic, and their work lives have been the focus of a lot of attention in the media and by researchers. Their family lives, not so much. But physicians have families, and the pandemic has upended almost everything about their lives, particularly where work life and home life intersect. School and day care closures, working from home, working extra hours, or working less – all of these changes have consequences on family life and the mental health of parents who are also physicians.

Findings from a Medscape survey published in early 2021 indicate that more female physicians than male physicians were either “conflicted” or “very conflicted” as parents because of work demands (42% vs. 23%) nearly 6 months into the pandemic.

In the current study, researchers from the University of Michigan, Harvard University, and the Medical University of South Carolina teamed up to investigate gender differences in how work/family factors affected the mental health of early-career physician parents in the United States during the first year of the COVID-19 pandemic. The results suggest that the pandemic has increased gender disparity and added disproportionately to the burden of female physicians.
 

Managing the household falls mostly on moms

Participants were physicians enrolled in the Intern Health Study, a longitudinal study that regularly surveys medical interns in the United States to assess stress and mood. When researchers compared survey results from before the onset of the pandemic (2018) with later results (2020), they found a striking gender difference in how the pandemic has changed family and work duties for physicians.

The authors of the study pointed out that previous research had found that female physicians take on a greater share of household and childcare duties than male physicians. The current study found that their share had increased with the pandemic. Physician moms are now 30 times more likely to be in charge of these tasks than physician dads.

In families in which both parents were physicians, none of the men said they took the primary role in managing the extra demands caused by the pandemic. In addition, women were twice as likely as men to work primarily from home and to work reduced hours.

The extra stress seems to be taking a toll on women physicians. In the 2020 survey, physician mothers had higher scores for anxiety and depression symptoms, compared with men. Notably, the 2018 survey did not show a significant difference in depression scores between men and women. Nor were there significant differences in depression and anxiety scores between women and men who were not parents or in reports of work/family conflict before and after the pandemic.

In general, the results indicate that the pandemic has only widened the gender gap between women and men physicians when it comes to managing family life and dealing with the stresses of maintaining a suitable work-life balance.
 

‘Long-term repercussions’ for gender equity in medicine

Although these are serious problems for women physicians and their families, the effects go beyond the home and beyond individuals. Even before the pandemic, women in medicine struggled for parity in career advancement and opportunities as well as in pay, and this new setback could make those challenges even greater.

“Even short-term adjustments can have serious long-term repercussions as they may lead to lower earnings and negatively impact opportunities for promotion, further exacerbating gender inequalities in compensation and advancement,” the study’s authors wrote.

The potential damage extends to the entire profession and the health care system itself. The profession is already struggling to retain young female physicians, and this situation is likely to make that problem worse and have long-term consequences. Citing data showing that female physicians spend more time with patients and that their patients may have better outcomes, the authors wrote that the consequences of losing more early-career female physicians “could be devastating to the U.S. health care system, particularly in the context of a global pandemic and an impending physician shortage.”

The sample size was small (276 U.S. physicians), and the study relied on self-reported data. The findings suggest that more research on this topic is needed, especially research that includes other demographic factors, such as sexual orientation and ethnicity. The authors recommend that institutional and public policymakers take into account the effects of the pandemic on physician mothers to ensure that recent gains in gender equity for women physicians do not fall victim to COVID-19.

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

COVID-19 has been difficult for parents trying to balance careers, home life, and keeping their loved ones safe. A new study indicates that, not only are physicians not immune to these stressors, but the long-term effects could be devastating for health care overall.

Juanmonino/Getty Images

In a study published Nov. 11, 2021, in JAMA Network Open , researchers found that stresses to work/life balance and family life caused by the pandemic have differed among men and women physicians. Women physicians have borne more of the burden, and the consequences could reach far beyond home.

Physicians and other health care workers have been at the front lines of the COVID-19 pandemic, and their work lives have been the focus of a lot of attention in the media and by researchers. Their family lives, not so much. But physicians have families, and the pandemic has upended almost everything about their lives, particularly where work life and home life intersect. School and day care closures, working from home, working extra hours, or working less – all of these changes have consequences on family life and the mental health of parents who are also physicians.

Findings from a Medscape survey published in early 2021 indicate that more female physicians than male physicians were either “conflicted” or “very conflicted” as parents because of work demands (42% vs. 23%) nearly 6 months into the pandemic.

In the current study, researchers from the University of Michigan, Harvard University, and the Medical University of South Carolina teamed up to investigate gender differences in how work/family factors affected the mental health of early-career physician parents in the United States during the first year of the COVID-19 pandemic. The results suggest that the pandemic has increased gender disparity and added disproportionately to the burden of female physicians.
 

Managing the household falls mostly on moms

Participants were physicians enrolled in the Intern Health Study, a longitudinal study that regularly surveys medical interns in the United States to assess stress and mood. When researchers compared survey results from before the onset of the pandemic (2018) with later results (2020), they found a striking gender difference in how the pandemic has changed family and work duties for physicians.

The authors of the study pointed out that previous research had found that female physicians take on a greater share of household and childcare duties than male physicians. The current study found that their share had increased with the pandemic. Physician moms are now 30 times more likely to be in charge of these tasks than physician dads.

In families in which both parents were physicians, none of the men said they took the primary role in managing the extra demands caused by the pandemic. In addition, women were twice as likely as men to work primarily from home and to work reduced hours.

The extra stress seems to be taking a toll on women physicians. In the 2020 survey, physician mothers had higher scores for anxiety and depression symptoms, compared with men. Notably, the 2018 survey did not show a significant difference in depression scores between men and women. Nor were there significant differences in depression and anxiety scores between women and men who were not parents or in reports of work/family conflict before and after the pandemic.

In general, the results indicate that the pandemic has only widened the gender gap between women and men physicians when it comes to managing family life and dealing with the stresses of maintaining a suitable work-life balance.
 

‘Long-term repercussions’ for gender equity in medicine

Although these are serious problems for women physicians and their families, the effects go beyond the home and beyond individuals. Even before the pandemic, women in medicine struggled for parity in career advancement and opportunities as well as in pay, and this new setback could make those challenges even greater.

“Even short-term adjustments can have serious long-term repercussions as they may lead to lower earnings and negatively impact opportunities for promotion, further exacerbating gender inequalities in compensation and advancement,” the study’s authors wrote.

The potential damage extends to the entire profession and the health care system itself. The profession is already struggling to retain young female physicians, and this situation is likely to make that problem worse and have long-term consequences. Citing data showing that female physicians spend more time with patients and that their patients may have better outcomes, the authors wrote that the consequences of losing more early-career female physicians “could be devastating to the U.S. health care system, particularly in the context of a global pandemic and an impending physician shortage.”

The sample size was small (276 U.S. physicians), and the study relied on self-reported data. The findings suggest that more research on this topic is needed, especially research that includes other demographic factors, such as sexual orientation and ethnicity. The authors recommend that institutional and public policymakers take into account the effects of the pandemic on physician mothers to ensure that recent gains in gender equity for women physicians do not fall victim to COVID-19.

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