MDedge Rheumatology

More patients with granulomatosis with polyangiitis (GPA) were in remission at 6 months if they had received rituximab (Rituxan) rather than cyclophosphamide (Cytoxan) as induction therapy, according to a target trial emulation performed by the French Vasculitis Study Group (FVSG).

Remission, which was defined as a score of zero on the validated Birmingham Vasculitis Activity Score (BVAS) and use of no more than 10 mg of prednisone a day, was documented in 73.1% of rituximab-treated patients and 40.1% of cyclophosphamide-treated patients.

Similar rates of remission were observed regardless of whether patients were newly diagnosed with GPA (76.1% vs. 41.6%) or had been recently treated for relapsing disease (75.2% vs. 44.5%), FVSG researchers reported in JAMA Network Open.

This research “may inform clinical decision-making regarding the choice of remission-inducing regimen for patients with GPA,” the researchers suggested.
 

Practice already shifting to rituximab

“The results are largely in line with previous perceptions,” David R.W. Jayne, MD, honorary consultant and director of the vasculitis and lupus service at Addenbrooke’s Hospital in Cambridge, England, observed in an emailed comment.

“The difference is a bit bigger [in favor of rituximab] than I would have expected,” said Dr. Jayne, who is also professor of clinical autoimmunity at the University of Cambridge. He noted that clinical practice was already moving toward using rituximab in place of cyclophosphamide.

Rituximab gained a European license to treat antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAV) just over a decade ago. Since then, it has slowly started to replace the use of cyclophosphamide and glucocorticoids, which were the preferred method up until then.

Part of the reason for this shift is the toxicity associated with cyclophosphamide, although that’s not to say that rituximab is free from safety concerns, Dr. Jayne said.

“Toxicity issues with rituximab, especially secondary immunodeficiency, more severe COVID, and blocking vaccine responses, are becoming bigger issues for day-to-day practice,” he noted. Nonetheless, “the introduction of rituximab has been a revolution in AAV treatment. It has encouraged pharma investment in the disease, such as recent approval of avacopan [Tavneos], and it is helping patients.”

Why simulate and not perform a randomized trial?

There were several reasons for performing the current evaluation, study coauthor Benjamin Terrier, MD, PhD, said in an interview.

“The pivotal study, published in 2010, that led to the approval of rituximab was a noninferiority study in comparison with cyclophosphamide, but it included patients with both GPA, granulomatosis with polyangiitis, and MPA, microscopic polyangiitis,” explained Dr. Terrier, professor of internal medicine at the National Referral Center for Rare Systemic Autoimmune Diseases at Cochin Hospital in Paris.

“A post hoc analysis showed that, in the patients with a PR3 [proteinase 3]-ANCA and in the patients with relapsing disease, rituximab was superior,” he added.

“So, there was some data which suggest that rituximab could be differentially effective between the different subgroups of patients. So that’s why we wanted to answer this question.”

Since it is not always feasible to do a randomized trial, particularly when it concerns a rare disease such as GPA, Dr. Terrier and associates decided to perform a target trial emulation using data from the FVSG registry, which collates information from 32 hospitals in France. Such studies are gaining in popularity and have been shown to provide a very good level of evidence, he said.
 

Data collections and secondary endpoint results

The researchers obtained data on 194 patients in the registry who were treated for GPA between April 2008 and April 2018. The majority (85.1%) of patients included were newly diagnosed with GPA, and 56.7% were men. The mean age of patients was 54 years.

Information on the PR3-ANCA status of patients was available for 182 patients, and this showed that the majority (80.8%) were positive for this autoantibody.

A weighted analysis was undertaken to iron out any differences in baseline characteristics, such as the fact that more patients had been treated with at least one dose of cyclophosphamide than rituximab (133 vs. 61).

The primary outcome was remission at 6 months, but a key secondary endpoint was the percentage of patients with a BVAS score of zero at this time point. This turned out to be similar among the rituximab- and cyclophosphamide-treated patients (85.5% vs. 82.6%, respectively).

Another secondary endpoint looked at the retention rate without failure at 24 months, with fewer postinclusion treatment failures seen with rituximab than with cyclophosphamide (7 vs. 51 patients, respectively). Most treatment failures were caused by relapses (7 vs. 33).

In terms of safety, the researchers said they found “no increased toxicity signal” for rituximab over cyclophosphamide. In fact, more severe adverse events were noted in the latter group.

Take-home messages

While of course there are limitations, considering the earlier data and the current results, “we probably have enough data to consider that, in the vast majority of GPA patients, in PR3-ANCA patients, rituximab is probably the best option,” Dr. Terrier said.

There are still patients for whom there isn’t a definitive answer on which drug may be best, such as those with severe disease who were not included in the trials or represent few patients in the registry. For them, it is “still a case-by-case discussion, and I think we have to decide really, with caution,” Dr. Terrier said.

What this study also shows is that emulated trials are possible, he added. “I think it shows that we could have some answers to other questions by emulating trials in this rare disease.”

The FVSG registry has received funding from the European Union’s Horizon 2020 research and innovation program. Dr. Terrier reported receiving personal fees from Vifor Pharma Group, GlaxoSmithKline, and AstraZeneca during the conduct of the study. Dr. Jayne has received lecture fees and a research grant from Roche/Genentech.

More patients with granulomatosis with polyangiitis (GPA) were in remission at 6 months if they had received rituximab (Rituxan) rather than cyclophosphamide (Cytoxan) as induction therapy, according to a target trial emulation performed by the French Vasculitis Study Group (FVSG).

Remission, which was defined as a score of zero on the validated Birmingham Vasculitis Activity Score (BVAS) and use of no more than 10 mg of prednisone a day, was documented in 73.1% of rituximab-treated patients and 40.1% of cyclophosphamide-treated patients.

Similar rates of remission were observed regardless of whether patients were newly diagnosed with GPA (76.1% vs. 41.6%) or had been recently treated for relapsing disease (75.2% vs. 44.5%), FVSG researchers reported in JAMA Network Open.

This research “may inform clinical decision-making regarding the choice of remission-inducing regimen for patients with GPA,” the researchers suggested.
 

Practice already shifting to rituximab

“The results are largely in line with previous perceptions,” David R.W. Jayne, MD, honorary consultant and director of the vasculitis and lupus service at Addenbrooke’s Hospital in Cambridge, England, observed in an emailed comment.

“The difference is a bit bigger [in favor of rituximab] than I would have expected,” said Dr. Jayne, who is also professor of clinical autoimmunity at the University of Cambridge. He noted that clinical practice was already moving toward using rituximab in place of cyclophosphamide.

Rituximab gained a European license to treat antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAV) just over a decade ago. Since then, it has slowly started to replace the use of cyclophosphamide and glucocorticoids, which were the preferred method up until then.

Part of the reason for this shift is the toxicity associated with cyclophosphamide, although that’s not to say that rituximab is free from safety concerns, Dr. Jayne said.

“Toxicity issues with rituximab, especially secondary immunodeficiency, more severe COVID, and blocking vaccine responses, are becoming bigger issues for day-to-day practice,” he noted. Nonetheless, “the introduction of rituximab has been a revolution in AAV treatment. It has encouraged pharma investment in the disease, such as recent approval of avacopan [Tavneos], and it is helping patients.”

Why simulate and not perform a randomized trial?

There were several reasons for performing the current evaluation, study coauthor Benjamin Terrier, MD, PhD, said in an interview.

“The pivotal study, published in 2010, that led to the approval of rituximab was a noninferiority study in comparison with cyclophosphamide, but it included patients with both GPA, granulomatosis with polyangiitis, and MPA, microscopic polyangiitis,” explained Dr. Terrier, professor of internal medicine at the National Referral Center for Rare Systemic Autoimmune Diseases at Cochin Hospital in Paris.

“A post hoc analysis showed that, in the patients with a PR3 [proteinase 3]-ANCA and in the patients with relapsing disease, rituximab was superior,” he added.

“So, there was some data which suggest that rituximab could be differentially effective between the different subgroups of patients. So that’s why we wanted to answer this question.”

Since it is not always feasible to do a randomized trial, particularly when it concerns a rare disease such as GPA, Dr. Terrier and associates decided to perform a target trial emulation using data from the FVSG registry, which collates information from 32 hospitals in France. Such studies are gaining in popularity and have been shown to provide a very good level of evidence, he said.
 

Data collections and secondary endpoint results

The researchers obtained data on 194 patients in the registry who were treated for GPA between April 2008 and April 2018. The majority (85.1%) of patients included were newly diagnosed with GPA, and 56.7% were men. The mean age of patients was 54 years.

Information on the PR3-ANCA status of patients was available for 182 patients, and this showed that the majority (80.8%) were positive for this autoantibody.

A weighted analysis was undertaken to iron out any differences in baseline characteristics, such as the fact that more patients had been treated with at least one dose of cyclophosphamide than rituximab (133 vs. 61).

The primary outcome was remission at 6 months, but a key secondary endpoint was the percentage of patients with a BVAS score of zero at this time point. This turned out to be similar among the rituximab- and cyclophosphamide-treated patients (85.5% vs. 82.6%, respectively).

Another secondary endpoint looked at the retention rate without failure at 24 months, with fewer postinclusion treatment failures seen with rituximab than with cyclophosphamide (7 vs. 51 patients, respectively). Most treatment failures were caused by relapses (7 vs. 33).

In terms of safety, the researchers said they found “no increased toxicity signal” for rituximab over cyclophosphamide. In fact, more severe adverse events were noted in the latter group.

Take-home messages

While of course there are limitations, considering the earlier data and the current results, “we probably have enough data to consider that, in the vast majority of GPA patients, in PR3-ANCA patients, rituximab is probably the best option,” Dr. Terrier said.

There are still patients for whom there isn’t a definitive answer on which drug may be best, such as those with severe disease who were not included in the trials or represent few patients in the registry. For them, it is “still a case-by-case discussion, and I think we have to decide really, with caution,” Dr. Terrier said.

What this study also shows is that emulated trials are possible, he added. “I think it shows that we could have some answers to other questions by emulating trials in this rare disease.”

The FVSG registry has received funding from the European Union’s Horizon 2020 research and innovation program. Dr. Terrier reported receiving personal fees from Vifor Pharma Group, GlaxoSmithKline, and AstraZeneca during the conduct of the study. Dr. Jayne has received lecture fees and a research grant from Roche/Genentech.

More patients with granulomatosis with polyangiitis (GPA) were in remission at 6 months if they had received rituximab (Rituxan) rather than cyclophosphamide (Cytoxan) as induction therapy, according to a target trial emulation performed by the French Vasculitis Study Group (FVSG).

Remission, which was defined as a score of zero on the validated Birmingham Vasculitis Activity Score (BVAS) and use of no more than 10 mg of prednisone a day, was documented in 73.1% of rituximab-treated patients and 40.1% of cyclophosphamide-treated patients.

Similar rates of remission were observed regardless of whether patients were newly diagnosed with GPA (76.1% vs. 41.6%) or had been recently treated for relapsing disease (75.2% vs. 44.5%), FVSG researchers reported in JAMA Network Open.

This research “may inform clinical decision-making regarding the choice of remission-inducing regimen for patients with GPA,” the researchers suggested.
 

Practice already shifting to rituximab

“The results are largely in line with previous perceptions,” David R.W. Jayne, MD, honorary consultant and director of the vasculitis and lupus service at Addenbrooke’s Hospital in Cambridge, England, observed in an emailed comment.

“The difference is a bit bigger [in favor of rituximab] than I would have expected,” said Dr. Jayne, who is also professor of clinical autoimmunity at the University of Cambridge. He noted that clinical practice was already moving toward using rituximab in place of cyclophosphamide.

Rituximab gained a European license to treat antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAV) just over a decade ago. Since then, it has slowly started to replace the use of cyclophosphamide and glucocorticoids, which were the preferred method up until then.

Part of the reason for this shift is the toxicity associated with cyclophosphamide, although that’s not to say that rituximab is free from safety concerns, Dr. Jayne said.

“Toxicity issues with rituximab, especially secondary immunodeficiency, more severe COVID, and blocking vaccine responses, are becoming bigger issues for day-to-day practice,” he noted. Nonetheless, “the introduction of rituximab has been a revolution in AAV treatment. It has encouraged pharma investment in the disease, such as recent approval of avacopan [Tavneos], and it is helping patients.”

Why simulate and not perform a randomized trial?

There were several reasons for performing the current evaluation, study coauthor Benjamin Terrier, MD, PhD, said in an interview.

“The pivotal study, published in 2010, that led to the approval of rituximab was a noninferiority study in comparison with cyclophosphamide, but it included patients with both GPA, granulomatosis with polyangiitis, and MPA, microscopic polyangiitis,” explained Dr. Terrier, professor of internal medicine at the National Referral Center for Rare Systemic Autoimmune Diseases at Cochin Hospital in Paris.

“A post hoc analysis showed that, in the patients with a PR3 [proteinase 3]-ANCA and in the patients with relapsing disease, rituximab was superior,” he added.

“So, there was some data which suggest that rituximab could be differentially effective between the different subgroups of patients. So that’s why we wanted to answer this question.”

Since it is not always feasible to do a randomized trial, particularly when it concerns a rare disease such as GPA, Dr. Terrier and associates decided to perform a target trial emulation using data from the FVSG registry, which collates information from 32 hospitals in France. Such studies are gaining in popularity and have been shown to provide a very good level of evidence, he said.
 

Data collections and secondary endpoint results

The researchers obtained data on 194 patients in the registry who were treated for GPA between April 2008 and April 2018. The majority (85.1%) of patients included were newly diagnosed with GPA, and 56.7% were men. The mean age of patients was 54 years.

Information on the PR3-ANCA status of patients was available for 182 patients, and this showed that the majority (80.8%) were positive for this autoantibody.

A weighted analysis was undertaken to iron out any differences in baseline characteristics, such as the fact that more patients had been treated with at least one dose of cyclophosphamide than rituximab (133 vs. 61).

The primary outcome was remission at 6 months, but a key secondary endpoint was the percentage of patients with a BVAS score of zero at this time point. This turned out to be similar among the rituximab- and cyclophosphamide-treated patients (85.5% vs. 82.6%, respectively).

Another secondary endpoint looked at the retention rate without failure at 24 months, with fewer postinclusion treatment failures seen with rituximab than with cyclophosphamide (7 vs. 51 patients, respectively). Most treatment failures were caused by relapses (7 vs. 33).

In terms of safety, the researchers said they found “no increased toxicity signal” for rituximab over cyclophosphamide. In fact, more severe adverse events were noted in the latter group.

Take-home messages

While of course there are limitations, considering the earlier data and the current results, “we probably have enough data to consider that, in the vast majority of GPA patients, in PR3-ANCA patients, rituximab is probably the best option,” Dr. Terrier said.

There are still patients for whom there isn’t a definitive answer on which drug may be best, such as those with severe disease who were not included in the trials or represent few patients in the registry. For them, it is “still a case-by-case discussion, and I think we have to decide really, with caution,” Dr. Terrier said.

What this study also shows is that emulated trials are possible, he added. “I think it shows that we could have some answers to other questions by emulating trials in this rare disease.”

The FVSG registry has received funding from the European Union’s Horizon 2020 research and innovation program. Dr. Terrier reported receiving personal fees from Vifor Pharma Group, GlaxoSmithKline, and AstraZeneca during the conduct of the study. Dr. Jayne has received lecture fees and a research grant from Roche/Genentech.

Several studies have addressed the efficacy of COVID vaccines in patients with autoimmune and rheumatic diseases owing to the concern for possible reduced vaccine immunogenicity in patients who are immunocompromised or taking immunosuppressive medications. With the availability of additional booster doses for the COVID vaccines, the effect of immunosuppressive medications on the humoral response to mRNA vaccines has been of increased interest in terms of counseling patients on how to manage their medications and vaccine timing. Prior studies have suggested that holding methotrexate after COVID vaccine administration improves antibody response to the COVID vaccine. Stahl and colleagues performed a retrospective study to look at vaccine response to a third (booster) dose in patients with rheumatoid arthritis (RA) over 65 years of age (vs those under 65 years of age) and found that patients over 65 receiving methotrexate had lower levels of neutralizing antibodies than did those receiving other treatments for RA, whereas no differences were seen with different treatments among patients under 65. Although COVID vaccine guidance continues to evolve, this finding raises the possibility of a need to tailor guidance in older patients with RA. However, the finding is far from conclusive given the small number of patients in the study.

In addition to COVID vaccine efficacy, the possibility of vaccine-related adverse effects has been a topic of concern in the rheumatology community, especially regarding the potential for a flare of autoimmune diseases. Anxiety regarding adverse effects may also exacerbate COVID vaccine hesitancy among some people. Naveen and colleagues performed an online international cross-sectional survey study regarding rheumatic diseases and 7-day adverse events. Over 9000 people completed the survey, about half of whom had autoimmune diseases (including nonrheumatic autoimmune diseases). Roughly three quarters of patients with RA reported adverse effects, with differences seen in frequencies of events between the different vaccine manufacturers. However, the majority of these adverse effects were minor (such as fatigue, headache, and body ache), without substantial differences between those with inactive and those with active RA.

The treat-to-target strategy is well-accepted in treatment of RA and pursuit of improved long-term disease outcomes. Hartman and colleagues evaluated the effect of using a treat-to-target strategy starting with the combination therapy with RA-light (COBRA-light) protocol (with initial methotrexate and tapering prednisolone) in early RA. Patients who were deemed at high risk for worsening RA (n = 150) received COBRA-light, whereas those in the low-risk category (n = 40) received methotrexate monotherapy. At 13 weeks, nonresponders were randomized to intensification or continuation of their regimens, with a primary endpoint of European Alliance of Associations for Rheumatology (EULAR) response and secondary endpoint of Disease Activity Score (DAS44). After 13 weeks, 73% of patients in the high-risk category achieved the targets of EULAR good response and DAS44 < 1.6, whereas after 26 weeks, 80% of patients who received intensified therapy and 44% of those who continued their regimens reached the target, though these numbers were small. Overall, the strategy appears to be successful in treatment of early RA in patients at high risk for disease progression, but it does lead to increased use of higher chronic glucocorticoid doses. In addition, the small numbers of patients in the low-risk category, as well as their less aggressive treatment, does not allow for a nuanced analysis of the best initial treatment in this group of patients.

Finally, a cohort study by Takanashi and colleagues evaluated the rates of seropositivity for rheumatoid factor (RF) and anti–cyclic citrullinated peptide (anti-CCP) in patients diagnosed with RA and its association with demographic categories. Seropositivity was associated with smoking and family history of RA, as expected. Among the 1685 patients, 83% of whom were women, older age at RA diagnosis was associated with seronegativity for RF and CCP in women but not in men. The decline in seropositivity with age among women cannot be further evaluated with the limited information in this small study and may have to do with other factors, including erosive or inflammatory osteoarthritis.

Several studies have addressed the efficacy of COVID vaccines in patients with autoimmune and rheumatic diseases owing to the concern for possible reduced vaccine immunogenicity in patients who are immunocompromised or taking immunosuppressive medications. With the availability of additional booster doses for the COVID vaccines, the effect of immunosuppressive medications on the humoral response to mRNA vaccines has been of increased interest in terms of counseling patients on how to manage their medications and vaccine timing. Prior studies have suggested that holding methotrexate after COVID vaccine administration improves antibody response to the COVID vaccine. Stahl and colleagues performed a retrospective study to look at vaccine response to a third (booster) dose in patients with rheumatoid arthritis (RA) over 65 years of age (vs those under 65 years of age) and found that patients over 65 receiving methotrexate had lower levels of neutralizing antibodies than did those receiving other treatments for RA, whereas no differences were seen with different treatments among patients under 65. Although COVID vaccine guidance continues to evolve, this finding raises the possibility of a need to tailor guidance in older patients with RA. However, the finding is far from conclusive given the small number of patients in the study.

In addition to COVID vaccine efficacy, the possibility of vaccine-related adverse effects has been a topic of concern in the rheumatology community, especially regarding the potential for a flare of autoimmune diseases. Anxiety regarding adverse effects may also exacerbate COVID vaccine hesitancy among some people. Naveen and colleagues performed an online international cross-sectional survey study regarding rheumatic diseases and 7-day adverse events. Over 9000 people completed the survey, about half of whom had autoimmune diseases (including nonrheumatic autoimmune diseases). Roughly three quarters of patients with RA reported adverse effects, with differences seen in frequencies of events between the different vaccine manufacturers. However, the majority of these adverse effects were minor (such as fatigue, headache, and body ache), without substantial differences between those with inactive and those with active RA.

The treat-to-target strategy is well-accepted in treatment of RA and pursuit of improved long-term disease outcomes. Hartman and colleagues evaluated the effect of using a treat-to-target strategy starting with the combination therapy with RA-light (COBRA-light) protocol (with initial methotrexate and tapering prednisolone) in early RA. Patients who were deemed at high risk for worsening RA (n = 150) received COBRA-light, whereas those in the low-risk category (n = 40) received methotrexate monotherapy. At 13 weeks, nonresponders were randomized to intensification or continuation of their regimens, with a primary endpoint of European Alliance of Associations for Rheumatology (EULAR) response and secondary endpoint of Disease Activity Score (DAS44). After 13 weeks, 73% of patients in the high-risk category achieved the targets of EULAR good response and DAS44 < 1.6, whereas after 26 weeks, 80% of patients who received intensified therapy and 44% of those who continued their regimens reached the target, though these numbers were small. Overall, the strategy appears to be successful in treatment of early RA in patients at high risk for disease progression, but it does lead to increased use of higher chronic glucocorticoid doses. In addition, the small numbers of patients in the low-risk category, as well as their less aggressive treatment, does not allow for a nuanced analysis of the best initial treatment in this group of patients.

Finally, a cohort study by Takanashi and colleagues evaluated the rates of seropositivity for rheumatoid factor (RF) and anti–cyclic citrullinated peptide (anti-CCP) in patients diagnosed with RA and its association with demographic categories. Seropositivity was associated with smoking and family history of RA, as expected. Among the 1685 patients, 83% of whom were women, older age at RA diagnosis was associated with seronegativity for RF and CCP in women but not in men. The decline in seropositivity with age among women cannot be further evaluated with the limited information in this small study and may have to do with other factors, including erosive or inflammatory osteoarthritis.

Several studies have addressed the efficacy of COVID vaccines in patients with autoimmune and rheumatic diseases owing to the concern for possible reduced vaccine immunogenicity in patients who are immunocompromised or taking immunosuppressive medications. With the availability of additional booster doses for the COVID vaccines, the effect of immunosuppressive medications on the humoral response to mRNA vaccines has been of increased interest in terms of counseling patients on how to manage their medications and vaccine timing. Prior studies have suggested that holding methotrexate after COVID vaccine administration improves antibody response to the COVID vaccine. Stahl and colleagues performed a retrospective study to look at vaccine response to a third (booster) dose in patients with rheumatoid arthritis (RA) over 65 years of age (vs those under 65 years of age) and found that patients over 65 receiving methotrexate had lower levels of neutralizing antibodies than did those receiving other treatments for RA, whereas no differences were seen with different treatments among patients under 65. Although COVID vaccine guidance continues to evolve, this finding raises the possibility of a need to tailor guidance in older patients with RA. However, the finding is far from conclusive given the small number of patients in the study.

In addition to COVID vaccine efficacy, the possibility of vaccine-related adverse effects has been a topic of concern in the rheumatology community, especially regarding the potential for a flare of autoimmune diseases. Anxiety regarding adverse effects may also exacerbate COVID vaccine hesitancy among some people. Naveen and colleagues performed an online international cross-sectional survey study regarding rheumatic diseases and 7-day adverse events. Over 9000 people completed the survey, about half of whom had autoimmune diseases (including nonrheumatic autoimmune diseases). Roughly three quarters of patients with RA reported adverse effects, with differences seen in frequencies of events between the different vaccine manufacturers. However, the majority of these adverse effects were minor (such as fatigue, headache, and body ache), without substantial differences between those with inactive and those with active RA.

The treat-to-target strategy is well-accepted in treatment of RA and pursuit of improved long-term disease outcomes. Hartman and colleagues evaluated the effect of using a treat-to-target strategy starting with the combination therapy with RA-light (COBRA-light) protocol (with initial methotrexate and tapering prednisolone) in early RA. Patients who were deemed at high risk for worsening RA (n = 150) received COBRA-light, whereas those in the low-risk category (n = 40) received methotrexate monotherapy. At 13 weeks, nonresponders were randomized to intensification or continuation of their regimens, with a primary endpoint of European Alliance of Associations for Rheumatology (EULAR) response and secondary endpoint of Disease Activity Score (DAS44). After 13 weeks, 73% of patients in the high-risk category achieved the targets of EULAR good response and DAS44 < 1.6, whereas after 26 weeks, 80% of patients who received intensified therapy and 44% of those who continued their regimens reached the target, though these numbers were small. Overall, the strategy appears to be successful in treatment of early RA in patients at high risk for disease progression, but it does lead to increased use of higher chronic glucocorticoid doses. In addition, the small numbers of patients in the low-risk category, as well as their less aggressive treatment, does not allow for a nuanced analysis of the best initial treatment in this group of patients.

Finally, a cohort study by Takanashi and colleagues evaluated the rates of seropositivity for rheumatoid factor (RF) and anti–cyclic citrullinated peptide (anti-CCP) in patients diagnosed with RA and its association with demographic categories. Seropositivity was associated with smoking and family history of RA, as expected. Among the 1685 patients, 83% of whom were women, older age at RA diagnosis was associated with seronegativity for RF and CCP in women but not in men. The decline in seropositivity with age among women cannot be further evaluated with the limited information in this small study and may have to do with other factors, including erosive or inflammatory osteoarthritis.

Research published during the past month focused mostly on sex differences, biomarkers, and treatment. Sex differences in psoriatic arthritis (PsA) are a significant focus of current research. One major question is how clinical features differ between men and women. Furer and colleagues investigated differences in musculoskeletal ultrasonographic features between men and women with PsA. In a prospective study including 70 men and 88 women, they demonstrated that although the total synovitis and tenosynovitis scores were similar between the two sexes, compared with women, men had higher total ultrasound and gray scale enthesitis scores (both P = .01) and sonographic active inflammatory score (P = .005). Given the uncertainty associated with the clinical diagnosis of enthesitis, this study emphasizes the importance of careful ultrasonographic evaluation when evaluating enthesitis patients, especially women.

It is important to investigate pregnancy outcomes in women with inflammatory arthritis, including PsA, to appropriately counsel and manage patients in the reproductive-age group. Preeclampsia is an important pregnancy outcome that is less well studied in PsA. Secher and colleagues analyzed data from registries in Sweden and Denmark that included singleton pregnant women with rheumatoid arthritis (n = 1739), axial spondyloarthritis (n = 819), and PsA (n = 489) who were matched with 17,390, 8190, and 4890 control pregnant women, respectively. They found that compared with the control women, the risk for preeclampsia was much higher in women with PsA (adjusted odds ratio [aOR; adjusted for country, maternal age, parity, year of delivery, body mass index (BMI), smoking, and education] 1.85; 95% CI 1.10-3.12), with the risk being primarily driven by the receipt of monotherapy for PsA before pregnancy (aOR 2.72; 95% CI 1.44-5.13), probably reflecting the presence of more severe disease. Women with PsA who tend to have higher BMI and active disease need to be counseled about the risk for preeclampsia and be carefully monitored.

The Disease Activity index for PsA (DAPSA) is a validated instrument used in clinical practice to assess PsA disease activity. One drawback of this instrument is that it requires testing for C-reactive protein (CRP), the results of which may not be available immediately, making it difficult to use DAPSA for implementing treating-to-target strategies during a clinic visit. To alleviate this issue, a quick quantitative CRP (qCRP) assay was developed. In a multicenter, cross-sectional study including 104 patients with PsA and available CRP values (measured by routine laboratory and qCRP assays), Proft and colleagues demonstrated that 98.1% of patients were similarly categorized into disease activity groups (remission and low, moderate, and high disease activity) using DAPSA based on qCRP (Q-DAPSA) and DAPSA. The agreement between the two instruments was excellent (weighted Cohen kappa 0.980; 95% CI 0.952-1.000). Thus, the Q-DAPSA may be used in place of DAPSA when evaluating PsA disease activity.

Regarding treatment, in an exploratory analysis of SELECT-PsA 1, McInnes and colleagues demonstrated that, at week 104, a similar proportion of patients receiving 15/30 mg upadacitinib vs adalimumab achieved ≥ 20% improvement in the American College of Rheumatology (ACR20) criteria (69.0%/69.5% vs 63.4%), whereas significantly more patients receiving 30 mg upadacitinib vs adalimumab achieved minimal disease activity (45.9% vs 37.8%; P < .05). The safety profiles of upadacitinib and adalimumab were comparable. Moreover, analyses of 52-week outcome data from the ongoing phase 3 KEEPsAKE 1 study of risankizumab (IL-23 inhibitor) by Kristensen and colleagues showed that among patients who received risankizumab continuously, the ACR20 response increased from 57.3% at week 24 to 70.0% at week 52. No new safety signals were identified. Thus, upadacitinib and risankizumab are newer, safe, and effective disease-modifying antirheumatic drugs for PsA.

Research published during the past month focused mostly on sex differences, biomarkers, and treatment. Sex differences in psoriatic arthritis (PsA) are a significant focus of current research. One major question is how clinical features differ between men and women. Furer and colleagues investigated differences in musculoskeletal ultrasonographic features between men and women with PsA. In a prospective study including 70 men and 88 women, they demonstrated that although the total synovitis and tenosynovitis scores were similar between the two sexes, compared with women, men had higher total ultrasound and gray scale enthesitis scores (both P = .01) and sonographic active inflammatory score (P = .005). Given the uncertainty associated with the clinical diagnosis of enthesitis, this study emphasizes the importance of careful ultrasonographic evaluation when evaluating enthesitis patients, especially women.

It is important to investigate pregnancy outcomes in women with inflammatory arthritis, including PsA, to appropriately counsel and manage patients in the reproductive-age group. Preeclampsia is an important pregnancy outcome that is less well studied in PsA. Secher and colleagues analyzed data from registries in Sweden and Denmark that included singleton pregnant women with rheumatoid arthritis (n = 1739), axial spondyloarthritis (n = 819), and PsA (n = 489) who were matched with 17,390, 8190, and 4890 control pregnant women, respectively. They found that compared with the control women, the risk for preeclampsia was much higher in women with PsA (adjusted odds ratio [aOR; adjusted for country, maternal age, parity, year of delivery, body mass index (BMI), smoking, and education] 1.85; 95% CI 1.10-3.12), with the risk being primarily driven by the receipt of monotherapy for PsA before pregnancy (aOR 2.72; 95% CI 1.44-5.13), probably reflecting the presence of more severe disease. Women with PsA who tend to have higher BMI and active disease need to be counseled about the risk for preeclampsia and be carefully monitored.

The Disease Activity index for PsA (DAPSA) is a validated instrument used in clinical practice to assess PsA disease activity. One drawback of this instrument is that it requires testing for C-reactive protein (CRP), the results of which may not be available immediately, making it difficult to use DAPSA for implementing treating-to-target strategies during a clinic visit. To alleviate this issue, a quick quantitative CRP (qCRP) assay was developed. In a multicenter, cross-sectional study including 104 patients with PsA and available CRP values (measured by routine laboratory and qCRP assays), Proft and colleagues demonstrated that 98.1% of patients were similarly categorized into disease activity groups (remission and low, moderate, and high disease activity) using DAPSA based on qCRP (Q-DAPSA) and DAPSA. The agreement between the two instruments was excellent (weighted Cohen kappa 0.980; 95% CI 0.952-1.000). Thus, the Q-DAPSA may be used in place of DAPSA when evaluating PsA disease activity.

Regarding treatment, in an exploratory analysis of SELECT-PsA 1, McInnes and colleagues demonstrated that, at week 104, a similar proportion of patients receiving 15/30 mg upadacitinib vs adalimumab achieved ≥ 20% improvement in the American College of Rheumatology (ACR20) criteria (69.0%/69.5% vs 63.4%), whereas significantly more patients receiving 30 mg upadacitinib vs adalimumab achieved minimal disease activity (45.9% vs 37.8%; P < .05). The safety profiles of upadacitinib and adalimumab were comparable. Moreover, analyses of 52-week outcome data from the ongoing phase 3 KEEPsAKE 1 study of risankizumab (IL-23 inhibitor) by Kristensen and colleagues showed that among patients who received risankizumab continuously, the ACR20 response increased from 57.3% at week 24 to 70.0% at week 52. No new safety signals were identified. Thus, upadacitinib and risankizumab are newer, safe, and effective disease-modifying antirheumatic drugs for PsA.

Research published during the past month focused mostly on sex differences, biomarkers, and treatment. Sex differences in psoriatic arthritis (PsA) are a significant focus of current research. One major question is how clinical features differ between men and women. Furer and colleagues investigated differences in musculoskeletal ultrasonographic features between men and women with PsA. In a prospective study including 70 men and 88 women, they demonstrated that although the total synovitis and tenosynovitis scores were similar between the two sexes, compared with women, men had higher total ultrasound and gray scale enthesitis scores (both P = .01) and sonographic active inflammatory score (P = .005). Given the uncertainty associated with the clinical diagnosis of enthesitis, this study emphasizes the importance of careful ultrasonographic evaluation when evaluating enthesitis patients, especially women.

It is important to investigate pregnancy outcomes in women with inflammatory arthritis, including PsA, to appropriately counsel and manage patients in the reproductive-age group. Preeclampsia is an important pregnancy outcome that is less well studied in PsA. Secher and colleagues analyzed data from registries in Sweden and Denmark that included singleton pregnant women with rheumatoid arthritis (n = 1739), axial spondyloarthritis (n = 819), and PsA (n = 489) who were matched with 17,390, 8190, and 4890 control pregnant women, respectively. They found that compared with the control women, the risk for preeclampsia was much higher in women with PsA (adjusted odds ratio [aOR; adjusted for country, maternal age, parity, year of delivery, body mass index (BMI), smoking, and education] 1.85; 95% CI 1.10-3.12), with the risk being primarily driven by the receipt of monotherapy for PsA before pregnancy (aOR 2.72; 95% CI 1.44-5.13), probably reflecting the presence of more severe disease. Women with PsA who tend to have higher BMI and active disease need to be counseled about the risk for preeclampsia and be carefully monitored.

The Disease Activity index for PsA (DAPSA) is a validated instrument used in clinical practice to assess PsA disease activity. One drawback of this instrument is that it requires testing for C-reactive protein (CRP), the results of which may not be available immediately, making it difficult to use DAPSA for implementing treating-to-target strategies during a clinic visit. To alleviate this issue, a quick quantitative CRP (qCRP) assay was developed. In a multicenter, cross-sectional study including 104 patients with PsA and available CRP values (measured by routine laboratory and qCRP assays), Proft and colleagues demonstrated that 98.1% of patients were similarly categorized into disease activity groups (remission and low, moderate, and high disease activity) using DAPSA based on qCRP (Q-DAPSA) and DAPSA. The agreement between the two instruments was excellent (weighted Cohen kappa 0.980; 95% CI 0.952-1.000). Thus, the Q-DAPSA may be used in place of DAPSA when evaluating PsA disease activity.

Regarding treatment, in an exploratory analysis of SELECT-PsA 1, McInnes and colleagues demonstrated that, at week 104, a similar proportion of patients receiving 15/30 mg upadacitinib vs adalimumab achieved ≥ 20% improvement in the American College of Rheumatology (ACR20) criteria (69.0%/69.5% vs 63.4%), whereas significantly more patients receiving 30 mg upadacitinib vs adalimumab achieved minimal disease activity (45.9% vs 37.8%; P < .05). The safety profiles of upadacitinib and adalimumab were comparable. Moreover, analyses of 52-week outcome data from the ongoing phase 3 KEEPsAKE 1 study of risankizumab (IL-23 inhibitor) by Kristensen and colleagues showed that among patients who received risankizumab continuously, the ACR20 response increased from 57.3% at week 24 to 70.0% at week 52. No new safety signals were identified. Thus, upadacitinib and risankizumab are newer, safe, and effective disease-modifying antirheumatic drugs for PsA.

In early September, about a week after recovering from COVID-19, Barri Sanders went to the bank to pay a bill. But by mistake, she transferred a large amount of money from the wrong account.

“I’m talking about $20,000,” she said. “I had to go back [later] and fix it.”

Ms. Sanders, 83, had not had confusion like that before. Suddenly, the Albuquerque, N.M., resident found herself looking up from a book and not remembering what she had just read. She would stand up from her chair and forget what she meant to do.

“I kind of thought it was just the aging process,” she said. Combined with sudden balance issues, insomnia, and a nagging postnasal drip, the overall effect was “subtle, but scary,” she said.

After 5 days of this, she went to bed and slept the whole night through. She woke up in the morning to find her balanced restored, her sinuses clear, and the mental fog gone. What she’d had, she realized, wasn’t a rapid start of dementia, but rather a mercifully short form of long COVID.

Somewhere between 22% and 32% of people who recover from COVID-19 get “brain fog,” a nonscientific term used to describe slow or sluggish thinking. While this is disturbing at any age, it can be particularly upsetting to older patients and their caregivers, who fear they’re having or witnessing not just an after-effect of a disease, but the start of a permanent loss of thinking skills. And some scientists are starting to confirm what doctors, patients, and their families can already see: Older patients who have had COVID-19 have a higher risk of getting dementia or, if they already have mental confusion, the illness may worsen their condition.

British scientists who studied medical records from around the world reported in the journal The Lancet Psychiatry that people who recovered from COVID-19 had a higher risk of problems with their thinking and dementia even after 2 years had passed.

Another 2022 study, published in JAMA Neurology, looked at older COVID-19 patients for a year after they were discharged from hospitals in Wuhan, China. Compared with uninfected people, those who survived a severe case of COVID-19 were at higher risk for early onset, late-onset, and progressive decline in their thinking skills. Those who survived a mild infection were at a higher risk for early onset decline, the study found.

Eran Metzger, MD, assistant professor of psychiatry at Beth Israel Deaconess Medical Center in Boston, said he’s noticed that COVID-19 makes some older patients confused, and their brains don’t regain their former clarity.

“We see a stepwise decline in their cognition during the COVID episode, and then they never get back up to their baseline,” said Dr. Metzger, medical director at Hebrew SeniorLife.

New research is beginning to back up such findings.

People who got COVID-19 were twice as likely to receive a diagnosis of Alzheimer’s disease in the 12 months after infection, compared to those who didn’t get COVID, according to a study published in the journal Nature Medicine , which analyzed the health care databases of the U.S. Department of Veterans Affairs.

Joshua Cahan, MD, a cognitive neurologist at Northwestern University, Chicago, advises caution about applying such a specific label simply from a patient’s medical chart. After all, he noted, few patients get tested to confirm that they have the proteins linked to Alzheimer’s.

“Probably the most appropriate conclusion from that is that there’s an increased risk of dementia after a COVID infection,” he said, “but we don’t know whether it’s truly Alzheimer’s disease or not.”

There could be a number of reasons why COVID-19 triggers a decline in thinking skills, says Michelle Monje, MD, a neuroscientist and neuro-oncologist at Stanford (Calif.) University.

In a paper published in the journal Neuron, Dr. Monje and her coauthor, Akiko Iwasaki, PhD, professor of immunobiology at Yale University, New Haven, Conn., propose possible triggers for brain fog caused by COVID: inflammation in the lungs and respiratory passages that leads to inflammation and dysregulation of the central nervous system; autoimmune reactions that damage the central nervous system; brain infection directly caused by the coronavirus (though, they note, this appears rare); a reactivation of an Epstein-Barr virus, which can lead to neuroinflammation; triggered by the coronavirus; and/or complications from severe cases of COVID-19, possibly involving periods of low blood oxygen and multi-organ failure.

Scientific understanding of brain fog is “part of an emerging picture that inflammation elsewhere in the body can be transmitted to become inflammation in the brain,” Dr. Monje said. “And once there’s inflammation in the brain … that can dysregulate other cell types that normally support healthy cognitive function.”

One issue with the concept of brain fog is that, like the term itself, the condition can be tough to define for doctors and patients alike and difficult, if not impossible, to capture on common cognition tests.

These days, patients often arrive at the Center of Excellence for Alzheimer’s Disease, in Syracuse, N.Y., complaining that they “don’t feel the same” as they did before contracting COVID-19, said Sharon Brangman, MD, the center’s director and the chair of the geriatrics department at Upstate Medical University.

But the evidence of diminished cognition just isn’t there.

“There’s nothing that we can find, objectively, that’s wrong with them,” she said. “They’re not severe enough to score low on mental status testing.”

But specialized, directed testing can find some probable signs, said Dr. Cahan, who evaluates patient cognition in a long COVID clinic at Northwestern University.

He often finds that his long COVID patients score in the low normal range on cognitive testing.

“Patients do have a complaint that something’s changed, and we don’t have prior testing,” he said. “So it’s possible that they were maybe in the high normal range or the superior range, but you just don’t know.”

He said he has seen very high-performing people, such as lawyers, executives, PhDs, and other professionals, who have tests that might be interpreted as normal, but given their level of achievement, “you would expect [higher scores].”

Like Ms. Sanders, many of those who do have muddled thinking after a COVID infection return to their former mental status. A study published in the journal Brain Communications  found that people who had recovered from COVID-19, even if they had a mild illness, were significantly more likely to have memory and other cognition issues in the months after infection. But after 9 months, the former COVID patients had returned to their normal level of cognition, the team at Britain’s University of Oxford reported.

Notably, though, the average age of the people in the study was 28.6.

At the Northwestern clinic, Dr. Cahan treats patients who have struggled with COVID-induced cognition issues for months or even years. A rehabilitation program involves working with patients to come up with ways to compensate for cognitive deficits – such as making lists – as well as brain exercises, Dr. Cahan said. Over time, patients may achieve a 75% to 85% improvement, he said.

Dr. Monje hopes that one day, science will come up with ways to fully reverse the decline.

“I think what is likely the most common contributor to brain fog is this neuroinflammation, causing dysfunction of other cell types,” she said. “And, at least in the laboratory, we can rescue that in mouse models of chemotherapy brain fog, which gives me hope that we can rescue that for people.”
 

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

In early September, about a week after recovering from COVID-19, Barri Sanders went to the bank to pay a bill. But by mistake, she transferred a large amount of money from the wrong account.

“I’m talking about $20,000,” she said. “I had to go back [later] and fix it.”

Ms. Sanders, 83, had not had confusion like that before. Suddenly, the Albuquerque, N.M., resident found herself looking up from a book and not remembering what she had just read. She would stand up from her chair and forget what she meant to do.

“I kind of thought it was just the aging process,” she said. Combined with sudden balance issues, insomnia, and a nagging postnasal drip, the overall effect was “subtle, but scary,” she said.

After 5 days of this, she went to bed and slept the whole night through. She woke up in the morning to find her balanced restored, her sinuses clear, and the mental fog gone. What she’d had, she realized, wasn’t a rapid start of dementia, but rather a mercifully short form of long COVID.

Somewhere between 22% and 32% of people who recover from COVID-19 get “brain fog,” a nonscientific term used to describe slow or sluggish thinking. While this is disturbing at any age, it can be particularly upsetting to older patients and their caregivers, who fear they’re having or witnessing not just an after-effect of a disease, but the start of a permanent loss of thinking skills. And some scientists are starting to confirm what doctors, patients, and their families can already see: Older patients who have had COVID-19 have a higher risk of getting dementia or, if they already have mental confusion, the illness may worsen their condition.

British scientists who studied medical records from around the world reported in the journal The Lancet Psychiatry that people who recovered from COVID-19 had a higher risk of problems with their thinking and dementia even after 2 years had passed.

Another 2022 study, published in JAMA Neurology, looked at older COVID-19 patients for a year after they were discharged from hospitals in Wuhan, China. Compared with uninfected people, those who survived a severe case of COVID-19 were at higher risk for early onset, late-onset, and progressive decline in their thinking skills. Those who survived a mild infection were at a higher risk for early onset decline, the study found.

Eran Metzger, MD, assistant professor of psychiatry at Beth Israel Deaconess Medical Center in Boston, said he’s noticed that COVID-19 makes some older patients confused, and their brains don’t regain their former clarity.

“We see a stepwise decline in their cognition during the COVID episode, and then they never get back up to their baseline,” said Dr. Metzger, medical director at Hebrew SeniorLife.

New research is beginning to back up such findings.

People who got COVID-19 were twice as likely to receive a diagnosis of Alzheimer’s disease in the 12 months after infection, compared to those who didn’t get COVID, according to a study published in the journal Nature Medicine , which analyzed the health care databases of the U.S. Department of Veterans Affairs.

Joshua Cahan, MD, a cognitive neurologist at Northwestern University, Chicago, advises caution about applying such a specific label simply from a patient’s medical chart. After all, he noted, few patients get tested to confirm that they have the proteins linked to Alzheimer’s.

“Probably the most appropriate conclusion from that is that there’s an increased risk of dementia after a COVID infection,” he said, “but we don’t know whether it’s truly Alzheimer’s disease or not.”

There could be a number of reasons why COVID-19 triggers a decline in thinking skills, says Michelle Monje, MD, a neuroscientist and neuro-oncologist at Stanford (Calif.) University.

In a paper published in the journal Neuron, Dr. Monje and her coauthor, Akiko Iwasaki, PhD, professor of immunobiology at Yale University, New Haven, Conn., propose possible triggers for brain fog caused by COVID: inflammation in the lungs and respiratory passages that leads to inflammation and dysregulation of the central nervous system; autoimmune reactions that damage the central nervous system; brain infection directly caused by the coronavirus (though, they note, this appears rare); a reactivation of an Epstein-Barr virus, which can lead to neuroinflammation; triggered by the coronavirus; and/or complications from severe cases of COVID-19, possibly involving periods of low blood oxygen and multi-organ failure.

Scientific understanding of brain fog is “part of an emerging picture that inflammation elsewhere in the body can be transmitted to become inflammation in the brain,” Dr. Monje said. “And once there’s inflammation in the brain … that can dysregulate other cell types that normally support healthy cognitive function.”

One issue with the concept of brain fog is that, like the term itself, the condition can be tough to define for doctors and patients alike and difficult, if not impossible, to capture on common cognition tests.

These days, patients often arrive at the Center of Excellence for Alzheimer’s Disease, in Syracuse, N.Y., complaining that they “don’t feel the same” as they did before contracting COVID-19, said Sharon Brangman, MD, the center’s director and the chair of the geriatrics department at Upstate Medical University.

But the evidence of diminished cognition just isn’t there.

“There’s nothing that we can find, objectively, that’s wrong with them,” she said. “They’re not severe enough to score low on mental status testing.”

But specialized, directed testing can find some probable signs, said Dr. Cahan, who evaluates patient cognition in a long COVID clinic at Northwestern University.

He often finds that his long COVID patients score in the low normal range on cognitive testing.

“Patients do have a complaint that something’s changed, and we don’t have prior testing,” he said. “So it’s possible that they were maybe in the high normal range or the superior range, but you just don’t know.”

He said he has seen very high-performing people, such as lawyers, executives, PhDs, and other professionals, who have tests that might be interpreted as normal, but given their level of achievement, “you would expect [higher scores].”

Like Ms. Sanders, many of those who do have muddled thinking after a COVID infection return to their former mental status. A study published in the journal Brain Communications  found that people who had recovered from COVID-19, even if they had a mild illness, were significantly more likely to have memory and other cognition issues in the months after infection. But after 9 months, the former COVID patients had returned to their normal level of cognition, the team at Britain’s University of Oxford reported.

Notably, though, the average age of the people in the study was 28.6.

At the Northwestern clinic, Dr. Cahan treats patients who have struggled with COVID-induced cognition issues for months or even years. A rehabilitation program involves working with patients to come up with ways to compensate for cognitive deficits – such as making lists – as well as brain exercises, Dr. Cahan said. Over time, patients may achieve a 75% to 85% improvement, he said.

Dr. Monje hopes that one day, science will come up with ways to fully reverse the decline.

“I think what is likely the most common contributor to brain fog is this neuroinflammation, causing dysfunction of other cell types,” she said. “And, at least in the laboratory, we can rescue that in mouse models of chemotherapy brain fog, which gives me hope that we can rescue that for people.”
 

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

In early September, about a week after recovering from COVID-19, Barri Sanders went to the bank to pay a bill. But by mistake, she transferred a large amount of money from the wrong account.

“I’m talking about $20,000,” she said. “I had to go back [later] and fix it.”

Ms. Sanders, 83, had not had confusion like that before. Suddenly, the Albuquerque, N.M., resident found herself looking up from a book and not remembering what she had just read. She would stand up from her chair and forget what she meant to do.

“I kind of thought it was just the aging process,” she said. Combined with sudden balance issues, insomnia, and a nagging postnasal drip, the overall effect was “subtle, but scary,” she said.

After 5 days of this, she went to bed and slept the whole night through. She woke up in the morning to find her balanced restored, her sinuses clear, and the mental fog gone. What she’d had, she realized, wasn’t a rapid start of dementia, but rather a mercifully short form of long COVID.

Somewhere between 22% and 32% of people who recover from COVID-19 get “brain fog,” a nonscientific term used to describe slow or sluggish thinking. While this is disturbing at any age, it can be particularly upsetting to older patients and their caregivers, who fear they’re having or witnessing not just an after-effect of a disease, but the start of a permanent loss of thinking skills. And some scientists are starting to confirm what doctors, patients, and their families can already see: Older patients who have had COVID-19 have a higher risk of getting dementia or, if they already have mental confusion, the illness may worsen their condition.

British scientists who studied medical records from around the world reported in the journal The Lancet Psychiatry that people who recovered from COVID-19 had a higher risk of problems with their thinking and dementia even after 2 years had passed.

Another 2022 study, published in JAMA Neurology, looked at older COVID-19 patients for a year after they were discharged from hospitals in Wuhan, China. Compared with uninfected people, those who survived a severe case of COVID-19 were at higher risk for early onset, late-onset, and progressive decline in their thinking skills. Those who survived a mild infection were at a higher risk for early onset decline, the study found.

Eran Metzger, MD, assistant professor of psychiatry at Beth Israel Deaconess Medical Center in Boston, said he’s noticed that COVID-19 makes some older patients confused, and their brains don’t regain their former clarity.

“We see a stepwise decline in their cognition during the COVID episode, and then they never get back up to their baseline,” said Dr. Metzger, medical director at Hebrew SeniorLife.

New research is beginning to back up such findings.

People who got COVID-19 were twice as likely to receive a diagnosis of Alzheimer’s disease in the 12 months after infection, compared to those who didn’t get COVID, according to a study published in the journal Nature Medicine , which analyzed the health care databases of the U.S. Department of Veterans Affairs.

Joshua Cahan, MD, a cognitive neurologist at Northwestern University, Chicago, advises caution about applying such a specific label simply from a patient’s medical chart. After all, he noted, few patients get tested to confirm that they have the proteins linked to Alzheimer’s.

“Probably the most appropriate conclusion from that is that there’s an increased risk of dementia after a COVID infection,” he said, “but we don’t know whether it’s truly Alzheimer’s disease or not.”

There could be a number of reasons why COVID-19 triggers a decline in thinking skills, says Michelle Monje, MD, a neuroscientist and neuro-oncologist at Stanford (Calif.) University.

In a paper published in the journal Neuron, Dr. Monje and her coauthor, Akiko Iwasaki, PhD, professor of immunobiology at Yale University, New Haven, Conn., propose possible triggers for brain fog caused by COVID: inflammation in the lungs and respiratory passages that leads to inflammation and dysregulation of the central nervous system; autoimmune reactions that damage the central nervous system; brain infection directly caused by the coronavirus (though, they note, this appears rare); a reactivation of an Epstein-Barr virus, which can lead to neuroinflammation; triggered by the coronavirus; and/or complications from severe cases of COVID-19, possibly involving periods of low blood oxygen and multi-organ failure.

Scientific understanding of brain fog is “part of an emerging picture that inflammation elsewhere in the body can be transmitted to become inflammation in the brain,” Dr. Monje said. “And once there’s inflammation in the brain … that can dysregulate other cell types that normally support healthy cognitive function.”

One issue with the concept of brain fog is that, like the term itself, the condition can be tough to define for doctors and patients alike and difficult, if not impossible, to capture on common cognition tests.

These days, patients often arrive at the Center of Excellence for Alzheimer’s Disease, in Syracuse, N.Y., complaining that they “don’t feel the same” as they did before contracting COVID-19, said Sharon Brangman, MD, the center’s director and the chair of the geriatrics department at Upstate Medical University.

But the evidence of diminished cognition just isn’t there.

“There’s nothing that we can find, objectively, that’s wrong with them,” she said. “They’re not severe enough to score low on mental status testing.”

But specialized, directed testing can find some probable signs, said Dr. Cahan, who evaluates patient cognition in a long COVID clinic at Northwestern University.

He often finds that his long COVID patients score in the low normal range on cognitive testing.

“Patients do have a complaint that something’s changed, and we don’t have prior testing,” he said. “So it’s possible that they were maybe in the high normal range or the superior range, but you just don’t know.”

He said he has seen very high-performing people, such as lawyers, executives, PhDs, and other professionals, who have tests that might be interpreted as normal, but given their level of achievement, “you would expect [higher scores].”

Like Ms. Sanders, many of those who do have muddled thinking after a COVID infection return to their former mental status. A study published in the journal Brain Communications  found that people who had recovered from COVID-19, even if they had a mild illness, were significantly more likely to have memory and other cognition issues in the months after infection. But after 9 months, the former COVID patients had returned to their normal level of cognition, the team at Britain’s University of Oxford reported.

Notably, though, the average age of the people in the study was 28.6.

At the Northwestern clinic, Dr. Cahan treats patients who have struggled with COVID-induced cognition issues for months or even years. A rehabilitation program involves working with patients to come up with ways to compensate for cognitive deficits – such as making lists – as well as brain exercises, Dr. Cahan said. Over time, patients may achieve a 75% to 85% improvement, he said.

Dr. Monje hopes that one day, science will come up with ways to fully reverse the decline.

“I think what is likely the most common contributor to brain fog is this neuroinflammation, causing dysfunction of other cell types,” she said. “And, at least in the laboratory, we can rescue that in mouse models of chemotherapy brain fog, which gives me hope that we can rescue that for people.”
 

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

CHICAGO – Taking NSAIDs for knee osteoarthritis may worsen inflammation and pain over time, suggest new data revealed at the annual meeting of the Radiological Society of North America.

Johanna Luitjens, MD, a postdoctoral scholar in the department of radiology and biomedical Imaging at the University of California, San Francisco, told this news organization that NSAIDs are frequently used to treat OA pain because inflammation is one of the main drivers of OA, but whether they actually help outcomes has been unclear. Her study suggests that they don’t help – and may actually worsen – outcomes.

Denise Fulton/MDedge News

In particular, this study looked at the impact of NSAIDs on synovitis – the inflammation of the membrane lining the knee joint – by using MRI-based structural biomarkers.

OA, the most common form of arthritis, affects more than 32 million adults in the United States and more than 500 million people worldwide.
 

No approved therapy to reduce OA progression

Little is known of the long-term effects of NSAIDs on OA progression. Currently, there’s no approved therapy to cure OA or to reduce its advance.

Dr. Luitjens noted, however, that the synovial membrane mediates development and progression of OA and may be a good therapeutic target.

Researchers studied participants from the Osteoarthritis Initiative (OAI) cohort with moderate to severe OA who used NSAIDs regularly for at least 1 year between baseline and 4-year follow-up. All participants had high-quality 3T MRI of the knee at baseline and after 4 years. Images were scored for biomarkers of inflammation, including cartilage thickness and composition.

Dr. Luitjens and associates studied 721 participants who matched the inclusion criteria (129 with and 592 participants without regular NSAID use). The available data did not further specify amounts of NSAIDs used.

At baseline, significantly higher signal intensity in the infrapatellar fat pad (IFP) was seen in patients who used NSAID, compared with controls (adjusted difference in score, 0.26; 95% confidence interval, –0.5 to –0.129; P = .039).

In addition, at the end of the study period, there was a significantly greater increase in signal intensity of IFP (adjusted difference in score, 0.46; 95% CI, 0.2-0.72; P < .001) and higher increase in effusion synovitis (adjusted difference in score, 0.27; 95% CI, 0.06-0.47;  P = .01) in NSAID users, compared with controls.

IFP size and synovial proliferation score did not different significantly between groups at the start of the study and showed no significant change over time.

The results showed no long-term benefit of NSAID use. Joint inflammation and cartilage quality were worse at baseline in the participants taking NSAIDs, compared with the control group, and worsened at 4-year follow-up.

Design limits strength

Amanda E. Nelson, MD, associate professor of medicine, division of rheumatology, allergy, and immunology at the University of North Carolina at Chapel Hill, cautioned against assuming causality, pointing out that the OAI is an observational cohort study. (Dr. Nelson was not involved in the OAI or Dr. Luitjens’ analysis.)

“[The OAI is] large and well known, but it wasn’t designed to compare these groups, and this was a small subset,” she said in an interview. Without randomization, it’s hard to judge the results.

“It may be that people on NSAIDs for the duration of the study had more pain and had more disease to begin with, or had more symptoms or had failed other treatments,” she said, adding that the effect sizes were small.

Measures such as the IFP are ranked 0-3, so “the clinical difference of a 0.26 difference on a 0-3 scale is a bit uncertain,” she said.

Dr. Luitjens said that the researchers tried to adjust for potential confounders but agreed that randomized controlled trials are needed to better advise physicians and patients on the benefits or harms of using NSAIDs for OA.

Weighing the risks in older adults

Una Makris, MD, associate professor of internal medicine in the division of rheumatic diseases at the University of Texas Southwestern Medical Center, Dallas, noted that NSAIDs are “not always the safest option.”

“We are still in desperate need of disease-modifying drugs in OA with rigorous randomized trials to show efficacy for outcomes that are most meaningful to patients,” Dr. Makris, who was not involved in the study, told this news organization.

“OA is most common in older adults, those often with multiple comorbidities, so we must always weigh the risks – including known adverse effects which can be amplified in older adults – and benefits with the goal of improved function and less pain,” Dr. Makris said.

NSAID use also should be considered in the context of body mass index, cardiovascular risk, prior trauma or injury, other medication use, and behavioral factors, including physical activity, she said.

Dr. Luitjens, Dr. Nelson, and Dr. Makris reported no relevant financial relationships.

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

CHICAGO – Taking NSAIDs for knee osteoarthritis may worsen inflammation and pain over time, suggest new data revealed at the annual meeting of the Radiological Society of North America.

Johanna Luitjens, MD, a postdoctoral scholar in the department of radiology and biomedical Imaging at the University of California, San Francisco, told this news organization that NSAIDs are frequently used to treat OA pain because inflammation is one of the main drivers of OA, but whether they actually help outcomes has been unclear. Her study suggests that they don’t help – and may actually worsen – outcomes.

Denise Fulton/MDedge News

In particular, this study looked at the impact of NSAIDs on synovitis – the inflammation of the membrane lining the knee joint – by using MRI-based structural biomarkers.

OA, the most common form of arthritis, affects more than 32 million adults in the United States and more than 500 million people worldwide.
 

No approved therapy to reduce OA progression

Little is known of the long-term effects of NSAIDs on OA progression. Currently, there’s no approved therapy to cure OA or to reduce its advance.

Dr. Luitjens noted, however, that the synovial membrane mediates development and progression of OA and may be a good therapeutic target.

Researchers studied participants from the Osteoarthritis Initiative (OAI) cohort with moderate to severe OA who used NSAIDs regularly for at least 1 year between baseline and 4-year follow-up. All participants had high-quality 3T MRI of the knee at baseline and after 4 years. Images were scored for biomarkers of inflammation, including cartilage thickness and composition.

Dr. Luitjens and associates studied 721 participants who matched the inclusion criteria (129 with and 592 participants without regular NSAID use). The available data did not further specify amounts of NSAIDs used.

At baseline, significantly higher signal intensity in the infrapatellar fat pad (IFP) was seen in patients who used NSAID, compared with controls (adjusted difference in score, 0.26; 95% confidence interval, –0.5 to –0.129; P = .039).

In addition, at the end of the study period, there was a significantly greater increase in signal intensity of IFP (adjusted difference in score, 0.46; 95% CI, 0.2-0.72; P < .001) and higher increase in effusion synovitis (adjusted difference in score, 0.27; 95% CI, 0.06-0.47;  P = .01) in NSAID users, compared with controls.

IFP size and synovial proliferation score did not different significantly between groups at the start of the study and showed no significant change over time.

The results showed no long-term benefit of NSAID use. Joint inflammation and cartilage quality were worse at baseline in the participants taking NSAIDs, compared with the control group, and worsened at 4-year follow-up.

Design limits strength

Amanda E. Nelson, MD, associate professor of medicine, division of rheumatology, allergy, and immunology at the University of North Carolina at Chapel Hill, cautioned against assuming causality, pointing out that the OAI is an observational cohort study. (Dr. Nelson was not involved in the OAI or Dr. Luitjens’ analysis.)

“[The OAI is] large and well known, but it wasn’t designed to compare these groups, and this was a small subset,” she said in an interview. Without randomization, it’s hard to judge the results.

“It may be that people on NSAIDs for the duration of the study had more pain and had more disease to begin with, or had more symptoms or had failed other treatments,” she said, adding that the effect sizes were small.

Measures such as the IFP are ranked 0-3, so “the clinical difference of a 0.26 difference on a 0-3 scale is a bit uncertain,” she said.

Dr. Luitjens said that the researchers tried to adjust for potential confounders but agreed that randomized controlled trials are needed to better advise physicians and patients on the benefits or harms of using NSAIDs for OA.

Weighing the risks in older adults

Una Makris, MD, associate professor of internal medicine in the division of rheumatic diseases at the University of Texas Southwestern Medical Center, Dallas, noted that NSAIDs are “not always the safest option.”

“We are still in desperate need of disease-modifying drugs in OA with rigorous randomized trials to show efficacy for outcomes that are most meaningful to patients,” Dr. Makris, who was not involved in the study, told this news organization.

“OA is most common in older adults, those often with multiple comorbidities, so we must always weigh the risks – including known adverse effects which can be amplified in older adults – and benefits with the goal of improved function and less pain,” Dr. Makris said.

NSAID use also should be considered in the context of body mass index, cardiovascular risk, prior trauma or injury, other medication use, and behavioral factors, including physical activity, she said.

Dr. Luitjens, Dr. Nelson, and Dr. Makris reported no relevant financial relationships.

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

CHICAGO – Taking NSAIDs for knee osteoarthritis may worsen inflammation and pain over time, suggest new data revealed at the annual meeting of the Radiological Society of North America.

Johanna Luitjens, MD, a postdoctoral scholar in the department of radiology and biomedical Imaging at the University of California, San Francisco, told this news organization that NSAIDs are frequently used to treat OA pain because inflammation is one of the main drivers of OA, but whether they actually help outcomes has been unclear. Her study suggests that they don’t help – and may actually worsen – outcomes.

Denise Fulton/MDedge News

In particular, this study looked at the impact of NSAIDs on synovitis – the inflammation of the membrane lining the knee joint – by using MRI-based structural biomarkers.

OA, the most common form of arthritis, affects more than 32 million adults in the United States and more than 500 million people worldwide.
 

No approved therapy to reduce OA progression

Little is known of the long-term effects of NSAIDs on OA progression. Currently, there’s no approved therapy to cure OA or to reduce its advance.

Dr. Luitjens noted, however, that the synovial membrane mediates development and progression of OA and may be a good therapeutic target.

Researchers studied participants from the Osteoarthritis Initiative (OAI) cohort with moderate to severe OA who used NSAIDs regularly for at least 1 year between baseline and 4-year follow-up. All participants had high-quality 3T MRI of the knee at baseline and after 4 years. Images were scored for biomarkers of inflammation, including cartilage thickness and composition.

Dr. Luitjens and associates studied 721 participants who matched the inclusion criteria (129 with and 592 participants without regular NSAID use). The available data did not further specify amounts of NSAIDs used.

At baseline, significantly higher signal intensity in the infrapatellar fat pad (IFP) was seen in patients who used NSAID, compared with controls (adjusted difference in score, 0.26; 95% confidence interval, –0.5 to –0.129; P = .039).

In addition, at the end of the study period, there was a significantly greater increase in signal intensity of IFP (adjusted difference in score, 0.46; 95% CI, 0.2-0.72; P < .001) and higher increase in effusion synovitis (adjusted difference in score, 0.27; 95% CI, 0.06-0.47;  P = .01) in NSAID users, compared with controls.

IFP size and synovial proliferation score did not different significantly between groups at the start of the study and showed no significant change over time.

The results showed no long-term benefit of NSAID use. Joint inflammation and cartilage quality were worse at baseline in the participants taking NSAIDs, compared with the control group, and worsened at 4-year follow-up.

Design limits strength

Amanda E. Nelson, MD, associate professor of medicine, division of rheumatology, allergy, and immunology at the University of North Carolina at Chapel Hill, cautioned against assuming causality, pointing out that the OAI is an observational cohort study. (Dr. Nelson was not involved in the OAI or Dr. Luitjens’ analysis.)

“[The OAI is] large and well known, but it wasn’t designed to compare these groups, and this was a small subset,” she said in an interview. Without randomization, it’s hard to judge the results.

“It may be that people on NSAIDs for the duration of the study had more pain and had more disease to begin with, or had more symptoms or had failed other treatments,” she said, adding that the effect sizes were small.

Measures such as the IFP are ranked 0-3, so “the clinical difference of a 0.26 difference on a 0-3 scale is a bit uncertain,” she said.

Dr. Luitjens said that the researchers tried to adjust for potential confounders but agreed that randomized controlled trials are needed to better advise physicians and patients on the benefits or harms of using NSAIDs for OA.

Weighing the risks in older adults

Una Makris, MD, associate professor of internal medicine in the division of rheumatic diseases at the University of Texas Southwestern Medical Center, Dallas, noted that NSAIDs are “not always the safest option.”

“We are still in desperate need of disease-modifying drugs in OA with rigorous randomized trials to show efficacy for outcomes that are most meaningful to patients,” Dr. Makris, who was not involved in the study, told this news organization.

“OA is most common in older adults, those often with multiple comorbidities, so we must always weigh the risks – including known adverse effects which can be amplified in older adults – and benefits with the goal of improved function and less pain,” Dr. Makris said.

NSAID use also should be considered in the context of body mass index, cardiovascular risk, prior trauma or injury, other medication use, and behavioral factors, including physical activity, she said.

Dr. Luitjens, Dr. Nelson, and Dr. Makris reported no relevant financial relationships.

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

Vitamin D supplements do not prevent muscle symptoms in new statin users or affect the likelihood of discontinuing a statin due to muscle pain and discomfort, a substudy of the VITAL trial indicates.

Among more than 2,000 randomized participants, statin-associated muscle symptoms (SAMS) were reported by 31% assigned to vitamin D and 31% assigned to placebo.

copyright Joss/Fotolia.com

The two groups were equally likely to stop taking a statin due to muscle symptoms, at 13%.

No significant difference was observed in SAMS (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.80-1.18) or statin discontinuations (OR, 1.04; 95% CI, 0.80-1.35) after adjustment for baseline variables and other characteristics, namely age, sex, and African-American race, previously found to be associated with SAMS in VITAL.

“We actually thought when we started out that maybe we were going to show something, that maybe it was going to be that the people who got the vitamin D were least likely to have a problem with a statin than all those who didn’t get vitamin D, but that is not what we showed,” senior author Neil J. Stone, MD, Northwestern University, Chicago, told this news organization.

He noted that patients in the clinic with low levels of vitamin D often have muscle pain and discomfort and that previous unblinded studies suggested vitamin D might benefit patients with SAMS and reduce statin intolerance.

As previously reported, the double-blind VITAL trial showed no difference in the primary prevention of cardiovascular disease or cancer at 5 years among 25,871 middle-aged adults randomized to vitamin D3 at 2000 IU/d or placebo, regardless of their baseline vitamin D level.

Unlike previous studies showing a benefit with vitamin D on SAMS, importantly, VITAL participants were unaware of whether they were taking vitamin D or placebo and were not expecting any help with their muscle symptoms, first author Mark A. Hlatky, MD, Stanford (Calif.) University, pointed out in an interview.

As to how many statin users turn to the popular supplement for SAMS, he said that number couldn’t be pinned down, despite a lengthy search. “But I think it’s very common, because up to half of people stop taking their statins within a year and many of these do so because of statin-associated muscle symptoms, and we found it in about 30% of people who have them. I have them myself and was motivated to study it because I thought this was an interesting question.”

The results were published online in JAMA Cardiology.
 

SAMS by baseline 25-OHD

The substudy included 2,083 patients who initiated statin therapy after randomization and were surveyed in early 2016 about their statin use and muscle symptoms.

Two-thirds, or 1,397 patients, had 25-hydroxy vitamin D (25-OHD) measured at baseline, with 47% having levels < 30 ng/mL and 13% levels < 20 ng/mL.

Serum 25-OHD levels were virtually identical in the two treatment groups (mean, 30.4 ng/mL; median, 30.0 ng/mL). The frequency of SAMS did not differ between those assigned to vitamin D or placebo (28% vs. 31%).

The odds ratios for the association with vitamin D on SAMS were:

• 0.86 in all respondents with 25-OHD measured (95% CI, 0.69-1.09).
• 0.87 in those with levels ≥ 30 ng/mL (95% CI, 0.64-1.19).
• 0.85 with levels of 20-30 ng/mL (95% CI, 0.56-1.28).
• 0.93 with levels < 20 ng/mL (95% CI, 0.50-1.74).

The test for treatment effect modification by baseline serum 25-OHD level was not significant (P for interaction = .83).

In addition, the rate of muscle symptoms was similar between participants randomized to vitamin D and placebo when researchers used a cutpoint to define low 25-OHD of < 30 ng/mL (27% vs. 30%) or < 20 ng/mL (33% vs. 35%).

“We didn’t find any evidence at all that the people who came into the study with low levels of vitamin D did better with the supplement in this case,” Dr. Hlatky said. “So that wasn’t the reason we didn’t see anything.”

Critics may suggest the trial didn’t use a high enough dose of vitamin D, but both Dr. Hlatky and Dr. Stone say that’s unlikely to be a factor in the results because 2,000 IU/d is a substantial dose and well above the recommended adult daily dose of 600-800 IU.

They caution that the substudy wasn’t prespecified, was smaller than the parent trial, and did not have a protocol in place to detail SAMS. They also can’t rule out the possibility that vitamin D may have an effect in patients who have confirmed intolerance to multiple statins, especially after adjustment for the statin type and dose.

“If you’re taking vitamin D to keep from having statin-associated muscle symptoms, this very carefully done substudy with the various caveats doesn’t support that and that’s not something I would give my patients,” Dr. Stone said.

“The most important thing from a negative study is that it allows you to focus your attention on things that may be much more productive rather than assuming that just giving everybody vitamin D will take care of the statin issue,” he added. “Maybe the answer is going to be somewhere else, and there’ll be a lot of people I’m sure who will offer their advice as what the answer is but, I would argue, we want to see more studies to pin it down. So people can get some science behind what they do to try to reduce statin-associated muscle symptoms.”

Paul D. Thompson, MD, chief of cardiology emeritus at Hartford (Conn.) Hospital, and a SAMS expert who was not involved with the research, said, “This is a useful publication, and it’s smart in that it took advantage of a study that was already done.”

He acknowledged being skeptical of a beneficial effect of vitamin D supplementation on SAMS, because some previous data have been retracted, but said that potential treatments are best tested in patients with confirmed statin myalgia, as was the case in his team’s negative trial of CoQ10 supplementation.

That said, the present “study was able to at least give some of the best evidence so far that vitamin D doesn’t do anything to improve symptoms,” Dr. Thompson said. “So maybe it will cut down on so many vitamin D levels [being measured] and use of vitamin D when you don’t really need it.”

The study was sponsored by the Hyperlipidemia Research Fund at Northwestern University. The VITAL trial was supported by grants from the National Institutes of Health, and Quest Diagnostics performed the laboratory measurements at no additional costs. Dr. Hlatky reports no relevant financial relationships. Dr. Stone reports a grant from the Hyperlipidemia Research Fund at Northwestern and honorarium for educational activity for Knowledge to Practice. Dr. Thompson is on the executive committee for a study examining bempedoic acid in patients with statin-associated muscle symptoms.

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

Vitamin D supplements do not prevent muscle symptoms in new statin users or affect the likelihood of discontinuing a statin due to muscle pain and discomfort, a substudy of the VITAL trial indicates.

Among more than 2,000 randomized participants, statin-associated muscle symptoms (SAMS) were reported by 31% assigned to vitamin D and 31% assigned to placebo.

copyright Joss/Fotolia.com

The two groups were equally likely to stop taking a statin due to muscle symptoms, at 13%.

No significant difference was observed in SAMS (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.80-1.18) or statin discontinuations (OR, 1.04; 95% CI, 0.80-1.35) after adjustment for baseline variables and other characteristics, namely age, sex, and African-American race, previously found to be associated with SAMS in VITAL.

“We actually thought when we started out that maybe we were going to show something, that maybe it was going to be that the people who got the vitamin D were least likely to have a problem with a statin than all those who didn’t get vitamin D, but that is not what we showed,” senior author Neil J. Stone, MD, Northwestern University, Chicago, told this news organization.

He noted that patients in the clinic with low levels of vitamin D often have muscle pain and discomfort and that previous unblinded studies suggested vitamin D might benefit patients with SAMS and reduce statin intolerance.

As previously reported, the double-blind VITAL trial showed no difference in the primary prevention of cardiovascular disease or cancer at 5 years among 25,871 middle-aged adults randomized to vitamin D3 at 2000 IU/d or placebo, regardless of their baseline vitamin D level.

Unlike previous studies showing a benefit with vitamin D on SAMS, importantly, VITAL participants were unaware of whether they were taking vitamin D or placebo and were not expecting any help with their muscle symptoms, first author Mark A. Hlatky, MD, Stanford (Calif.) University, pointed out in an interview.

As to how many statin users turn to the popular supplement for SAMS, he said that number couldn’t be pinned down, despite a lengthy search. “But I think it’s very common, because up to half of people stop taking their statins within a year and many of these do so because of statin-associated muscle symptoms, and we found it in about 30% of people who have them. I have them myself and was motivated to study it because I thought this was an interesting question.”

The results were published online in JAMA Cardiology.
 

SAMS by baseline 25-OHD

The substudy included 2,083 patients who initiated statin therapy after randomization and were surveyed in early 2016 about their statin use and muscle symptoms.

Two-thirds, or 1,397 patients, had 25-hydroxy vitamin D (25-OHD) measured at baseline, with 47% having levels < 30 ng/mL and 13% levels < 20 ng/mL.

Serum 25-OHD levels were virtually identical in the two treatment groups (mean, 30.4 ng/mL; median, 30.0 ng/mL). The frequency of SAMS did not differ between those assigned to vitamin D or placebo (28% vs. 31%).

The odds ratios for the association with vitamin D on SAMS were:

• 0.86 in all respondents with 25-OHD measured (95% CI, 0.69-1.09).
• 0.87 in those with levels ≥ 30 ng/mL (95% CI, 0.64-1.19).
• 0.85 with levels of 20-30 ng/mL (95% CI, 0.56-1.28).
• 0.93 with levels < 20 ng/mL (95% CI, 0.50-1.74).

The test for treatment effect modification by baseline serum 25-OHD level was not significant (P for interaction = .83).

In addition, the rate of muscle symptoms was similar between participants randomized to vitamin D and placebo when researchers used a cutpoint to define low 25-OHD of < 30 ng/mL (27% vs. 30%) or < 20 ng/mL (33% vs. 35%).

“We didn’t find any evidence at all that the people who came into the study with low levels of vitamin D did better with the supplement in this case,” Dr. Hlatky said. “So that wasn’t the reason we didn’t see anything.”

Critics may suggest the trial didn’t use a high enough dose of vitamin D, but both Dr. Hlatky and Dr. Stone say that’s unlikely to be a factor in the results because 2,000 IU/d is a substantial dose and well above the recommended adult daily dose of 600-800 IU.

They caution that the substudy wasn’t prespecified, was smaller than the parent trial, and did not have a protocol in place to detail SAMS. They also can’t rule out the possibility that vitamin D may have an effect in patients who have confirmed intolerance to multiple statins, especially after adjustment for the statin type and dose.

“If you’re taking vitamin D to keep from having statin-associated muscle symptoms, this very carefully done substudy with the various caveats doesn’t support that and that’s not something I would give my patients,” Dr. Stone said.

“The most important thing from a negative study is that it allows you to focus your attention on things that may be much more productive rather than assuming that just giving everybody vitamin D will take care of the statin issue,” he added. “Maybe the answer is going to be somewhere else, and there’ll be a lot of people I’m sure who will offer their advice as what the answer is but, I would argue, we want to see more studies to pin it down. So people can get some science behind what they do to try to reduce statin-associated muscle symptoms.”

Paul D. Thompson, MD, chief of cardiology emeritus at Hartford (Conn.) Hospital, and a SAMS expert who was not involved with the research, said, “This is a useful publication, and it’s smart in that it took advantage of a study that was already done.”

He acknowledged being skeptical of a beneficial effect of vitamin D supplementation on SAMS, because some previous data have been retracted, but said that potential treatments are best tested in patients with confirmed statin myalgia, as was the case in his team’s negative trial of CoQ10 supplementation.

That said, the present “study was able to at least give some of the best evidence so far that vitamin D doesn’t do anything to improve symptoms,” Dr. Thompson said. “So maybe it will cut down on so many vitamin D levels [being measured] and use of vitamin D when you don’t really need it.”

The study was sponsored by the Hyperlipidemia Research Fund at Northwestern University. The VITAL trial was supported by grants from the National Institutes of Health, and Quest Diagnostics performed the laboratory measurements at no additional costs. Dr. Hlatky reports no relevant financial relationships. Dr. Stone reports a grant from the Hyperlipidemia Research Fund at Northwestern and honorarium for educational activity for Knowledge to Practice. Dr. Thompson is on the executive committee for a study examining bempedoic acid in patients with statin-associated muscle symptoms.

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

Vitamin D supplements do not prevent muscle symptoms in new statin users or affect the likelihood of discontinuing a statin due to muscle pain and discomfort, a substudy of the VITAL trial indicates.

Among more than 2,000 randomized participants, statin-associated muscle symptoms (SAMS) were reported by 31% assigned to vitamin D and 31% assigned to placebo.

copyright Joss/Fotolia.com

The two groups were equally likely to stop taking a statin due to muscle symptoms, at 13%.

No significant difference was observed in SAMS (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.80-1.18) or statin discontinuations (OR, 1.04; 95% CI, 0.80-1.35) after adjustment for baseline variables and other characteristics, namely age, sex, and African-American race, previously found to be associated with SAMS in VITAL.

“We actually thought when we started out that maybe we were going to show something, that maybe it was going to be that the people who got the vitamin D were least likely to have a problem with a statin than all those who didn’t get vitamin D, but that is not what we showed,” senior author Neil J. Stone, MD, Northwestern University, Chicago, told this news organization.

He noted that patients in the clinic with low levels of vitamin D often have muscle pain and discomfort and that previous unblinded studies suggested vitamin D might benefit patients with SAMS and reduce statin intolerance.

As previously reported, the double-blind VITAL trial showed no difference in the primary prevention of cardiovascular disease or cancer at 5 years among 25,871 middle-aged adults randomized to vitamin D3 at 2000 IU/d or placebo, regardless of their baseline vitamin D level.

Unlike previous studies showing a benefit with vitamin D on SAMS, importantly, VITAL participants were unaware of whether they were taking vitamin D or placebo and were not expecting any help with their muscle symptoms, first author Mark A. Hlatky, MD, Stanford (Calif.) University, pointed out in an interview.

As to how many statin users turn to the popular supplement for SAMS, he said that number couldn’t be pinned down, despite a lengthy search. “But I think it’s very common, because up to half of people stop taking their statins within a year and many of these do so because of statin-associated muscle symptoms, and we found it in about 30% of people who have them. I have them myself and was motivated to study it because I thought this was an interesting question.”

The results were published online in JAMA Cardiology.
 

SAMS by baseline 25-OHD

The substudy included 2,083 patients who initiated statin therapy after randomization and were surveyed in early 2016 about their statin use and muscle symptoms.

Two-thirds, or 1,397 patients, had 25-hydroxy vitamin D (25-OHD) measured at baseline, with 47% having levels < 30 ng/mL and 13% levels < 20 ng/mL.

Serum 25-OHD levels were virtually identical in the two treatment groups (mean, 30.4 ng/mL; median, 30.0 ng/mL). The frequency of SAMS did not differ between those assigned to vitamin D or placebo (28% vs. 31%).

The odds ratios for the association with vitamin D on SAMS were:

• 0.86 in all respondents with 25-OHD measured (95% CI, 0.69-1.09).
• 0.87 in those with levels ≥ 30 ng/mL (95% CI, 0.64-1.19).
• 0.85 with levels of 20-30 ng/mL (95% CI, 0.56-1.28).
• 0.93 with levels < 20 ng/mL (95% CI, 0.50-1.74).

The test for treatment effect modification by baseline serum 25-OHD level was not significant (P for interaction = .83).

In addition, the rate of muscle symptoms was similar between participants randomized to vitamin D and placebo when researchers used a cutpoint to define low 25-OHD of < 30 ng/mL (27% vs. 30%) or < 20 ng/mL (33% vs. 35%).

“We didn’t find any evidence at all that the people who came into the study with low levels of vitamin D did better with the supplement in this case,” Dr. Hlatky said. “So that wasn’t the reason we didn’t see anything.”

Critics may suggest the trial didn’t use a high enough dose of vitamin D, but both Dr. Hlatky and Dr. Stone say that’s unlikely to be a factor in the results because 2,000 IU/d is a substantial dose and well above the recommended adult daily dose of 600-800 IU.

They caution that the substudy wasn’t prespecified, was smaller than the parent trial, and did not have a protocol in place to detail SAMS. They also can’t rule out the possibility that vitamin D may have an effect in patients who have confirmed intolerance to multiple statins, especially after adjustment for the statin type and dose.

“If you’re taking vitamin D to keep from having statin-associated muscle symptoms, this very carefully done substudy with the various caveats doesn’t support that and that’s not something I would give my patients,” Dr. Stone said.

“The most important thing from a negative study is that it allows you to focus your attention on things that may be much more productive rather than assuming that just giving everybody vitamin D will take care of the statin issue,” he added. “Maybe the answer is going to be somewhere else, and there’ll be a lot of people I’m sure who will offer their advice as what the answer is but, I would argue, we want to see more studies to pin it down. So people can get some science behind what they do to try to reduce statin-associated muscle symptoms.”

Paul D. Thompson, MD, chief of cardiology emeritus at Hartford (Conn.) Hospital, and a SAMS expert who was not involved with the research, said, “This is a useful publication, and it’s smart in that it took advantage of a study that was already done.”

He acknowledged being skeptical of a beneficial effect of vitamin D supplementation on SAMS, because some previous data have been retracted, but said that potential treatments are best tested in patients with confirmed statin myalgia, as was the case in his team’s negative trial of CoQ10 supplementation.

That said, the present “study was able to at least give some of the best evidence so far that vitamin D doesn’t do anything to improve symptoms,” Dr. Thompson said. “So maybe it will cut down on so many vitamin D levels [being measured] and use of vitamin D when you don’t really need it.”

The study was sponsored by the Hyperlipidemia Research Fund at Northwestern University. The VITAL trial was supported by grants from the National Institutes of Health, and Quest Diagnostics performed the laboratory measurements at no additional costs. Dr. Hlatky reports no relevant financial relationships. Dr. Stone reports a grant from the Hyperlipidemia Research Fund at Northwestern and honorarium for educational activity for Knowledge to Practice. Dr. Thompson is on the executive committee for a study examining bempedoic acid in patients with statin-associated muscle symptoms.

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

For the first time, the majority of people dying from COVID-19 in America have been vaccinated.

“We can no longer say this is a pandemic of the unvaccinated,” Kaiser Family Foundation Vice President Cynthia Cox, who conducted the analysis, told The Washington Post.

People who had been vaccinated or boosted made up 58% of COVID-19 deaths in August, the analysis showed. The rate has been on the rise: 23% of coronavirus deaths were among vaccinated people in September 2021, and the vaccinated made up 42% of deaths in January and February 2022, the Post reported.

Research continues to show that people who are vaccinated or boosted have a lower risk of death. The rise in deaths among the vaccinated is the result of three factors, Ms. Cox said.

• A large majority of people in the United States have been vaccinated (267 million people, the  said).
• People who are at the greatest risk of dying from COVID-19 are more likely to be vaccinated and boosted, such as the elderly.
• Vaccines lose their effectiveness over time; the virus changes to avoid vaccines; and people need to choose to get boosters to continue to be protected.

The case for the effectiveness of vaccines and boosters versus skipping the shots remains strong. People age 6 months and older who are unvaccinated are six times more likely to die of COVID-19, compared to those who got the primary series of shots, the Post reported. Survival rates were even better with additional booster shots, particularly among older people.

“I feel very confident that if people continue to get vaccinated at good numbers, if people get boosted, we can absolutely have a very safe and healthy holiday season,” Ashish Jha, White House coronavirus czar, said on Nov. 22.

The number of Americans who have gotten the most recent booster has been increasing ahead of the holidays. CDC data show that 12% of the U.S. population age 5 and older has received a booster.

A new study by a team of researchers from Harvard University and Yale University estimates that 94% of the U.S. population has been infected with COVID-19 at least once, leaving just 1 in 20 people who have never had the virus.

“Despite these high exposure numbers, there is still substantial population susceptibility to infection with an Omicron variant,” the authors wrote.

They said that if all states achieved the vaccination levels of Vermont, where 55% of people had at least one booster and 22% got a second one, there would be “an appreciable improvement in population immunity, with greater relative impact for protection against infection versus severe disease. This additional protection results from both the recovery of immunity lost due to waning and the increased effectiveness of the bivalent booster against Omicron infections.”

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

For the first time, the majority of people dying from COVID-19 in America have been vaccinated.

“We can no longer say this is a pandemic of the unvaccinated,” Kaiser Family Foundation Vice President Cynthia Cox, who conducted the analysis, told The Washington Post.

People who had been vaccinated or boosted made up 58% of COVID-19 deaths in August, the analysis showed. The rate has been on the rise: 23% of coronavirus deaths were among vaccinated people in September 2021, and the vaccinated made up 42% of deaths in January and February 2022, the Post reported.

Research continues to show that people who are vaccinated or boosted have a lower risk of death. The rise in deaths among the vaccinated is the result of three factors, Ms. Cox said.

• A large majority of people in the United States have been vaccinated (267 million people, the  said).
• People who are at the greatest risk of dying from COVID-19 are more likely to be vaccinated and boosted, such as the elderly.
• Vaccines lose their effectiveness over time; the virus changes to avoid vaccines; and people need to choose to get boosters to continue to be protected.

The case for the effectiveness of vaccines and boosters versus skipping the shots remains strong. People age 6 months and older who are unvaccinated are six times more likely to die of COVID-19, compared to those who got the primary series of shots, the Post reported. Survival rates were even better with additional booster shots, particularly among older people.

“I feel very confident that if people continue to get vaccinated at good numbers, if people get boosted, we can absolutely have a very safe and healthy holiday season,” Ashish Jha, White House coronavirus czar, said on Nov. 22.

The number of Americans who have gotten the most recent booster has been increasing ahead of the holidays. CDC data show that 12% of the U.S. population age 5 and older has received a booster.

A new study by a team of researchers from Harvard University and Yale University estimates that 94% of the U.S. population has been infected with COVID-19 at least once, leaving just 1 in 20 people who have never had the virus.

“Despite these high exposure numbers, there is still substantial population susceptibility to infection with an Omicron variant,” the authors wrote.

They said that if all states achieved the vaccination levels of Vermont, where 55% of people had at least one booster and 22% got a second one, there would be “an appreciable improvement in population immunity, with greater relative impact for protection against infection versus severe disease. This additional protection results from both the recovery of immunity lost due to waning and the increased effectiveness of the bivalent booster against Omicron infections.”

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

For the first time, the majority of people dying from COVID-19 in America have been vaccinated.

“We can no longer say this is a pandemic of the unvaccinated,” Kaiser Family Foundation Vice President Cynthia Cox, who conducted the analysis, told The Washington Post.

People who had been vaccinated or boosted made up 58% of COVID-19 deaths in August, the analysis showed. The rate has been on the rise: 23% of coronavirus deaths were among vaccinated people in September 2021, and the vaccinated made up 42% of deaths in January and February 2022, the Post reported.

Research continues to show that people who are vaccinated or boosted have a lower risk of death. The rise in deaths among the vaccinated is the result of three factors, Ms. Cox said.

• A large majority of people in the United States have been vaccinated (267 million people, the  said).
• People who are at the greatest risk of dying from COVID-19 are more likely to be vaccinated and boosted, such as the elderly.
• Vaccines lose their effectiveness over time; the virus changes to avoid vaccines; and people need to choose to get boosters to continue to be protected.

The case for the effectiveness of vaccines and boosters versus skipping the shots remains strong. People age 6 months and older who are unvaccinated are six times more likely to die of COVID-19, compared to those who got the primary series of shots, the Post reported. Survival rates were even better with additional booster shots, particularly among older people.

“I feel very confident that if people continue to get vaccinated at good numbers, if people get boosted, we can absolutely have a very safe and healthy holiday season,” Ashish Jha, White House coronavirus czar, said on Nov. 22.

The number of Americans who have gotten the most recent booster has been increasing ahead of the holidays. CDC data show that 12% of the U.S. population age 5 and older has received a booster.

A new study by a team of researchers from Harvard University and Yale University estimates that 94% of the U.S. population has been infected with COVID-19 at least once, leaving just 1 in 20 people who have never had the virus.

“Despite these high exposure numbers, there is still substantial population susceptibility to infection with an Omicron variant,” the authors wrote.

They said that if all states achieved the vaccination levels of Vermont, where 55% of people had at least one booster and 22% got a second one, there would be “an appreciable improvement in population immunity, with greater relative impact for protection against infection versus severe disease. This additional protection results from both the recovery of immunity lost due to waning and the increased effectiveness of the bivalent booster against Omicron infections.”

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

When Mark Cucuzzella, MD, meets a new patient at the West Virginia Medical School clinic, he introduces himself as “Mark.” For one thing, says Dr. Cucuzzella, his last name is a mouthful. For another, the 56-year-old general practitioner asserts that getting on a first-name basis with his patients is integral to delivering the best care.

“I’m trying to break down the old paternalistic barriers of the doctor/patient relationship,” he says. “Titles create an environment where the doctors are making all the decisions and not involving the patient in any course of action.”

Aniruddh Setya, MD, has a different take on informality between patients and doctors: It’s not OK. “I am not your friend,” says the 35-year-old pediatrician from Florida-based KIDZ Medical Services. “There has to be a level of respect for the education and accomplishment of being a physician.”

The issue of “untitling” a doctor and failing to use their honorific is becoming increasingly common, according to a recent study published in JAMA Network Open. But that doesn’t mean most physicians support the practice. In fact, some doctors contend that it can be harmful, particularly to female physicians.

“My concern is that untitling (so termed by Amy Diehl, PhD, and Leanne Dzubinski, PhD) intrudes upon important professional boundaries and might be correlated with diminishing the value of someone’s time,” says Leah Witt, MD, a geriatrician at UCSF Health, San Francisco. Dr. Witt, along with colleague Lekshmi Santhosh, MD, a pulmonologist, offered commentary on the study results. “Studies have shown that women physicians get more patient portal messages, spend more time in the electronic health record, and have longer visits,” Dr. Witt said. “Dr. Santhosh and I wonder if untitling is a signifier of this diminished value of our time, and an assumption of increased ease of access leading to this higher workload.”

To compile the results reported in JAMA Network Open, Mayo Clinic researchers analyzed more than 90,000 emails from patients to doctors over the course of 3 years, beginning in 2018. Of those emails, more than 32% included the physician’s first name in greeting or salutation. For women physicians, the odds were twice as high that their titles would be omitted in the correspondence. The same holds true for doctors of osteopathic medicine (DOs) compared with MDs, and primary care physicians had similar odds for a title drop compared with specialists.

Dr. Witt says the findings are not surprising. “They match my experience as a woman in medicine, as Dr. Santhosh and I write in our commentary,” she says. “We think the findings could easily be replicated at other centers.”

Indeed, research on 321 speaker introductions at a medical rounds found that when female physicians introduced other physicians, they usually applied the doctor title. When the job of introducing colleagues fell to male physicians, however, the stats fell to 72.4% for male peers and only 49.2% when introducing female peers.

The Mayo Clinic study authors identified the pitfalls of patients who informally address their doctors. They wrote, “Untitling may have a negative impact on physicians, demonstrate lack of respect, and can lead to reduction in formality of the physician/patient relationship or workplace.”
 

Physician preferences vary

Although the results of the Mayo Clinic analysis didn’t and couldn’t address physician sentiments on patient informality, Dr. Setya observes that American culture is becoming less formal. “I’ve been practicing for over 10 years, and the number of people who consider doctors as equals is growing,” he says. “This has been particularly true over the last couple of years.”

This change was documented in 2015. Add in the pandemic and an entire society that is now accustomed to working from home in sweats, and it’s not a stretch to understand why some patients have become less formal in many settings. The 2015 article noted, however, that most physicians prefer to keep titles in the mix.

Perhaps most troublesome, says Dr. Setya, is that patients forgo asking whether it’s OK to use his first name and simply assume it’s acceptable. “It bothers me,” he says. “I became a doctor for more than the money.”

He suspects that his cultural background (Dr. Setya is of Indian descent) plays a role in how strongly he feels about patient-doctor informality. “As a British colony, Indian culture dictates that you pay respect to elders and to accomplishment,” he points out. “America is far looser when it comes to salutations.”

Dr. Cucuzzella largely agrees with Dr. Setya, but has a different view of the role culture plays in how physicians prefer to be addressed. “If your last name is difficult to pronounce, it can put the patient at ease if you give them an option,” he says. “I like my patients to feel comfortable and have a friendly conversation, so I don’t ask them to try to manage my last name.”

When patients revert to using Dr. Cucuzzella’s last name and title, this often breaks down along generational lines, Dr. Cucuzzella has found: Older patients might drop his title, whereas younger patients might keep it as a sign of respect. In some cases, Dr. Cucuzzella tries to bridge this gap, and offers the option of “Dr. Mark.” In his small West Virginia community, this is how people often refer to him.

Dr. Setya says that most of the older physicians he works with still prefer that patients and younger colleagues use their title, but he has witnessed exceptions to this. “My boss in residence hated to be called ‘Sir’ or ‘Doctor,’ ” he says. “In a situation like that, it is reasonable to ask, ‘How can I address you?’ But it has to be mutually agreed upon.”

Dr. Cucuzzella cites informality as the preferred mode for older patients. “If I have a 70-year-old patient, it seems natural they shouldn’t use my title,” he says. “They are worthy of equality in the community. If I’m talking to a retired CEO or state delegate, it’s uncomfortable if they call me doctor.”

Moreover, Dr. Cucuzzella maintains that establishing a less formal environment with patients leads to better outcomes. “Shared decision-making is a basic human right,” he says. “In 2022, doctors shouldn’t make decisions without patient input, unless it’s an emergency situation. Removing the title barriers makes that easier.”
 

How to handle informality

If you fall more in line with Dr. Setya, there are strategies you can use to try to keep formality in your doctor-patient relationships. Dr. Setya’s approach is indirect. “I don’t correct a patient if they use my first name, because that might seem hostile,” he says. “But I alert them in the way I address them back. A Sir, a Mrs., or a Mr. needs to go both ways.”

This particularly holds true in pediatrics, Dr. Setya has found. He has witnessed many colleagues addressing parents as “Mommy and Daddy,” something he says lacks respect and sets too informal a tone. “It’s almost universal that parents don’t like that, and we need to act accordingly.”

Dr. Witt also avoids directly correcting patients, but struggles when they drop her title. “The standard signature I use to sign every patient portal message I respond to includes my first and last name and credentials,” she says. “I maintain formality in most circumstances with that standard reply.”

Beneath the surface, however, Dr. Witt wishes it were easier. “I have struggled with answering the question, ‘Is it OK if I call you Leah?’ she says. “I want to keep our interaction anchored in professionalism without sacrificing the warmth I think is important to a productive patient-physician relationship. For this reason, I tend to say yes to this request, even though I’d rather patients didn’t make such requests.”

In the Fast Company article by Amy Diehl, PhD, and Leanne Dzubinski, PhD, on the topic of untitling professional women, the authors suggest several actions, beginning with leadership that sets expectations on the topic. They also suggest that physicians use polite corrections if patients untitle them. Supplying positive reinforcement when patients include your title can help, too. If all else fails, you can call out the offensive untitling. More often than not, especially with female physicians, the patient is demonstrating an unconscious bias rather than something deliberate.

Opinions vary on the topic of untitling, and ultimately each physician must make the decision for themselves. But creating informal cultures in an organization can have unintended consequences, especially for female peers.

Says Dr. Witt, “We all want to give our patients the best care we can, but professional boundaries are critical to time management, equitable care, and maintaining work-life balance. I would love to see a study that examines untitling by self-reported race and/or ethnicity of physicians, because we know that women of color experience higher rates of burnout and depression, and I wonder if untitling may be part of this.”

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

When Mark Cucuzzella, MD, meets a new patient at the West Virginia Medical School clinic, he introduces himself as “Mark.” For one thing, says Dr. Cucuzzella, his last name is a mouthful. For another, the 56-year-old general practitioner asserts that getting on a first-name basis with his patients is integral to delivering the best care.

“I’m trying to break down the old paternalistic barriers of the doctor/patient relationship,” he says. “Titles create an environment where the doctors are making all the decisions and not involving the patient in any course of action.”

Aniruddh Setya, MD, has a different take on informality between patients and doctors: It’s not OK. “I am not your friend,” says the 35-year-old pediatrician from Florida-based KIDZ Medical Services. “There has to be a level of respect for the education and accomplishment of being a physician.”

The issue of “untitling” a doctor and failing to use their honorific is becoming increasingly common, according to a recent study published in JAMA Network Open. But that doesn’t mean most physicians support the practice. In fact, some doctors contend that it can be harmful, particularly to female physicians.

“My concern is that untitling (so termed by Amy Diehl, PhD, and Leanne Dzubinski, PhD) intrudes upon important professional boundaries and might be correlated with diminishing the value of someone’s time,” says Leah Witt, MD, a geriatrician at UCSF Health, San Francisco. Dr. Witt, along with colleague Lekshmi Santhosh, MD, a pulmonologist, offered commentary on the study results. “Studies have shown that women physicians get more patient portal messages, spend more time in the electronic health record, and have longer visits,” Dr. Witt said. “Dr. Santhosh and I wonder if untitling is a signifier of this diminished value of our time, and an assumption of increased ease of access leading to this higher workload.”

To compile the results reported in JAMA Network Open, Mayo Clinic researchers analyzed more than 90,000 emails from patients to doctors over the course of 3 years, beginning in 2018. Of those emails, more than 32% included the physician’s first name in greeting or salutation. For women physicians, the odds were twice as high that their titles would be omitted in the correspondence. The same holds true for doctors of osteopathic medicine (DOs) compared with MDs, and primary care physicians had similar odds for a title drop compared with specialists.

Dr. Witt says the findings are not surprising. “They match my experience as a woman in medicine, as Dr. Santhosh and I write in our commentary,” she says. “We think the findings could easily be replicated at other centers.”

Indeed, research on 321 speaker introductions at a medical rounds found that when female physicians introduced other physicians, they usually applied the doctor title. When the job of introducing colleagues fell to male physicians, however, the stats fell to 72.4% for male peers and only 49.2% when introducing female peers.

The Mayo Clinic study authors identified the pitfalls of patients who informally address their doctors. They wrote, “Untitling may have a negative impact on physicians, demonstrate lack of respect, and can lead to reduction in formality of the physician/patient relationship or workplace.”
 

Physician preferences vary

Although the results of the Mayo Clinic analysis didn’t and couldn’t address physician sentiments on patient informality, Dr. Setya observes that American culture is becoming less formal. “I’ve been practicing for over 10 years, and the number of people who consider doctors as equals is growing,” he says. “This has been particularly true over the last couple of years.”

This change was documented in 2015. Add in the pandemic and an entire society that is now accustomed to working from home in sweats, and it’s not a stretch to understand why some patients have become less formal in many settings. The 2015 article noted, however, that most physicians prefer to keep titles in the mix.

Perhaps most troublesome, says Dr. Setya, is that patients forgo asking whether it’s OK to use his first name and simply assume it’s acceptable. “It bothers me,” he says. “I became a doctor for more than the money.”

He suspects that his cultural background (Dr. Setya is of Indian descent) plays a role in how strongly he feels about patient-doctor informality. “As a British colony, Indian culture dictates that you pay respect to elders and to accomplishment,” he points out. “America is far looser when it comes to salutations.”

Dr. Cucuzzella largely agrees with Dr. Setya, but has a different view of the role culture plays in how physicians prefer to be addressed. “If your last name is difficult to pronounce, it can put the patient at ease if you give them an option,” he says. “I like my patients to feel comfortable and have a friendly conversation, so I don’t ask them to try to manage my last name.”

When patients revert to using Dr. Cucuzzella’s last name and title, this often breaks down along generational lines, Dr. Cucuzzella has found: Older patients might drop his title, whereas younger patients might keep it as a sign of respect. In some cases, Dr. Cucuzzella tries to bridge this gap, and offers the option of “Dr. Mark.” In his small West Virginia community, this is how people often refer to him.

Dr. Setya says that most of the older physicians he works with still prefer that patients and younger colleagues use their title, but he has witnessed exceptions to this. “My boss in residence hated to be called ‘Sir’ or ‘Doctor,’ ” he says. “In a situation like that, it is reasonable to ask, ‘How can I address you?’ But it has to be mutually agreed upon.”

Dr. Cucuzzella cites informality as the preferred mode for older patients. “If I have a 70-year-old patient, it seems natural they shouldn’t use my title,” he says. “They are worthy of equality in the community. If I’m talking to a retired CEO or state delegate, it’s uncomfortable if they call me doctor.”

Moreover, Dr. Cucuzzella maintains that establishing a less formal environment with patients leads to better outcomes. “Shared decision-making is a basic human right,” he says. “In 2022, doctors shouldn’t make decisions without patient input, unless it’s an emergency situation. Removing the title barriers makes that easier.”
 

How to handle informality

If you fall more in line with Dr. Setya, there are strategies you can use to try to keep formality in your doctor-patient relationships. Dr. Setya’s approach is indirect. “I don’t correct a patient if they use my first name, because that might seem hostile,” he says. “But I alert them in the way I address them back. A Sir, a Mrs., or a Mr. needs to go both ways.”

This particularly holds true in pediatrics, Dr. Setya has found. He has witnessed many colleagues addressing parents as “Mommy and Daddy,” something he says lacks respect and sets too informal a tone. “It’s almost universal that parents don’t like that, and we need to act accordingly.”

Dr. Witt also avoids directly correcting patients, but struggles when they drop her title. “The standard signature I use to sign every patient portal message I respond to includes my first and last name and credentials,” she says. “I maintain formality in most circumstances with that standard reply.”

Beneath the surface, however, Dr. Witt wishes it were easier. “I have struggled with answering the question, ‘Is it OK if I call you Leah?’ she says. “I want to keep our interaction anchored in professionalism without sacrificing the warmth I think is important to a productive patient-physician relationship. For this reason, I tend to say yes to this request, even though I’d rather patients didn’t make such requests.”

In the Fast Company article by Amy Diehl, PhD, and Leanne Dzubinski, PhD, on the topic of untitling professional women, the authors suggest several actions, beginning with leadership that sets expectations on the topic. They also suggest that physicians use polite corrections if patients untitle them. Supplying positive reinforcement when patients include your title can help, too. If all else fails, you can call out the offensive untitling. More often than not, especially with female physicians, the patient is demonstrating an unconscious bias rather than something deliberate.

Opinions vary on the topic of untitling, and ultimately each physician must make the decision for themselves. But creating informal cultures in an organization can have unintended consequences, especially for female peers.

Says Dr. Witt, “We all want to give our patients the best care we can, but professional boundaries are critical to time management, equitable care, and maintaining work-life balance. I would love to see a study that examines untitling by self-reported race and/or ethnicity of physicians, because we know that women of color experience higher rates of burnout and depression, and I wonder if untitling may be part of this.”

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

When Mark Cucuzzella, MD, meets a new patient at the West Virginia Medical School clinic, he introduces himself as “Mark.” For one thing, says Dr. Cucuzzella, his last name is a mouthful. For another, the 56-year-old general practitioner asserts that getting on a first-name basis with his patients is integral to delivering the best care.

“I’m trying to break down the old paternalistic barriers of the doctor/patient relationship,” he says. “Titles create an environment where the doctors are making all the decisions and not involving the patient in any course of action.”

Aniruddh Setya, MD, has a different take on informality between patients and doctors: It’s not OK. “I am not your friend,” says the 35-year-old pediatrician from Florida-based KIDZ Medical Services. “There has to be a level of respect for the education and accomplishment of being a physician.”

The issue of “untitling” a doctor and failing to use their honorific is becoming increasingly common, according to a recent study published in JAMA Network Open. But that doesn’t mean most physicians support the practice. In fact, some doctors contend that it can be harmful, particularly to female physicians.

“My concern is that untitling (so termed by Amy Diehl, PhD, and Leanne Dzubinski, PhD) intrudes upon important professional boundaries and might be correlated with diminishing the value of someone’s time,” says Leah Witt, MD, a geriatrician at UCSF Health, San Francisco. Dr. Witt, along with colleague Lekshmi Santhosh, MD, a pulmonologist, offered commentary on the study results. “Studies have shown that women physicians get more patient portal messages, spend more time in the electronic health record, and have longer visits,” Dr. Witt said. “Dr. Santhosh and I wonder if untitling is a signifier of this diminished value of our time, and an assumption of increased ease of access leading to this higher workload.”

To compile the results reported in JAMA Network Open, Mayo Clinic researchers analyzed more than 90,000 emails from patients to doctors over the course of 3 years, beginning in 2018. Of those emails, more than 32% included the physician’s first name in greeting or salutation. For women physicians, the odds were twice as high that their titles would be omitted in the correspondence. The same holds true for doctors of osteopathic medicine (DOs) compared with MDs, and primary care physicians had similar odds for a title drop compared with specialists.

Dr. Witt says the findings are not surprising. “They match my experience as a woman in medicine, as Dr. Santhosh and I write in our commentary,” she says. “We think the findings could easily be replicated at other centers.”

Indeed, research on 321 speaker introductions at a medical rounds found that when female physicians introduced other physicians, they usually applied the doctor title. When the job of introducing colleagues fell to male physicians, however, the stats fell to 72.4% for male peers and only 49.2% when introducing female peers.

The Mayo Clinic study authors identified the pitfalls of patients who informally address their doctors. They wrote, “Untitling may have a negative impact on physicians, demonstrate lack of respect, and can lead to reduction in formality of the physician/patient relationship or workplace.”
 

Physician preferences vary

Although the results of the Mayo Clinic analysis didn’t and couldn’t address physician sentiments on patient informality, Dr. Setya observes that American culture is becoming less formal. “I’ve been practicing for over 10 years, and the number of people who consider doctors as equals is growing,” he says. “This has been particularly true over the last couple of years.”

This change was documented in 2015. Add in the pandemic and an entire society that is now accustomed to working from home in sweats, and it’s not a stretch to understand why some patients have become less formal in many settings. The 2015 article noted, however, that most physicians prefer to keep titles in the mix.

Perhaps most troublesome, says Dr. Setya, is that patients forgo asking whether it’s OK to use his first name and simply assume it’s acceptable. “It bothers me,” he says. “I became a doctor for more than the money.”

He suspects that his cultural background (Dr. Setya is of Indian descent) plays a role in how strongly he feels about patient-doctor informality. “As a British colony, Indian culture dictates that you pay respect to elders and to accomplishment,” he points out. “America is far looser when it comes to salutations.”

Dr. Cucuzzella largely agrees with Dr. Setya, but has a different view of the role culture plays in how physicians prefer to be addressed. “If your last name is difficult to pronounce, it can put the patient at ease if you give them an option,” he says. “I like my patients to feel comfortable and have a friendly conversation, so I don’t ask them to try to manage my last name.”

When patients revert to using Dr. Cucuzzella’s last name and title, this often breaks down along generational lines, Dr. Cucuzzella has found: Older patients might drop his title, whereas younger patients might keep it as a sign of respect. In some cases, Dr. Cucuzzella tries to bridge this gap, and offers the option of “Dr. Mark.” In his small West Virginia community, this is how people often refer to him.

Dr. Setya says that most of the older physicians he works with still prefer that patients and younger colleagues use their title, but he has witnessed exceptions to this. “My boss in residence hated to be called ‘Sir’ or ‘Doctor,’ ” he says. “In a situation like that, it is reasonable to ask, ‘How can I address you?’ But it has to be mutually agreed upon.”

Dr. Cucuzzella cites informality as the preferred mode for older patients. “If I have a 70-year-old patient, it seems natural they shouldn’t use my title,” he says. “They are worthy of equality in the community. If I’m talking to a retired CEO or state delegate, it’s uncomfortable if they call me doctor.”

Moreover, Dr. Cucuzzella maintains that establishing a less formal environment with patients leads to better outcomes. “Shared decision-making is a basic human right,” he says. “In 2022, doctors shouldn’t make decisions without patient input, unless it’s an emergency situation. Removing the title barriers makes that easier.”
 

How to handle informality

If you fall more in line with Dr. Setya, there are strategies you can use to try to keep formality in your doctor-patient relationships. Dr. Setya’s approach is indirect. “I don’t correct a patient if they use my first name, because that might seem hostile,” he says. “But I alert them in the way I address them back. A Sir, a Mrs., or a Mr. needs to go both ways.”

This particularly holds true in pediatrics, Dr. Setya has found. He has witnessed many colleagues addressing parents as “Mommy and Daddy,” something he says lacks respect and sets too informal a tone. “It’s almost universal that parents don’t like that, and we need to act accordingly.”

Dr. Witt also avoids directly correcting patients, but struggles when they drop her title. “The standard signature I use to sign every patient portal message I respond to includes my first and last name and credentials,” she says. “I maintain formality in most circumstances with that standard reply.”

Beneath the surface, however, Dr. Witt wishes it were easier. “I have struggled with answering the question, ‘Is it OK if I call you Leah?’ she says. “I want to keep our interaction anchored in professionalism without sacrificing the warmth I think is important to a productive patient-physician relationship. For this reason, I tend to say yes to this request, even though I’d rather patients didn’t make such requests.”

In the Fast Company article by Amy Diehl, PhD, and Leanne Dzubinski, PhD, on the topic of untitling professional women, the authors suggest several actions, beginning with leadership that sets expectations on the topic. They also suggest that physicians use polite corrections if patients untitle them. Supplying positive reinforcement when patients include your title can help, too. If all else fails, you can call out the offensive untitling. More often than not, especially with female physicians, the patient is demonstrating an unconscious bias rather than something deliberate.

Opinions vary on the topic of untitling, and ultimately each physician must make the decision for themselves. But creating informal cultures in an organization can have unintended consequences, especially for female peers.

Says Dr. Witt, “We all want to give our patients the best care we can, but professional boundaries are critical to time management, equitable care, and maintaining work-life balance. I would love to see a study that examines untitling by self-reported race and/or ethnicity of physicians, because we know that women of color experience higher rates of burnout and depression, and I wonder if untitling may be part of this.”

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

Competition between five biologic drugs and their skinny-label biosimilars saved Medicare an estimated $1.5 billion during 2015-2020. But these savings accruing to Medicare and the availability of those and other biosimilars through skinny labeling is under threat from recent court rulings, according to a research letter published online in JAMA Internal Medicine.

The authors highlighted the need for such savings by noting that, while biologics comprise less than 5% of prescription drug use, their price tag amounts to about 40% of U.S. drug spending, Biologic manufacturers often delay the availability of biosimilars for additional years beyond the original patent expiration through further patents for supplemental indications. To provide a counterbalance, federal law allows the Food and Drug Administration to approve “skinny-label” generics and biosimilars that carve out patent-protected indications or regulatory exclusivities. But once a generic drug reaches the market through this process with a skinny label, it may often be substituted for indications that go beyond the ones listed on the skinny label. In fact, some state laws mandate that pharmacists substitute interchangeable generics for brand-name drugs, helping to decrease drug prices. In response to legal threats to the skinny-label pathway, Alexander C. Egilman and colleagues at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, assessed the frequency of approval and marketing of skinny-label biosimilars from 2015 to 2021 and the resultant savings to Medicare.

TheaDesign/Thinkstock

The authors estimated annual Part B (clinician-administered) savings from skinny-label biosimilars through 2020 by comparing actual biologic and skinny-label biosimilar spending with estimated biologic spending without competition using the Medicare Dashboard. They assumed that the unit price of the biologic would increase at its 5-year compound annual growth rate prior to competition.

In that period, the FDA approved 33 biosimilars linked to 11 biologics. Among them, 22 (66.7%) had a skinny label. Of 21 biosimilars marketed before 2022, 13 (61.9%) were launched with a skinny label. Of the 8 biologics linked to these 21 biosimilars, 5 of the first-to-market biosimilars had skinny labels (bevacizumab, filgrastim, infliximab, pegfilgrastim, and rituximab), leading to earlier competition through 2021.

The estimated $1.5 billion in savings to Medicare from these skinny-label biosimilars over the 2015-2020 span represents 4.9% of the $30.2 billion that Medicare spent on the five biologics during this period. The researchers pointed out that once adalimumab (Humira) faces skinny-label biosimilar competition in 2023, savings will likely grow substantially.

In response to the research letter, an editor’s note by JAMA Internal Medicine Editorial Fellow Eric Ward, MD, and JAMA Internal Medicine Editor at Large and Online Editor Robert Steinbrook, MD, stated that, between 2015 and 2019, 24 (43%) of 56 brand-name drugs had competition from skinny-labeled generic formulations after first becoming available as generics.

The editors also referenced a JAMA Viewpoints article from 2021 that reviewed the most recent case challenging the skinny-label pathway in which GlaxoSmithKline sued Teva for its marketing of a skinny-label generic of the brand-name beta-blocker carvedilol (Coreg) that the plaintive claimed “induced physicians to prescribe carvedilol for indications that had been carved out by Teva’s skinny label, thus infringing GlaxoSmithKline’s patents.” A $235 million judgment against Teva was overturned by a district court and then reversed again by a Federal Circuit court that, after receiving criticism, reconsidered the case, and a panel affirmed the judgment against Teva.

“The Federal Circuit panel’s decision has the potential to put generic drugs that fail to adequately carve out indications from the brand name labeling at risk for damages related to infringement,” the authors wrote. Similar claims of infringement are being heard in other courts, they wrote, and they urged careful targeting of skinny-label carveouts, and suggest also that challenges to the arguments used against Teva focus on preservation of First Amendment rights as protection for lawful and accurate speech in drug labels.

“The legal uncertainties are likely to continue, as manufacturers pursue novel and complex strategies to protect the patents and regulatory exclusivities of brand-name drugs and biologics,” Dr. Ward and Dr. Steinbrook wrote, adding that “the path forward is for Congress to enact additional legislation that reaffirms and strengthens the permissibility of skinny labeling.”

The research letter’s corresponding author, Ameet Sarpatwari, PhD, JD, assistant professor at Harvard Medical School, and assistant director for the Harvard Program On Regulation, Therapeutics, And Law, echoed concerns over the Teva case in an interview. “There has certainly been concern that should the appellate decision stand, there will be a chilling effect. As the lone dissenter in that case noted, ‘no skinny-label generic is safe.’ I think many generic and biosimilar manufacturers are awaiting to see whether the Supreme Court will take the case.”

He added: “I do not believe the likelihood of skinny-label-supportive legislation making it through Congress will be greatly diminished in a divided Congress. Democrats and Republicans alike should seek to promote competition in the marketplace, which is what the skinny-labeling pathway accomplishes.”

The authors reported no relevant conflicts of interest. The research was funded by a grant from Arnold Ventures.

Competition between five biologic drugs and their skinny-label biosimilars saved Medicare an estimated $1.5 billion during 2015-2020. But these savings accruing to Medicare and the availability of those and other biosimilars through skinny labeling is under threat from recent court rulings, according to a research letter published online in JAMA Internal Medicine.

The authors highlighted the need for such savings by noting that, while biologics comprise less than 5% of prescription drug use, their price tag amounts to about 40% of U.S. drug spending, Biologic manufacturers often delay the availability of biosimilars for additional years beyond the original patent expiration through further patents for supplemental indications. To provide a counterbalance, federal law allows the Food and Drug Administration to approve “skinny-label” generics and biosimilars that carve out patent-protected indications or regulatory exclusivities. But once a generic drug reaches the market through this process with a skinny label, it may often be substituted for indications that go beyond the ones listed on the skinny label. In fact, some state laws mandate that pharmacists substitute interchangeable generics for brand-name drugs, helping to decrease drug prices. In response to legal threats to the skinny-label pathway, Alexander C. Egilman and colleagues at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, assessed the frequency of approval and marketing of skinny-label biosimilars from 2015 to 2021 and the resultant savings to Medicare.

TheaDesign/Thinkstock

The authors estimated annual Part B (clinician-administered) savings from skinny-label biosimilars through 2020 by comparing actual biologic and skinny-label biosimilar spending with estimated biologic spending without competition using the Medicare Dashboard. They assumed that the unit price of the biologic would increase at its 5-year compound annual growth rate prior to competition.

In that period, the FDA approved 33 biosimilars linked to 11 biologics. Among them, 22 (66.7%) had a skinny label. Of 21 biosimilars marketed before 2022, 13 (61.9%) were launched with a skinny label. Of the 8 biologics linked to these 21 biosimilars, 5 of the first-to-market biosimilars had skinny labels (bevacizumab, filgrastim, infliximab, pegfilgrastim, and rituximab), leading to earlier competition through 2021.

The estimated $1.5 billion in savings to Medicare from these skinny-label biosimilars over the 2015-2020 span represents 4.9% of the $30.2 billion that Medicare spent on the five biologics during this period. The researchers pointed out that once adalimumab (Humira) faces skinny-label biosimilar competition in 2023, savings will likely grow substantially.

In response to the research letter, an editor’s note by JAMA Internal Medicine Editorial Fellow Eric Ward, MD, and JAMA Internal Medicine Editor at Large and Online Editor Robert Steinbrook, MD, stated that, between 2015 and 2019, 24 (43%) of 56 brand-name drugs had competition from skinny-labeled generic formulations after first becoming available as generics.

The editors also referenced a JAMA Viewpoints article from 2021 that reviewed the most recent case challenging the skinny-label pathway in which GlaxoSmithKline sued Teva for its marketing of a skinny-label generic of the brand-name beta-blocker carvedilol (Coreg) that the plaintive claimed “induced physicians to prescribe carvedilol for indications that had been carved out by Teva’s skinny label, thus infringing GlaxoSmithKline’s patents.” A $235 million judgment against Teva was overturned by a district court and then reversed again by a Federal Circuit court that, after receiving criticism, reconsidered the case, and a panel affirmed the judgment against Teva.

“The Federal Circuit panel’s decision has the potential to put generic drugs that fail to adequately carve out indications from the brand name labeling at risk for damages related to infringement,” the authors wrote. Similar claims of infringement are being heard in other courts, they wrote, and they urged careful targeting of skinny-label carveouts, and suggest also that challenges to the arguments used against Teva focus on preservation of First Amendment rights as protection for lawful and accurate speech in drug labels.

“The legal uncertainties are likely to continue, as manufacturers pursue novel and complex strategies to protect the patents and regulatory exclusivities of brand-name drugs and biologics,” Dr. Ward and Dr. Steinbrook wrote, adding that “the path forward is for Congress to enact additional legislation that reaffirms and strengthens the permissibility of skinny labeling.”

The research letter’s corresponding author, Ameet Sarpatwari, PhD, JD, assistant professor at Harvard Medical School, and assistant director for the Harvard Program On Regulation, Therapeutics, And Law, echoed concerns over the Teva case in an interview. “There has certainly been concern that should the appellate decision stand, there will be a chilling effect. As the lone dissenter in that case noted, ‘no skinny-label generic is safe.’ I think many generic and biosimilar manufacturers are awaiting to see whether the Supreme Court will take the case.”

He added: “I do not believe the likelihood of skinny-label-supportive legislation making it through Congress will be greatly diminished in a divided Congress. Democrats and Republicans alike should seek to promote competition in the marketplace, which is what the skinny-labeling pathway accomplishes.”

The authors reported no relevant conflicts of interest. The research was funded by a grant from Arnold Ventures.

Competition between five biologic drugs and their skinny-label biosimilars saved Medicare an estimated $1.5 billion during 2015-2020. But these savings accruing to Medicare and the availability of those and other biosimilars through skinny labeling is under threat from recent court rulings, according to a research letter published online in JAMA Internal Medicine.

The authors highlighted the need for such savings by noting that, while biologics comprise less than 5% of prescription drug use, their price tag amounts to about 40% of U.S. drug spending, Biologic manufacturers often delay the availability of biosimilars for additional years beyond the original patent expiration through further patents for supplemental indications. To provide a counterbalance, federal law allows the Food and Drug Administration to approve “skinny-label” generics and biosimilars that carve out patent-protected indications or regulatory exclusivities. But once a generic drug reaches the market through this process with a skinny label, it may often be substituted for indications that go beyond the ones listed on the skinny label. In fact, some state laws mandate that pharmacists substitute interchangeable generics for brand-name drugs, helping to decrease drug prices. In response to legal threats to the skinny-label pathway, Alexander C. Egilman and colleagues at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, assessed the frequency of approval and marketing of skinny-label biosimilars from 2015 to 2021 and the resultant savings to Medicare.

TheaDesign/Thinkstock

The authors estimated annual Part B (clinician-administered) savings from skinny-label biosimilars through 2020 by comparing actual biologic and skinny-label biosimilar spending with estimated biologic spending without competition using the Medicare Dashboard. They assumed that the unit price of the biologic would increase at its 5-year compound annual growth rate prior to competition.

In that period, the FDA approved 33 biosimilars linked to 11 biologics. Among them, 22 (66.7%) had a skinny label. Of 21 biosimilars marketed before 2022, 13 (61.9%) were launched with a skinny label. Of the 8 biologics linked to these 21 biosimilars, 5 of the first-to-market biosimilars had skinny labels (bevacizumab, filgrastim, infliximab, pegfilgrastim, and rituximab), leading to earlier competition through 2021.

The estimated $1.5 billion in savings to Medicare from these skinny-label biosimilars over the 2015-2020 span represents 4.9% of the $30.2 billion that Medicare spent on the five biologics during this period. The researchers pointed out that once adalimumab (Humira) faces skinny-label biosimilar competition in 2023, savings will likely grow substantially.

In response to the research letter, an editor’s note by JAMA Internal Medicine Editorial Fellow Eric Ward, MD, and JAMA Internal Medicine Editor at Large and Online Editor Robert Steinbrook, MD, stated that, between 2015 and 2019, 24 (43%) of 56 brand-name drugs had competition from skinny-labeled generic formulations after first becoming available as generics.

The editors also referenced a JAMA Viewpoints article from 2021 that reviewed the most recent case challenging the skinny-label pathway in which GlaxoSmithKline sued Teva for its marketing of a skinny-label generic of the brand-name beta-blocker carvedilol (Coreg) that the plaintive claimed “induced physicians to prescribe carvedilol for indications that had been carved out by Teva’s skinny label, thus infringing GlaxoSmithKline’s patents.” A $235 million judgment against Teva was overturned by a district court and then reversed again by a Federal Circuit court that, after receiving criticism, reconsidered the case, and a panel affirmed the judgment against Teva.

“The Federal Circuit panel’s decision has the potential to put generic drugs that fail to adequately carve out indications from the brand name labeling at risk for damages related to infringement,” the authors wrote. Similar claims of infringement are being heard in other courts, they wrote, and they urged careful targeting of skinny-label carveouts, and suggest also that challenges to the arguments used against Teva focus on preservation of First Amendment rights as protection for lawful and accurate speech in drug labels.

“The legal uncertainties are likely to continue, as manufacturers pursue novel and complex strategies to protect the patents and regulatory exclusivities of brand-name drugs and biologics,” Dr. Ward and Dr. Steinbrook wrote, adding that “the path forward is for Congress to enact additional legislation that reaffirms and strengthens the permissibility of skinny labeling.”

The research letter’s corresponding author, Ameet Sarpatwari, PhD, JD, assistant professor at Harvard Medical School, and assistant director for the Harvard Program On Regulation, Therapeutics, And Law, echoed concerns over the Teva case in an interview. “There has certainly been concern that should the appellate decision stand, there will be a chilling effect. As the lone dissenter in that case noted, ‘no skinny-label generic is safe.’ I think many generic and biosimilar manufacturers are awaiting to see whether the Supreme Court will take the case.”

He added: “I do not believe the likelihood of skinny-label-supportive legislation making it through Congress will be greatly diminished in a divided Congress. Democrats and Republicans alike should seek to promote competition in the marketplace, which is what the skinny-labeling pathway accomplishes.”

The authors reported no relevant conflicts of interest. The research was funded by a grant from Arnold Ventures.

Rheumatologists tend to order the same types of tests to monitor their patients’ responses to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), but they vary widely in how often they order tests and how they respond to abnormal results, responses to a survey suggest.

“The study found that, although guidelines exist, people didn’t follow them consistently. They also responded to abnormal test results in wildly different ways,” senior study author Philip C. Robinson, MBChB, PhD, of the University of Queensland, Herston, Australia, said in an interview.

“The take-home message of this study is that everyone is doing something different, which means that the system likely has a lot of low-value activity and that money is being wasted,” he added. “However, we don’t have the evidence to guide people to make better choices.”

The literature on laboratory monitoring of people taking csDMARDs for rheumatic disease is scant, the authors wrote in BMC Rheumatology, and current guidelines on csDMARD monitoring vary, likely because of the lack of high-quality evidence for specific monitoring regimens.

“An enormous amount of money is spent on DMARD monitoring with little evidence to support current practices,” Dr. Robinson said. So he and his colleagues asked rheumatologists and rheumatology trainees about their attitudes and practices related to laboratory monitoring of csDMARDs in an online questionnaire.

They used the Australian Rheumatology Association newsletter to invite around 530 Australian rheumatologists and trainees, around 4,500 of Dr. Robinson’s Twitter followers, and 25 Australian and overseas email contacts, to respond to questions about csDMARDs they prescribed, frequency and patterns of monitoring, influences of additional factors and combination therapy, responses to abnormal tests, and attitudes toward monitoring frequency.

The researchers based their questions on csDMARD monitoring guidelines published by the American College of Rheumatology (which recommends monitoring every 2-4 weeks from initiation to 3 months, every 8-12 weeks during months 3-6, and every 12 weeks from 6 months onward), and from the British Society for Rheumatology (whose guidance is similar but bases monitoring frequency on how long DMARD doses remain stable).

The 221 valid responses they collected included 53 from Australia and 39 from the United States. Overall, 53% of respondents were in public practice, 56% were women, and 56% had practiced rheumatology for 11 or more years.

Respondents reported more frequent monitoring of patients with multiple comorbidities and those taking csDMARD combinations, including methotrexate and leflunomide. Responses to abnormal monitoring results varied widely, and 40% of respondents reported that monitoring tests are performed too often. Compared with females, males reported greater tolerance of significant test abnormalities before acting. They also were more likely to report that guidelines recommend, and doctors perform, tests too frequently.
 

Testing, monitoring patterns can differ from current guidelines

Rheumatologists who were asked to comment on the survey welcomed its results.

They came as no surprise to Daniel E. Furst, MD, professor emeritus of medicine at the University of California, Los Angeles.

“Most guidelines point out in the introduction that they are recommendations and need to be modified by specific patient and environmental needs,” he noted in an interview.

Stephen Myers, MD, assistant professor of clinical medicine in the division of rheumatology at the University of Southern California, Los Angeles, said: “The findings seem generally consistent with my observed practices and those of my peers, with the exception of sulfasalazine, which we tend to monitor every 3 months, similar to the way we monitor other csDMARDs.”

Caoilfhionn Connolly, MD, MSc, postdoctoral fellow in rheumatology at Johns Hopkins University, Baltimore, called “the variability in monitoring somewhat surprising given that both the American College of Rheumatology and the British Society for Rheumatology provide guidance statements on optimal monitoring.

“As the authors highlight,” she added, “the variability in monitoring and response to lab abnormalities is likely driven by the lack of a high-quality evidence base, which should ideally be derived from clinical trials.”

Medication monitoring is critical to ensuring patient safety in rheumatology and other specialties, said Puja Khanna, MD, MPH, a rheumatologist and clinical associate professor of medicine at the University of Michigan, Ann Arbor.

Dr. Khanna described how in 2018, the Michigan Medicine health care system revisited its processes and protocols for medication monitoring.

Previously, “we were reliant on society guidelines that were not used consistently across the academic and community rheumatology practices,” she said. “Using lean thinking methodology, we found that we lacked familiarity with laboratory monitoring protocols amongst the interdisciplinary teams involved in the process and that we had a clear need for consensus.

“A consistent departmental protocol was created to help streamline the workflow for ancillary support staff, to close identified operational gaps, and to reduce delays in monitoring that impacted safe practice patterns,” Dr. Khanna added.

“We developed standardized medication- and disease-based monitoring protocols for eight medical specialties, where the person who writes a prescription that requires monitoring can utilize standard work flows to enroll the patient in the medication monitoring program and have dedicated ancillary support staff follow the results periodically and alert clinicians in a timely manner,” she explained. “Almost 15,000 patients are currently monitored in this collaborative program involving clinicians, nurses, pharmacists, and IT and administrative teams.”
 

Guidelines may not capture clinical realities of csDMARD monitoring

Dr. Myers and colleagues may monitor testing more intensively if, for example, a patient becomes ill, has side effects, or has taken medication incorrectly. But they’ll less intensively monitor a patient who’s been stable on a csDMARD.

“In my current academic practice, deciding lab monitoring frequency is left up to physicians. In my previous private practice experience, lab monitoring seemed to be more frequent than the current guidelines for many patients, compared to public or academic practice,” he said. “It would be interesting to compare monitoring practices in private, public, and academic settings.

“The clinical reality is that frequent monitoring depends on the regular follow-up, which for some patients is difficult, due to socioeconomic factors including lack of childcare and public transport,” Dr. Myers added.

Dr. Khanna mentioned that “guidelines tend to provide details of extant practice patterns, usually taken from evidence-based data. With monitoring, however, that is tough to achieve, unless substantial data can be found in large national registries of patients on immunosuppressive medications.”

Experience and comfort with using immunosuppressive medications, and medicolegal liability considerations, especially because many immunomodulatory agents confer adverse effects, can contribute to clinicians’ behaviors varying from guidelines, she added.
 

A good scoping review, and further research needed

“This article did what it was supposed to do: Define the various approaches to monitoring,” Dr. Furst said. “It is the next steps that will make a difference in practice.

“Next steps ... may require delving into large observational data sets such as registries to ascertain the consequences of different monitoring strategies for various patient groups and disparate drugs and drug combinations,” added Dr. Furst, who coauthored a 2017 review summarizing guidelines for laboratory monitoring in patients with rheumatoid arthritis.

“A significant oversight is the lack of consideration regarding monitoring for corticosteroids, which are well known to have very consequential adverse events and require careful monitoring,” Dr. Furst observed.

“The difference between men’s and women’s monitoring strategies is of some interest,” he added, “but will only be important if it leads to an understanding of and change in monitoring recommendations.”

Dr. Connolly also noted the differences in strategies between male and female respondents.

“Of interest, male respondents were more likely to feel that monitoring was performed too frequently and were also more tolerant of significant abnormalities,” she said. “This begs the question of whether rheumatologist gender differentially impacts other areas of clinical practice.”

Despite the small sample size that limits generalizability, the results provide preliminary insight into the varied practices among rheumatologists worldwide, Dr. Connolly added.

“Given the frequency of csDMARD prescription, the study highlights the clinical unmet need for a more robust evidence base to guide clinical practice,” she said. “The study also adds to important efforts to provide high-value care to patients with rheumatic diseases and may form the basis for larger studies to facilitate the pragmatic utilization of lab monitoring and ultimately optimize both the quality and value of rheumatological care globally.”

Dr. Robinson and coauthors urged further research. “We need more studies of higher quality to help inform the best strategy for protecting our patients from harm from our commonly used rheumatic medicines,” he said.

Dr. Robinson and two coauthors reported relationships with pharmaceutical companies. The remaining authors and all uninvolved sources, who commented by email, reported no relevant relationships. The study received no funding.

Rheumatologists tend to order the same types of tests to monitor their patients’ responses to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), but they vary widely in how often they order tests and how they respond to abnormal results, responses to a survey suggest.

“The study found that, although guidelines exist, people didn’t follow them consistently. They also responded to abnormal test results in wildly different ways,” senior study author Philip C. Robinson, MBChB, PhD, of the University of Queensland, Herston, Australia, said in an interview.

“The take-home message of this study is that everyone is doing something different, which means that the system likely has a lot of low-value activity and that money is being wasted,” he added. “However, we don’t have the evidence to guide people to make better choices.”

The literature on laboratory monitoring of people taking csDMARDs for rheumatic disease is scant, the authors wrote in BMC Rheumatology, and current guidelines on csDMARD monitoring vary, likely because of the lack of high-quality evidence for specific monitoring regimens.

“An enormous amount of money is spent on DMARD monitoring with little evidence to support current practices,” Dr. Robinson said. So he and his colleagues asked rheumatologists and rheumatology trainees about their attitudes and practices related to laboratory monitoring of csDMARDs in an online questionnaire.

They used the Australian Rheumatology Association newsletter to invite around 530 Australian rheumatologists and trainees, around 4,500 of Dr. Robinson’s Twitter followers, and 25 Australian and overseas email contacts, to respond to questions about csDMARDs they prescribed, frequency and patterns of monitoring, influences of additional factors and combination therapy, responses to abnormal tests, and attitudes toward monitoring frequency.

The researchers based their questions on csDMARD monitoring guidelines published by the American College of Rheumatology (which recommends monitoring every 2-4 weeks from initiation to 3 months, every 8-12 weeks during months 3-6, and every 12 weeks from 6 months onward), and from the British Society for Rheumatology (whose guidance is similar but bases monitoring frequency on how long DMARD doses remain stable).

The 221 valid responses they collected included 53 from Australia and 39 from the United States. Overall, 53% of respondents were in public practice, 56% were women, and 56% had practiced rheumatology for 11 or more years.

Respondents reported more frequent monitoring of patients with multiple comorbidities and those taking csDMARD combinations, including methotrexate and leflunomide. Responses to abnormal monitoring results varied widely, and 40% of respondents reported that monitoring tests are performed too often. Compared with females, males reported greater tolerance of significant test abnormalities before acting. They also were more likely to report that guidelines recommend, and doctors perform, tests too frequently.
 

Testing, monitoring patterns can differ from current guidelines

Rheumatologists who were asked to comment on the survey welcomed its results.

They came as no surprise to Daniel E. Furst, MD, professor emeritus of medicine at the University of California, Los Angeles.

“Most guidelines point out in the introduction that they are recommendations and need to be modified by specific patient and environmental needs,” he noted in an interview.

Stephen Myers, MD, assistant professor of clinical medicine in the division of rheumatology at the University of Southern California, Los Angeles, said: “The findings seem generally consistent with my observed practices and those of my peers, with the exception of sulfasalazine, which we tend to monitor every 3 months, similar to the way we monitor other csDMARDs.”

Caoilfhionn Connolly, MD, MSc, postdoctoral fellow in rheumatology at Johns Hopkins University, Baltimore, called “the variability in monitoring somewhat surprising given that both the American College of Rheumatology and the British Society for Rheumatology provide guidance statements on optimal monitoring.

“As the authors highlight,” she added, “the variability in monitoring and response to lab abnormalities is likely driven by the lack of a high-quality evidence base, which should ideally be derived from clinical trials.”

Medication monitoring is critical to ensuring patient safety in rheumatology and other specialties, said Puja Khanna, MD, MPH, a rheumatologist and clinical associate professor of medicine at the University of Michigan, Ann Arbor.

Dr. Khanna described how in 2018, the Michigan Medicine health care system revisited its processes and protocols for medication monitoring.

Previously, “we were reliant on society guidelines that were not used consistently across the academic and community rheumatology practices,” she said. “Using lean thinking methodology, we found that we lacked familiarity with laboratory monitoring protocols amongst the interdisciplinary teams involved in the process and that we had a clear need for consensus.

“A consistent departmental protocol was created to help streamline the workflow for ancillary support staff, to close identified operational gaps, and to reduce delays in monitoring that impacted safe practice patterns,” Dr. Khanna added.

“We developed standardized medication- and disease-based monitoring protocols for eight medical specialties, where the person who writes a prescription that requires monitoring can utilize standard work flows to enroll the patient in the medication monitoring program and have dedicated ancillary support staff follow the results periodically and alert clinicians in a timely manner,” she explained. “Almost 15,000 patients are currently monitored in this collaborative program involving clinicians, nurses, pharmacists, and IT and administrative teams.”
 

Guidelines may not capture clinical realities of csDMARD monitoring

Dr. Myers and colleagues may monitor testing more intensively if, for example, a patient becomes ill, has side effects, or has taken medication incorrectly. But they’ll less intensively monitor a patient who’s been stable on a csDMARD.

“In my current academic practice, deciding lab monitoring frequency is left up to physicians. In my previous private practice experience, lab monitoring seemed to be more frequent than the current guidelines for many patients, compared to public or academic practice,” he said. “It would be interesting to compare monitoring practices in private, public, and academic settings.

“The clinical reality is that frequent monitoring depends on the regular follow-up, which for some patients is difficult, due to socioeconomic factors including lack of childcare and public transport,” Dr. Myers added.

Dr. Khanna mentioned that “guidelines tend to provide details of extant practice patterns, usually taken from evidence-based data. With monitoring, however, that is tough to achieve, unless substantial data can be found in large national registries of patients on immunosuppressive medications.”

Experience and comfort with using immunosuppressive medications, and medicolegal liability considerations, especially because many immunomodulatory agents confer adverse effects, can contribute to clinicians’ behaviors varying from guidelines, she added.
 

A good scoping review, and further research needed

“This article did what it was supposed to do: Define the various approaches to monitoring,” Dr. Furst said. “It is the next steps that will make a difference in practice.

“Next steps ... may require delving into large observational data sets such as registries to ascertain the consequences of different monitoring strategies for various patient groups and disparate drugs and drug combinations,” added Dr. Furst, who coauthored a 2017 review summarizing guidelines for laboratory monitoring in patients with rheumatoid arthritis.

“A significant oversight is the lack of consideration regarding monitoring for corticosteroids, which are well known to have very consequential adverse events and require careful monitoring,” Dr. Furst observed.

“The difference between men’s and women’s monitoring strategies is of some interest,” he added, “but will only be important if it leads to an understanding of and change in monitoring recommendations.”

Dr. Connolly also noted the differences in strategies between male and female respondents.

“Of interest, male respondents were more likely to feel that monitoring was performed too frequently and were also more tolerant of significant abnormalities,” she said. “This begs the question of whether rheumatologist gender differentially impacts other areas of clinical practice.”

Despite the small sample size that limits generalizability, the results provide preliminary insight into the varied practices among rheumatologists worldwide, Dr. Connolly added.

“Given the frequency of csDMARD prescription, the study highlights the clinical unmet need for a more robust evidence base to guide clinical practice,” she said. “The study also adds to important efforts to provide high-value care to patients with rheumatic diseases and may form the basis for larger studies to facilitate the pragmatic utilization of lab monitoring and ultimately optimize both the quality and value of rheumatological care globally.”

Dr. Robinson and coauthors urged further research. “We need more studies of higher quality to help inform the best strategy for protecting our patients from harm from our commonly used rheumatic medicines,” he said.

Dr. Robinson and two coauthors reported relationships with pharmaceutical companies. The remaining authors and all uninvolved sources, who commented by email, reported no relevant relationships. The study received no funding.

Rheumatologists tend to order the same types of tests to monitor their patients’ responses to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), but they vary widely in how often they order tests and how they respond to abnormal results, responses to a survey suggest.

“The study found that, although guidelines exist, people didn’t follow them consistently. They also responded to abnormal test results in wildly different ways,” senior study author Philip C. Robinson, MBChB, PhD, of the University of Queensland, Herston, Australia, said in an interview.

“The take-home message of this study is that everyone is doing something different, which means that the system likely has a lot of low-value activity and that money is being wasted,” he added. “However, we don’t have the evidence to guide people to make better choices.”

The literature on laboratory monitoring of people taking csDMARDs for rheumatic disease is scant, the authors wrote in BMC Rheumatology, and current guidelines on csDMARD monitoring vary, likely because of the lack of high-quality evidence for specific monitoring regimens.

“An enormous amount of money is spent on DMARD monitoring with little evidence to support current practices,” Dr. Robinson said. So he and his colleagues asked rheumatologists and rheumatology trainees about their attitudes and practices related to laboratory monitoring of csDMARDs in an online questionnaire.

They used the Australian Rheumatology Association newsletter to invite around 530 Australian rheumatologists and trainees, around 4,500 of Dr. Robinson’s Twitter followers, and 25 Australian and overseas email contacts, to respond to questions about csDMARDs they prescribed, frequency and patterns of monitoring, influences of additional factors and combination therapy, responses to abnormal tests, and attitudes toward monitoring frequency.

The researchers based their questions on csDMARD monitoring guidelines published by the American College of Rheumatology (which recommends monitoring every 2-4 weeks from initiation to 3 months, every 8-12 weeks during months 3-6, and every 12 weeks from 6 months onward), and from the British Society for Rheumatology (whose guidance is similar but bases monitoring frequency on how long DMARD doses remain stable).

The 221 valid responses they collected included 53 from Australia and 39 from the United States. Overall, 53% of respondents were in public practice, 56% were women, and 56% had practiced rheumatology for 11 or more years.

Respondents reported more frequent monitoring of patients with multiple comorbidities and those taking csDMARD combinations, including methotrexate and leflunomide. Responses to abnormal monitoring results varied widely, and 40% of respondents reported that monitoring tests are performed too often. Compared with females, males reported greater tolerance of significant test abnormalities before acting. They also were more likely to report that guidelines recommend, and doctors perform, tests too frequently.
 

Testing, monitoring patterns can differ from current guidelines

Rheumatologists who were asked to comment on the survey welcomed its results.

They came as no surprise to Daniel E. Furst, MD, professor emeritus of medicine at the University of California, Los Angeles.

“Most guidelines point out in the introduction that they are recommendations and need to be modified by specific patient and environmental needs,” he noted in an interview.

Stephen Myers, MD, assistant professor of clinical medicine in the division of rheumatology at the University of Southern California, Los Angeles, said: “The findings seem generally consistent with my observed practices and those of my peers, with the exception of sulfasalazine, which we tend to monitor every 3 months, similar to the way we monitor other csDMARDs.”

Caoilfhionn Connolly, MD, MSc, postdoctoral fellow in rheumatology at Johns Hopkins University, Baltimore, called “the variability in monitoring somewhat surprising given that both the American College of Rheumatology and the British Society for Rheumatology provide guidance statements on optimal monitoring.

“As the authors highlight,” she added, “the variability in monitoring and response to lab abnormalities is likely driven by the lack of a high-quality evidence base, which should ideally be derived from clinical trials.”

Medication monitoring is critical to ensuring patient safety in rheumatology and other specialties, said Puja Khanna, MD, MPH, a rheumatologist and clinical associate professor of medicine at the University of Michigan, Ann Arbor.

Dr. Khanna described how in 2018, the Michigan Medicine health care system revisited its processes and protocols for medication monitoring.

Previously, “we were reliant on society guidelines that were not used consistently across the academic and community rheumatology practices,” she said. “Using lean thinking methodology, we found that we lacked familiarity with laboratory monitoring protocols amongst the interdisciplinary teams involved in the process and that we had a clear need for consensus.

“A consistent departmental protocol was created to help streamline the workflow for ancillary support staff, to close identified operational gaps, and to reduce delays in monitoring that impacted safe practice patterns,” Dr. Khanna added.

“We developed standardized medication- and disease-based monitoring protocols for eight medical specialties, where the person who writes a prescription that requires monitoring can utilize standard work flows to enroll the patient in the medication monitoring program and have dedicated ancillary support staff follow the results periodically and alert clinicians in a timely manner,” she explained. “Almost 15,000 patients are currently monitored in this collaborative program involving clinicians, nurses, pharmacists, and IT and administrative teams.”
 

Guidelines may not capture clinical realities of csDMARD monitoring

Dr. Myers and colleagues may monitor testing more intensively if, for example, a patient becomes ill, has side effects, or has taken medication incorrectly. But they’ll less intensively monitor a patient who’s been stable on a csDMARD.

“In my current academic practice, deciding lab monitoring frequency is left up to physicians. In my previous private practice experience, lab monitoring seemed to be more frequent than the current guidelines for many patients, compared to public or academic practice,” he said. “It would be interesting to compare monitoring practices in private, public, and academic settings.

“The clinical reality is that frequent monitoring depends on the regular follow-up, which for some patients is difficult, due to socioeconomic factors including lack of childcare and public transport,” Dr. Myers added.

Dr. Khanna mentioned that “guidelines tend to provide details of extant practice patterns, usually taken from evidence-based data. With monitoring, however, that is tough to achieve, unless substantial data can be found in large national registries of patients on immunosuppressive medications.”

Experience and comfort with using immunosuppressive medications, and medicolegal liability considerations, especially because many immunomodulatory agents confer adverse effects, can contribute to clinicians’ behaviors varying from guidelines, she added.
 

A good scoping review, and further research needed

“This article did what it was supposed to do: Define the various approaches to monitoring,” Dr. Furst said. “It is the next steps that will make a difference in practice.

“Next steps ... may require delving into large observational data sets such as registries to ascertain the consequences of different monitoring strategies for various patient groups and disparate drugs and drug combinations,” added Dr. Furst, who coauthored a 2017 review summarizing guidelines for laboratory monitoring in patients with rheumatoid arthritis.

“A significant oversight is the lack of consideration regarding monitoring for corticosteroids, which are well known to have very consequential adverse events and require careful monitoring,” Dr. Furst observed.

“The difference between men’s and women’s monitoring strategies is of some interest,” he added, “but will only be important if it leads to an understanding of and change in monitoring recommendations.”

Dr. Connolly also noted the differences in strategies between male and female respondents.

“Of interest, male respondents were more likely to feel that monitoring was performed too frequently and were also more tolerant of significant abnormalities,” she said. “This begs the question of whether rheumatologist gender differentially impacts other areas of clinical practice.”

Despite the small sample size that limits generalizability, the results provide preliminary insight into the varied practices among rheumatologists worldwide, Dr. Connolly added.

“Given the frequency of csDMARD prescription, the study highlights the clinical unmet need for a more robust evidence base to guide clinical practice,” she said. “The study also adds to important efforts to provide high-value care to patients with rheumatic diseases and may form the basis for larger studies to facilitate the pragmatic utilization of lab monitoring and ultimately optimize both the quality and value of rheumatological care globally.”

Dr. Robinson and coauthors urged further research. “We need more studies of higher quality to help inform the best strategy for protecting our patients from harm from our commonly used rheumatic medicines,” he said.

Dr. Robinson and two coauthors reported relationships with pharmaceutical companies. The remaining authors and all uninvolved sources, who commented by email, reported no relevant relationships. The study received no funding.