Rheumatology News

Patients with Cushing disease have an increased risk for new-onset autoimmune disease in the 3 years after surgical remission, according to a new retrospective study published on February 20 in Annals of Internal Medicine.

Outcomes for patients with Cushing disease were compared against those with nonfunctioning pituitary adenomas (NFPAs). New-onset autoimmune disease occurred in 10.4% with Cushing disease and 1.6% among patients with NFPA (hazard ratio, 7.80; 95% CI, 2.88-21.10).

“Understanding and recognizing new and recurrent autoimmune disease in this setting is important to avoid misclassifying such patients with glucocorticoid withdrawal syndrome, which could result in failure to treat underlying autoimmune disease, as well as erroneous diagnosis of steroid withdrawal cases,” wrote Dennis Delasi Nyanyo of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues.

Given the general population’s annual incidence of major autoimmune diseases, estimated at about 100 cases per 100,000 people, and the 3-year incidence of 10.4% found in this study’s cohort, “our findings suggest that Cushing disease remission may trigger development of autoimmune disease,” the authors wrote.
 

Monitor Patients With Family History of Autoimmune Disease?

The study results were not necessarily surprising to Anthony P. Heaney, MD, PhD, an endocrinologist and professor of medicine at the University of California, Los Angeles, because past research has raised similar questions. The authors’ suggestion that the rapid postsurgical drop in cortisol that occurs as a result of treating Cushing disease becomes some sort of autoimmune trigger is interesting but remains speculative, Dr. Heaney pointed out.

If future evidence supports that possibility, “it would suggest, in terms of managing those patients in the postoperative setting, that there may be some merit to giving them higher concentrations of glucocorticoids for a short period of time,” Dr. Heaney said, thereby bringing their levels down more gradually rather than taking them off a cliff, in a sense. Or, if more evidence bears out the authors’ hypothesis, another approach might be treating patients with medicine to bring down the cortisol before surgery, though there are challenges to that approach, Dr. Heaney said.

At the same time, those who developed new autoimmune disease remain a small subset of patients with Cushing disease, so such approaches may become only potentially appropriate to consider in patients with risk factors, such as a family history of autoimmune disease.

The researchers conducted a retrospective chart review of adult patients who underwent transsphenoidal surgery for either Cushing disease or NFPA at Massachusetts General Hospital between 2005 and 2019.

The study involved 194 patients with Cushing disease who had postsurgical remission and at least one follow-up visit with a pituitary expert and 92 patients with NFPA who were matched to patients with Cushing disease based on age and sex. The authors regarded autoimmune disease diagnosed within 36 months of the surgery to be temporally associated with Cushing disease remission. Among the autoimmune diseases considered were “rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, autoimmune thyroiditis, celiac disease, psoriasis, vitiligo, autoimmune neuropathy, multiple sclerosis, myasthenia gravis, and ulcerative colitis.”

Patients differed in average body mass index and tumor size, but family history of autoimmune disease was similar in both groups. Average BMI was 34.5 in the Cushing group and 29.5 in the NFPA group. Average tumor size was 5.7 mm in the Cushing group and 21.3 mm in the NFPA group.

Before surgery, 2.9% of patients with Cushing disease and 15.4% of patients with NFPA had central hypothyroidism, and 8% in the Cushing group and 56.8% in the NFPA group had hyperprolactinemia. Central adrenal insufficiency occurred in 11% with NFPA and in all with Cushing disease, by definition.

After surgery, 93.8% in the Cushing group and 16.5% in the NFPA group had adrenal insufficiency. In addition, patients with Cushing disease had lower postsurgical nadir serum cortisol levels (63.8 nmol/L) than those with NFPA (282.3 nmol/L).

Of the 17 patients with Cushing disease — all women — who developed autoimmune disease within 3 years, 6 had a personal history of autoimmune disease and 7 had a family history of it. In addition, 41.2% of them had adrenal insufficiency when they developed the new autoimmune disease. Among the diseases were six autoimmune thyroiditis cases, three Sjögren syndrome cases, and two autoimmune seronegative spondyloarthropathy.

Dr. Heaney said he found it interesting that more than half of the new autoimmune diseases in patients with Cushing disease were related to the thyroid. “In this kind of setting, where you have a patient who has been producing too much steroid over a period of time and then you take that away, it’s almost like you release a brake on the TSH [thyroid-stimulating hormone],” Dr. Heaney said. “So, there’s probably some rebound in TSH that occurs, and that could be driving the thyroiditis, to some extent, that we see in these patients.”

Only one patient with NFPA developed new-onset autoimmune disease, a woman who developed Graves disease 22 months after surgery. When the researchers excluded patients in both groups with central hypothyroidism, new-onset autoimmune disease was still significantly higher (11.4%) in the Cushing group than in the NFPA group (1.9%; HR, 7.02; 95% CI, 2.54-19.39).
 

Could Postoperative Adrenal Insufficiency Contribute to Risk?

Within the Cushing cohort, those who developed autoimmune disease had a lower BMI (31.8 vs 34.8) and larger tumor size (7.2 vs 5.6 mm) than those who didn’t develop new autoimmune disease. Patients who developed autoimmune disease also had a lower baseline urine free cortisol ratio (2.7 vs 6.3) before surgery and more family history of autoimmune disease (41.2% vs 20.9%) than those who didn’t develop one.

“The higher prevalence of adrenal insufficiency and the lower nadir serum cortisol levels in the Cushing disease group suggest that the postoperative adrenal insufficiency in the Cushing disease group might have contributed to autoimmune disease pathogenesis,” the authors wrote. “This finding is clinically significant because cortisol plays a pivotal role in modulating the immune system.”

Most postoperative management among patients with Cushing disease was similar, with all but one patient receiving 0.5 or 1 mg daily dexamethasone within the first week after surgery. (The one outlier received 5 mg daily prednisone.) However, fewer patients who developed autoimmune disease (17.6%) received supraphysiologic doses of glucocorticoid — equivalent to at least 25 mg hydrocortisone — compared with patients who didn’t develop autoimmune disease (41.8%).

“Although the daily average hydrocortisone equivalent replacement doses within the first month and during long-term follow-up were within the physiologic range in both subgroups, patients with Cushing disease who had autoimmune disease received slightly lower doses of glucocorticoid replacement within the first month after surgery,” the authors reported. “The immediate postoperative period might be a critical window where supraphysiologic glucocorticoids seem to be protective with regard to development of autoimmune disease,” they wrote, though they acknowledged the study’s retrospective design as a limitation in drawing that conclusion.

At the least, they suggested that new symptoms in patients with Cushing disease, particularly those with a family history of autoimmune disease, should prompt investigation of potential autoimmune disease.

Recordati Rare Diseases funded the study. The research was also conducted with support from Harvard Catalyst (the Harvard Clinical and Translational Science Center) as well as financial contributions from Harvard University and its affiliated academic healthcare centers. One author reported holding stocks in Pfizer and Amgen, and another reported receiving consulting fees from Corcept. Dr. Heaney reported receiving institutional grants for trials from Corcept, Ascendis, Crinetics, and Sparrow Pharm; serving on the advisory board for Xeris, Recordati, Corcept, Novo Nordisk, Lundbeck, and Crinetics; and serving as a speaker for Chiesi, Novo Nordisk, and Corcept.
 

A version of this article appeared on Medscape.com.

Patients with Cushing disease have an increased risk for new-onset autoimmune disease in the 3 years after surgical remission, according to a new retrospective study published on February 20 in Annals of Internal Medicine.

Outcomes for patients with Cushing disease were compared against those with nonfunctioning pituitary adenomas (NFPAs). New-onset autoimmune disease occurred in 10.4% with Cushing disease and 1.6% among patients with NFPA (hazard ratio, 7.80; 95% CI, 2.88-21.10).

“Understanding and recognizing new and recurrent autoimmune disease in this setting is important to avoid misclassifying such patients with glucocorticoid withdrawal syndrome, which could result in failure to treat underlying autoimmune disease, as well as erroneous diagnosis of steroid withdrawal cases,” wrote Dennis Delasi Nyanyo of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues.

Given the general population’s annual incidence of major autoimmune diseases, estimated at about 100 cases per 100,000 people, and the 3-year incidence of 10.4% found in this study’s cohort, “our findings suggest that Cushing disease remission may trigger development of autoimmune disease,” the authors wrote.
 

Monitor Patients With Family History of Autoimmune Disease?

The study results were not necessarily surprising to Anthony P. Heaney, MD, PhD, an endocrinologist and professor of medicine at the University of California, Los Angeles, because past research has raised similar questions. The authors’ suggestion that the rapid postsurgical drop in cortisol that occurs as a result of treating Cushing disease becomes some sort of autoimmune trigger is interesting but remains speculative, Dr. Heaney pointed out.

If future evidence supports that possibility, “it would suggest, in terms of managing those patients in the postoperative setting, that there may be some merit to giving them higher concentrations of glucocorticoids for a short period of time,” Dr. Heaney said, thereby bringing their levels down more gradually rather than taking them off a cliff, in a sense. Or, if more evidence bears out the authors’ hypothesis, another approach might be treating patients with medicine to bring down the cortisol before surgery, though there are challenges to that approach, Dr. Heaney said.

At the same time, those who developed new autoimmune disease remain a small subset of patients with Cushing disease, so such approaches may become only potentially appropriate to consider in patients with risk factors, such as a family history of autoimmune disease.

The researchers conducted a retrospective chart review of adult patients who underwent transsphenoidal surgery for either Cushing disease or NFPA at Massachusetts General Hospital between 2005 and 2019.

The study involved 194 patients with Cushing disease who had postsurgical remission and at least one follow-up visit with a pituitary expert and 92 patients with NFPA who were matched to patients with Cushing disease based on age and sex. The authors regarded autoimmune disease diagnosed within 36 months of the surgery to be temporally associated with Cushing disease remission. Among the autoimmune diseases considered were “rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, autoimmune thyroiditis, celiac disease, psoriasis, vitiligo, autoimmune neuropathy, multiple sclerosis, myasthenia gravis, and ulcerative colitis.”

Patients differed in average body mass index and tumor size, but family history of autoimmune disease was similar in both groups. Average BMI was 34.5 in the Cushing group and 29.5 in the NFPA group. Average tumor size was 5.7 mm in the Cushing group and 21.3 mm in the NFPA group.

Before surgery, 2.9% of patients with Cushing disease and 15.4% of patients with NFPA had central hypothyroidism, and 8% in the Cushing group and 56.8% in the NFPA group had hyperprolactinemia. Central adrenal insufficiency occurred in 11% with NFPA and in all with Cushing disease, by definition.

After surgery, 93.8% in the Cushing group and 16.5% in the NFPA group had adrenal insufficiency. In addition, patients with Cushing disease had lower postsurgical nadir serum cortisol levels (63.8 nmol/L) than those with NFPA (282.3 nmol/L).

Of the 17 patients with Cushing disease — all women — who developed autoimmune disease within 3 years, 6 had a personal history of autoimmune disease and 7 had a family history of it. In addition, 41.2% of them had adrenal insufficiency when they developed the new autoimmune disease. Among the diseases were six autoimmune thyroiditis cases, three Sjögren syndrome cases, and two autoimmune seronegative spondyloarthropathy.

Dr. Heaney said he found it interesting that more than half of the new autoimmune diseases in patients with Cushing disease were related to the thyroid. “In this kind of setting, where you have a patient who has been producing too much steroid over a period of time and then you take that away, it’s almost like you release a brake on the TSH [thyroid-stimulating hormone],” Dr. Heaney said. “So, there’s probably some rebound in TSH that occurs, and that could be driving the thyroiditis, to some extent, that we see in these patients.”

Only one patient with NFPA developed new-onset autoimmune disease, a woman who developed Graves disease 22 months after surgery. When the researchers excluded patients in both groups with central hypothyroidism, new-onset autoimmune disease was still significantly higher (11.4%) in the Cushing group than in the NFPA group (1.9%; HR, 7.02; 95% CI, 2.54-19.39).
 

Could Postoperative Adrenal Insufficiency Contribute to Risk?

Within the Cushing cohort, those who developed autoimmune disease had a lower BMI (31.8 vs 34.8) and larger tumor size (7.2 vs 5.6 mm) than those who didn’t develop new autoimmune disease. Patients who developed autoimmune disease also had a lower baseline urine free cortisol ratio (2.7 vs 6.3) before surgery and more family history of autoimmune disease (41.2% vs 20.9%) than those who didn’t develop one.

“The higher prevalence of adrenal insufficiency and the lower nadir serum cortisol levels in the Cushing disease group suggest that the postoperative adrenal insufficiency in the Cushing disease group might have contributed to autoimmune disease pathogenesis,” the authors wrote. “This finding is clinically significant because cortisol plays a pivotal role in modulating the immune system.”

Most postoperative management among patients with Cushing disease was similar, with all but one patient receiving 0.5 or 1 mg daily dexamethasone within the first week after surgery. (The one outlier received 5 mg daily prednisone.) However, fewer patients who developed autoimmune disease (17.6%) received supraphysiologic doses of glucocorticoid — equivalent to at least 25 mg hydrocortisone — compared with patients who didn’t develop autoimmune disease (41.8%).

“Although the daily average hydrocortisone equivalent replacement doses within the first month and during long-term follow-up were within the physiologic range in both subgroups, patients with Cushing disease who had autoimmune disease received slightly lower doses of glucocorticoid replacement within the first month after surgery,” the authors reported. “The immediate postoperative period might be a critical window where supraphysiologic glucocorticoids seem to be protective with regard to development of autoimmune disease,” they wrote, though they acknowledged the study’s retrospective design as a limitation in drawing that conclusion.

At the least, they suggested that new symptoms in patients with Cushing disease, particularly those with a family history of autoimmune disease, should prompt investigation of potential autoimmune disease.

Recordati Rare Diseases funded the study. The research was also conducted with support from Harvard Catalyst (the Harvard Clinical and Translational Science Center) as well as financial contributions from Harvard University and its affiliated academic healthcare centers. One author reported holding stocks in Pfizer and Amgen, and another reported receiving consulting fees from Corcept. Dr. Heaney reported receiving institutional grants for trials from Corcept, Ascendis, Crinetics, and Sparrow Pharm; serving on the advisory board for Xeris, Recordati, Corcept, Novo Nordisk, Lundbeck, and Crinetics; and serving as a speaker for Chiesi, Novo Nordisk, and Corcept.
 

A version of this article appeared on Medscape.com.

Patients with Cushing disease have an increased risk for new-onset autoimmune disease in the 3 years after surgical remission, according to a new retrospective study published on February 20 in Annals of Internal Medicine.

Outcomes for patients with Cushing disease were compared against those with nonfunctioning pituitary adenomas (NFPAs). New-onset autoimmune disease occurred in 10.4% with Cushing disease and 1.6% among patients with NFPA (hazard ratio, 7.80; 95% CI, 2.88-21.10).

“Understanding and recognizing new and recurrent autoimmune disease in this setting is important to avoid misclassifying such patients with glucocorticoid withdrawal syndrome, which could result in failure to treat underlying autoimmune disease, as well as erroneous diagnosis of steroid withdrawal cases,” wrote Dennis Delasi Nyanyo of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues.

Given the general population’s annual incidence of major autoimmune diseases, estimated at about 100 cases per 100,000 people, and the 3-year incidence of 10.4% found in this study’s cohort, “our findings suggest that Cushing disease remission may trigger development of autoimmune disease,” the authors wrote.
 

Monitor Patients With Family History of Autoimmune Disease?

The study results were not necessarily surprising to Anthony P. Heaney, MD, PhD, an endocrinologist and professor of medicine at the University of California, Los Angeles, because past research has raised similar questions. The authors’ suggestion that the rapid postsurgical drop in cortisol that occurs as a result of treating Cushing disease becomes some sort of autoimmune trigger is interesting but remains speculative, Dr. Heaney pointed out.

If future evidence supports that possibility, “it would suggest, in terms of managing those patients in the postoperative setting, that there may be some merit to giving them higher concentrations of glucocorticoids for a short period of time,” Dr. Heaney said, thereby bringing their levels down more gradually rather than taking them off a cliff, in a sense. Or, if more evidence bears out the authors’ hypothesis, another approach might be treating patients with medicine to bring down the cortisol before surgery, though there are challenges to that approach, Dr. Heaney said.

At the same time, those who developed new autoimmune disease remain a small subset of patients with Cushing disease, so such approaches may become only potentially appropriate to consider in patients with risk factors, such as a family history of autoimmune disease.

The researchers conducted a retrospective chart review of adult patients who underwent transsphenoidal surgery for either Cushing disease or NFPA at Massachusetts General Hospital between 2005 and 2019.

The study involved 194 patients with Cushing disease who had postsurgical remission and at least one follow-up visit with a pituitary expert and 92 patients with NFPA who were matched to patients with Cushing disease based on age and sex. The authors regarded autoimmune disease diagnosed within 36 months of the surgery to be temporally associated with Cushing disease remission. Among the autoimmune diseases considered were “rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, autoimmune thyroiditis, celiac disease, psoriasis, vitiligo, autoimmune neuropathy, multiple sclerosis, myasthenia gravis, and ulcerative colitis.”

Patients differed in average body mass index and tumor size, but family history of autoimmune disease was similar in both groups. Average BMI was 34.5 in the Cushing group and 29.5 in the NFPA group. Average tumor size was 5.7 mm in the Cushing group and 21.3 mm in the NFPA group.

Before surgery, 2.9% of patients with Cushing disease and 15.4% of patients with NFPA had central hypothyroidism, and 8% in the Cushing group and 56.8% in the NFPA group had hyperprolactinemia. Central adrenal insufficiency occurred in 11% with NFPA and in all with Cushing disease, by definition.

After surgery, 93.8% in the Cushing group and 16.5% in the NFPA group had adrenal insufficiency. In addition, patients with Cushing disease had lower postsurgical nadir serum cortisol levels (63.8 nmol/L) than those with NFPA (282.3 nmol/L).

Of the 17 patients with Cushing disease — all women — who developed autoimmune disease within 3 years, 6 had a personal history of autoimmune disease and 7 had a family history of it. In addition, 41.2% of them had adrenal insufficiency when they developed the new autoimmune disease. Among the diseases were six autoimmune thyroiditis cases, three Sjögren syndrome cases, and two autoimmune seronegative spondyloarthropathy.

Dr. Heaney said he found it interesting that more than half of the new autoimmune diseases in patients with Cushing disease were related to the thyroid. “In this kind of setting, where you have a patient who has been producing too much steroid over a period of time and then you take that away, it’s almost like you release a brake on the TSH [thyroid-stimulating hormone],” Dr. Heaney said. “So, there’s probably some rebound in TSH that occurs, and that could be driving the thyroiditis, to some extent, that we see in these patients.”

Only one patient with NFPA developed new-onset autoimmune disease, a woman who developed Graves disease 22 months after surgery. When the researchers excluded patients in both groups with central hypothyroidism, new-onset autoimmune disease was still significantly higher (11.4%) in the Cushing group than in the NFPA group (1.9%; HR, 7.02; 95% CI, 2.54-19.39).
 

Could Postoperative Adrenal Insufficiency Contribute to Risk?

Within the Cushing cohort, those who developed autoimmune disease had a lower BMI (31.8 vs 34.8) and larger tumor size (7.2 vs 5.6 mm) than those who didn’t develop new autoimmune disease. Patients who developed autoimmune disease also had a lower baseline urine free cortisol ratio (2.7 vs 6.3) before surgery and more family history of autoimmune disease (41.2% vs 20.9%) than those who didn’t develop one.

“The higher prevalence of adrenal insufficiency and the lower nadir serum cortisol levels in the Cushing disease group suggest that the postoperative adrenal insufficiency in the Cushing disease group might have contributed to autoimmune disease pathogenesis,” the authors wrote. “This finding is clinically significant because cortisol plays a pivotal role in modulating the immune system.”

Most postoperative management among patients with Cushing disease was similar, with all but one patient receiving 0.5 or 1 mg daily dexamethasone within the first week after surgery. (The one outlier received 5 mg daily prednisone.) However, fewer patients who developed autoimmune disease (17.6%) received supraphysiologic doses of glucocorticoid — equivalent to at least 25 mg hydrocortisone — compared with patients who didn’t develop autoimmune disease (41.8%).

“Although the daily average hydrocortisone equivalent replacement doses within the first month and during long-term follow-up were within the physiologic range in both subgroups, patients with Cushing disease who had autoimmune disease received slightly lower doses of glucocorticoid replacement within the first month after surgery,” the authors reported. “The immediate postoperative period might be a critical window where supraphysiologic glucocorticoids seem to be protective with regard to development of autoimmune disease,” they wrote, though they acknowledged the study’s retrospective design as a limitation in drawing that conclusion.

At the least, they suggested that new symptoms in patients with Cushing disease, particularly those with a family history of autoimmune disease, should prompt investigation of potential autoimmune disease.

Recordati Rare Diseases funded the study. The research was also conducted with support from Harvard Catalyst (the Harvard Clinical and Translational Science Center) as well as financial contributions from Harvard University and its affiliated academic healthcare centers. One author reported holding stocks in Pfizer and Amgen, and another reported receiving consulting fees from Corcept. Dr. Heaney reported receiving institutional grants for trials from Corcept, Ascendis, Crinetics, and Sparrow Pharm; serving on the advisory board for Xeris, Recordati, Corcept, Novo Nordisk, Lundbeck, and Crinetics; and serving as a speaker for Chiesi, Novo Nordisk, and Corcept.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Age older than 65 years and serum creatinine greater than 140 micromol/L at the time of systemic polyarteritis nodosa (PAN) diagnosis were significant predictors of mortality.

METHODOLOGY:

• A total of 358 patients diagnosed with PAN between 1990 and 2020 were identified from retrospective chart reviews and prospective cohorts from nine countries as a part of GLOBAL-PAN, a collaboration of the European Vasculitis Society, the Vasculitis Clinical Research Consortium, and other networks.
• The goal of the retrospective chart review was to characterize the nature, presentation, and survival rates of patients with PAN.
• The study population included 174 female and 184 male patients; 282 had systemic PAN (sPAN) and 76 had cutaneous PAN (cPAN); the mean age at diagnosis was 44.3 years.

TAKEAWAY:

• Overall survival rates at 1, 5, and 10 years for patients with sPAN were 97.1%, 94.0%, and 89.0%, respectively.
• Significant independent predictors of mortality were age ≥ 65 years at the time of sPAN diagnosis (hazard ratio [HR], 3.85), serum creatinine > 140 micromol/L at the time of diagnosis (HR, 4.93), gastrointestinal involvement (HR, 3.51), and central nervous system involvement (HR, 3.56).
• Constitutional symptoms were significantly more common in patients with sPAN vs cPAN (78.8% vs 44.7%), while patients with cPAN were significantly more likely to be female and have more skin nodules than patients with sPAN.
• Relapse over a median disease duration of 59.6 months was slightly higher for cPAN vs sPAN (38.8% vs 32.1%).

IN PRACTICE:

“This study helps better define the demographic and clinical characteristics of patients with PAN and differentiates sPAN from cPAN,” the researchers wrote.

SOURCE:

The lead author of the study was Omer Karadag, MD, of Hacettepe University, Ankara, Turkey. The study was published online on February 12 in Arthritis & Rheumatology.

LIMITATIONS:

Study limitations included the combination of prospective and retrospective data, varying approaches to patient assessment, and lack of data on treatment effects.

DISCLOSURES:

The study was supported by the Vasculitis Clinical Research Consortium, which received funding from the National Center for Advancing Translational Science, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Center for Research Resources. Dr. Karadag disclosed research grants from AbbVie, Novartis, Viela-Bio, and TR-Pharma, and consulting fees from AbbVie, Abdi Ibrahim, Celltrion, Novartis, Pfizer, Sandoz, and UCB.

A version of this article appeared on Medscape.com.

TOPLINE:

Age older than 65 years and serum creatinine greater than 140 micromol/L at the time of systemic polyarteritis nodosa (PAN) diagnosis were significant predictors of mortality.

METHODOLOGY:

• A total of 358 patients diagnosed with PAN between 1990 and 2020 were identified from retrospective chart reviews and prospective cohorts from nine countries as a part of GLOBAL-PAN, a collaboration of the European Vasculitis Society, the Vasculitis Clinical Research Consortium, and other networks.
• The goal of the retrospective chart review was to characterize the nature, presentation, and survival rates of patients with PAN.
• The study population included 174 female and 184 male patients; 282 had systemic PAN (sPAN) and 76 had cutaneous PAN (cPAN); the mean age at diagnosis was 44.3 years.

TAKEAWAY:

• Overall survival rates at 1, 5, and 10 years for patients with sPAN were 97.1%, 94.0%, and 89.0%, respectively.
• Significant independent predictors of mortality were age ≥ 65 years at the time of sPAN diagnosis (hazard ratio [HR], 3.85), serum creatinine > 140 micromol/L at the time of diagnosis (HR, 4.93), gastrointestinal involvement (HR, 3.51), and central nervous system involvement (HR, 3.56).
• Constitutional symptoms were significantly more common in patients with sPAN vs cPAN (78.8% vs 44.7%), while patients with cPAN were significantly more likely to be female and have more skin nodules than patients with sPAN.
• Relapse over a median disease duration of 59.6 months was slightly higher for cPAN vs sPAN (38.8% vs 32.1%).

IN PRACTICE:

“This study helps better define the demographic and clinical characteristics of patients with PAN and differentiates sPAN from cPAN,” the researchers wrote.

SOURCE:

The lead author of the study was Omer Karadag, MD, of Hacettepe University, Ankara, Turkey. The study was published online on February 12 in Arthritis & Rheumatology.

LIMITATIONS:

Study limitations included the combination of prospective and retrospective data, varying approaches to patient assessment, and lack of data on treatment effects.

DISCLOSURES:

The study was supported by the Vasculitis Clinical Research Consortium, which received funding from the National Center for Advancing Translational Science, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Center for Research Resources. Dr. Karadag disclosed research grants from AbbVie, Novartis, Viela-Bio, and TR-Pharma, and consulting fees from AbbVie, Abdi Ibrahim, Celltrion, Novartis, Pfizer, Sandoz, and UCB.

A version of this article appeared on Medscape.com.

TOPLINE:

Age older than 65 years and serum creatinine greater than 140 micromol/L at the time of systemic polyarteritis nodosa (PAN) diagnosis were significant predictors of mortality.

METHODOLOGY:

• A total of 358 patients diagnosed with PAN between 1990 and 2020 were identified from retrospective chart reviews and prospective cohorts from nine countries as a part of GLOBAL-PAN, a collaboration of the European Vasculitis Society, the Vasculitis Clinical Research Consortium, and other networks.
• The goal of the retrospective chart review was to characterize the nature, presentation, and survival rates of patients with PAN.
• The study population included 174 female and 184 male patients; 282 had systemic PAN (sPAN) and 76 had cutaneous PAN (cPAN); the mean age at diagnosis was 44.3 years.

TAKEAWAY:

• Overall survival rates at 1, 5, and 10 years for patients with sPAN were 97.1%, 94.0%, and 89.0%, respectively.
• Significant independent predictors of mortality were age ≥ 65 years at the time of sPAN diagnosis (hazard ratio [HR], 3.85), serum creatinine > 140 micromol/L at the time of diagnosis (HR, 4.93), gastrointestinal involvement (HR, 3.51), and central nervous system involvement (HR, 3.56).
• Constitutional symptoms were significantly more common in patients with sPAN vs cPAN (78.8% vs 44.7%), while patients with cPAN were significantly more likely to be female and have more skin nodules than patients with sPAN.
• Relapse over a median disease duration of 59.6 months was slightly higher for cPAN vs sPAN (38.8% vs 32.1%).

IN PRACTICE:

“This study helps better define the demographic and clinical characteristics of patients with PAN and differentiates sPAN from cPAN,” the researchers wrote.

SOURCE:

The lead author of the study was Omer Karadag, MD, of Hacettepe University, Ankara, Turkey. The study was published online on February 12 in Arthritis & Rheumatology.

LIMITATIONS:

Study limitations included the combination of prospective and retrospective data, varying approaches to patient assessment, and lack of data on treatment effects.

DISCLOSURES:

The study was supported by the Vasculitis Clinical Research Consortium, which received funding from the National Center for Advancing Translational Science, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Center for Research Resources. Dr. Karadag disclosed research grants from AbbVie, Novartis, Viela-Bio, and TR-Pharma, and consulting fees from AbbVie, Abdi Ibrahim, Celltrion, Novartis, Pfizer, Sandoz, and UCB.

A version of this article appeared on Medscape.com.

Postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a distinct, centrally mediated condition, with evidence of autonomic, immune, and metabolic dysfunction, new "deep phenotyping" data suggested.

The study was initiated in 2016 at the US National Institutes of Health. Its aim was to better elucidate the underlying pathophysiology of ME/CFS, a multisystem disorder characterized by persistent and disabling fatigue, post-exertional malaise, cognitive complaints, and other physical symptoms. A total of 17 carefully selected individuals with PI-ME/CFS onset within the prior 5 years were compared with 21 healthy volunteers on a more extensive set of biologic measurements than has been examined in any prior study of the condition.

Overall, the findings suggested that ME/CFS is “a distinct entity characterized by somatic and cognitive complaints that are centrally mediated,” with fatigue that is “defined by effort preferences and central autonomic dysfunction,” Brian T. Walitt, MD, of the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland, and colleagues wrote in the paper, published on February 21 in Nature Communications.

In addition, “there are distinct sex signatures of immune and metabolic dysregulation which suggest persistent antigenic stimulation.” Physical deconditioning over time, while not the source of the condition, “is an important consequence,” the authors added.

Asked to comment, Hector Bonilla, MD, director of the ME/CFS Clinic and codirector of the Stanford Post-Acute COVID-19 Syndrome Clinic, Atherton, California, pointed out that the sample was small and the study was cross-sectional and therefore likely missed dynamic changes in the patients.

Nonetheless, Dr. Bonilla told this news organization, “they have shown clear objective changes in patients with ME/CFS not seen in the controls. These are present in the microbiome, in the immune system, and in metabolites, especially in spinal fluid, that lead to a neuroinflammatory condition. And these are linked with autonomic dysfunction that can explain many of the symptoms that patients experience ... The symptoms are not manufactured by them.”

Thus far, the only treatments for ME/CFS are symptomatic. Understanding the pathophysiology is essential to identifying disease-modifying therapy, study lead author Avindra Nath, MD, Senior Investigator and Clinical Director of Intramural Research at NINDS, told this news organization.

“The disease is real. But our medical profession is limited in what they can do to diagnose or impact them ... The first thing we need to do is try to understand the pathophysiology. So that’s why the study was put together,” Dr. Nath said.

Postinfectious syndromes including ME/CFS have been given many names, including post-Lyme disease, Gulf War illness, and more recently, long COVID. With ME/CFS, the Epstein-Barr virus has historically been one of the most commonly associated triggers, although several other viral, bacterial, and environmental toxins have been implicated.

“There are a whole host of these things that have very similar symptoms or overlapping symptoms ... It’s quite possible that the underlying pathophysiology overlaps between all these syndromes,” Dr. Nath noted.

Another ME/CFS expert not involved in the study, researcher Michael VanElzakker, PhD, of the Neurotherapeutics Division at Harvard Medical School and Massachusetts General Hospital, Boston, said that the possibility of antigen persistence of the infectious pathogen arising from the immune system profiling conducted in the study is noteworthy and merits further study.

“To me, the obvious next step would be techniques like tissue-based assays and T-cell sequencing to try and understand what exactly those antigens are and what their source might be. Importantly, it is probably not the same antigen or pathogen source in all patients, but that’s a question that needs an answer,” Dr. VanElzakker said.

Of note, the 17 study participants had been adjudicated by an expert panel from an initial 484 inquiries and 217 who underwent detailed case reviews. They had to meet at least one of three published ME/CFS criteria and to have moderate to severe clinical symptom severity as determined by several fatigue scores. None met the criteria for psychiatric diagnoses.

Yet, even in the cases that met study criteria, underlying causes emerged in 20% of the participants over time, suggesting diagnostic misattribution. “This misclassification bias has important ramifications on the interpretation of the existing ME/CFS research literature,” the authors wrote.

Dr. VanElzakker noted, “The fact that this research study was probably the most detailed workup many of these patients had ever gotten is a serious indictment of our current profit-based healthcare system’s prioritization of 15-minute doctor’s appointments. It is almost certain that other patients would also benefit from an intensive detailed workup.”
 

Multiple Abnormalities Identified

There were no differences between the PI-ME/CFS and control groups in ventilatory function, muscle oxygenation, mechanical efficiency, resting energy expenditure, basal mitochondrial function of immune cells, muscle fiber composition, or body composition, suggesting the absence of a resting low-energy state, the authors said.

In 40-minute head-up tilt-table testing, there were no differences between the ME/CFS and control groups in frequency or orthostatic hypotension or extensive orthostatic tachycardia. However, a 24-hour ambulatory electrocardiogram showed that the patients with PI-ME/CFS had diminished heart rate variability. They also showed increased heart rate throughout the day, suggesting increased sympathetic activity, and a diminished drop in nighttime heart rate, suggesting decreased parasympathetic activity.

“Considered together, these data suggest that there is an alteration in autonomic tone, implying central nervous system regulatory change,” Dr. Walitt and colleagues wrote.

On the “Effort-Expenditure for Rewards Task,” the participants with PI-ME/CFS showed significant differences in “effort preference,” or a tendency to avoid the harder tasks, as well as a slowing of button-pushing over time, compared with the controls, even with easier tasks. This pattern suggests that those with PI-ME/CFS were “pacing to limit exertion and associated feelings of discomfort,” the authors wrote.

Dr. Nath describes this behavior as akin to “if you develop a flu, you feel that you just want to lay down in bed and not hurt yourself. It’s not that you’re not capable of doing [the task], but your body tells you don’t do it. Your body just wants to fight the infection ... these people just never bounce back.”

Compared with the controls, the participants with PI-ME/CFS failed to maintain a moderate grip force even though there was no difference in maximum grip strength or arm muscle mass. This performance difference correlated with decreased activity of the right temporal-parietal junction, a novel observation suggesting that the fatigue in the PI-ME/CFS group “is due to dysfunction of integrative brain regions that drive the motor cortex, the cause of which needs to be further explored,” Dr. Walitt and colleagues wrote.

On cardiopulmonary testing, peak power, peak respiratory rate, peak heart rate, and peak VO₂ were all lower in the PI-ME/CFS group, correlating to a difference of approximately 3.3 metabolic equivalent of task units. The differential cardiorespiratory performance relates to “autonomic function, hypothalamic-pituitary-adrenal axis hyporesponsiveness, and muscular deconditioning from disuse that clinically impacts activities of daily life,” they said.

In the participants with PI-ME/CFS, catechol levels in cerebrospinal fluid correlated with grip strength and effort preference, and several metabolites of the dopamine pathway correlated with several cognitive symptoms.

“This suggests that central nervous system catechol pathways are dysregulated in PI-ME/CFS and may play a role in effort preference and cognitive complaints,” as well as decreased central catecholamine biosynthesis. Similar findings have been seen in patients with long COVID, the authors noted.

There were increased naive B cells and decreased switched memory B cells in blood of participants with PI-ME/CFS. Contrary to prior studies, there was no consistent pattern of autoimmunity across all participants with PI-ME/CFS, and no previously undescribed antibodies were identified.

However, programmed cell death protein 1, a marker of T-cell exhaustion and activation, was elevated in the cerebrospinal fluid of the patients with PI-ME/CFS.

Several sex-based differences were noted, including in immune cell expression in cerebrospinal fluid, peripheral blood mononuclear cell gene expression, and muscle gene expression. Males and females also differed in the cerebrospinal metabolomics that distinguished the participants with PI-ME/CFS from controls.
 

What Do These Findings Suggest About Treatment?

The data point to several treatment implications. For one, the finding of possible immune exhaustion suggests that immune checkpoint inhibitors may be therapeutic by promoting clearance of foreign antigens. Immune dysfunction leads to neurochemical alterations that affect neuronal circuits, which may be another point of intervention, the authors suggested.

On the other hand, “attempting to target downstream mechanisms with exercise, cognitive behavioral therapy, or autonomic directed therapies may have limited impact on symptom burden, as it would not address the root cause of PI-ME/CFS,” they noted.

Combination therapy targeting multiple pathways along with a personalized medicine approach should be considered, they said.

“I think the most important thing is not to discount these patients,” Dr. Nath told this news organization. “They have a real disease, and we need to be empathetic towards them. We also need to make sure that they don’t have something underlying that is treatable, and then treat them symptomatically the best that you can. If not, then refer them to ME/CFS studies or clinics where people specialize in these conditions and work with them.”

The study authors and Dr. VanElzakker reported no relevant financial relationships. Dr. Bonilla consults for United Health and Resverlogix.
 

A version of this article appeared on Medscape.com.

Postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a distinct, centrally mediated condition, with evidence of autonomic, immune, and metabolic dysfunction, new "deep phenotyping" data suggested.

The study was initiated in 2016 at the US National Institutes of Health. Its aim was to better elucidate the underlying pathophysiology of ME/CFS, a multisystem disorder characterized by persistent and disabling fatigue, post-exertional malaise, cognitive complaints, and other physical symptoms. A total of 17 carefully selected individuals with PI-ME/CFS onset within the prior 5 years were compared with 21 healthy volunteers on a more extensive set of biologic measurements than has been examined in any prior study of the condition.

Overall, the findings suggested that ME/CFS is “a distinct entity characterized by somatic and cognitive complaints that are centrally mediated,” with fatigue that is “defined by effort preferences and central autonomic dysfunction,” Brian T. Walitt, MD, of the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland, and colleagues wrote in the paper, published on February 21 in Nature Communications.

In addition, “there are distinct sex signatures of immune and metabolic dysregulation which suggest persistent antigenic stimulation.” Physical deconditioning over time, while not the source of the condition, “is an important consequence,” the authors added.

Asked to comment, Hector Bonilla, MD, director of the ME/CFS Clinic and codirector of the Stanford Post-Acute COVID-19 Syndrome Clinic, Atherton, California, pointed out that the sample was small and the study was cross-sectional and therefore likely missed dynamic changes in the patients.

Nonetheless, Dr. Bonilla told this news organization, “they have shown clear objective changes in patients with ME/CFS not seen in the controls. These are present in the microbiome, in the immune system, and in metabolites, especially in spinal fluid, that lead to a neuroinflammatory condition. And these are linked with autonomic dysfunction that can explain many of the symptoms that patients experience ... The symptoms are not manufactured by them.”

Thus far, the only treatments for ME/CFS are symptomatic. Understanding the pathophysiology is essential to identifying disease-modifying therapy, study lead author Avindra Nath, MD, Senior Investigator and Clinical Director of Intramural Research at NINDS, told this news organization.

“The disease is real. But our medical profession is limited in what they can do to diagnose or impact them ... The first thing we need to do is try to understand the pathophysiology. So that’s why the study was put together,” Dr. Nath said.

Postinfectious syndromes including ME/CFS have been given many names, including post-Lyme disease, Gulf War illness, and more recently, long COVID. With ME/CFS, the Epstein-Barr virus has historically been one of the most commonly associated triggers, although several other viral, bacterial, and environmental toxins have been implicated.

“There are a whole host of these things that have very similar symptoms or overlapping symptoms ... It’s quite possible that the underlying pathophysiology overlaps between all these syndromes,” Dr. Nath noted.

Another ME/CFS expert not involved in the study, researcher Michael VanElzakker, PhD, of the Neurotherapeutics Division at Harvard Medical School and Massachusetts General Hospital, Boston, said that the possibility of antigen persistence of the infectious pathogen arising from the immune system profiling conducted in the study is noteworthy and merits further study.

“To me, the obvious next step would be techniques like tissue-based assays and T-cell sequencing to try and understand what exactly those antigens are and what their source might be. Importantly, it is probably not the same antigen or pathogen source in all patients, but that’s a question that needs an answer,” Dr. VanElzakker said.

Of note, the 17 study participants had been adjudicated by an expert panel from an initial 484 inquiries and 217 who underwent detailed case reviews. They had to meet at least one of three published ME/CFS criteria and to have moderate to severe clinical symptom severity as determined by several fatigue scores. None met the criteria for psychiatric diagnoses.

Yet, even in the cases that met study criteria, underlying causes emerged in 20% of the participants over time, suggesting diagnostic misattribution. “This misclassification bias has important ramifications on the interpretation of the existing ME/CFS research literature,” the authors wrote.

Dr. VanElzakker noted, “The fact that this research study was probably the most detailed workup many of these patients had ever gotten is a serious indictment of our current profit-based healthcare system’s prioritization of 15-minute doctor’s appointments. It is almost certain that other patients would also benefit from an intensive detailed workup.”
 

Multiple Abnormalities Identified

There were no differences between the PI-ME/CFS and control groups in ventilatory function, muscle oxygenation, mechanical efficiency, resting energy expenditure, basal mitochondrial function of immune cells, muscle fiber composition, or body composition, suggesting the absence of a resting low-energy state, the authors said.

In 40-minute head-up tilt-table testing, there were no differences between the ME/CFS and control groups in frequency or orthostatic hypotension or extensive orthostatic tachycardia. However, a 24-hour ambulatory electrocardiogram showed that the patients with PI-ME/CFS had diminished heart rate variability. They also showed increased heart rate throughout the day, suggesting increased sympathetic activity, and a diminished drop in nighttime heart rate, suggesting decreased parasympathetic activity.

“Considered together, these data suggest that there is an alteration in autonomic tone, implying central nervous system regulatory change,” Dr. Walitt and colleagues wrote.

On the “Effort-Expenditure for Rewards Task,” the participants with PI-ME/CFS showed significant differences in “effort preference,” or a tendency to avoid the harder tasks, as well as a slowing of button-pushing over time, compared with the controls, even with easier tasks. This pattern suggests that those with PI-ME/CFS were “pacing to limit exertion and associated feelings of discomfort,” the authors wrote.

Dr. Nath describes this behavior as akin to “if you develop a flu, you feel that you just want to lay down in bed and not hurt yourself. It’s not that you’re not capable of doing [the task], but your body tells you don’t do it. Your body just wants to fight the infection ... these people just never bounce back.”

Compared with the controls, the participants with PI-ME/CFS failed to maintain a moderate grip force even though there was no difference in maximum grip strength or arm muscle mass. This performance difference correlated with decreased activity of the right temporal-parietal junction, a novel observation suggesting that the fatigue in the PI-ME/CFS group “is due to dysfunction of integrative brain regions that drive the motor cortex, the cause of which needs to be further explored,” Dr. Walitt and colleagues wrote.

On cardiopulmonary testing, peak power, peak respiratory rate, peak heart rate, and peak VO₂ were all lower in the PI-ME/CFS group, correlating to a difference of approximately 3.3 metabolic equivalent of task units. The differential cardiorespiratory performance relates to “autonomic function, hypothalamic-pituitary-adrenal axis hyporesponsiveness, and muscular deconditioning from disuse that clinically impacts activities of daily life,” they said.

In the participants with PI-ME/CFS, catechol levels in cerebrospinal fluid correlated with grip strength and effort preference, and several metabolites of the dopamine pathway correlated with several cognitive symptoms.

“This suggests that central nervous system catechol pathways are dysregulated in PI-ME/CFS and may play a role in effort preference and cognitive complaints,” as well as decreased central catecholamine biosynthesis. Similar findings have been seen in patients with long COVID, the authors noted.

There were increased naive B cells and decreased switched memory B cells in blood of participants with PI-ME/CFS. Contrary to prior studies, there was no consistent pattern of autoimmunity across all participants with PI-ME/CFS, and no previously undescribed antibodies were identified.

However, programmed cell death protein 1, a marker of T-cell exhaustion and activation, was elevated in the cerebrospinal fluid of the patients with PI-ME/CFS.

Several sex-based differences were noted, including in immune cell expression in cerebrospinal fluid, peripheral blood mononuclear cell gene expression, and muscle gene expression. Males and females also differed in the cerebrospinal metabolomics that distinguished the participants with PI-ME/CFS from controls.
 

What Do These Findings Suggest About Treatment?

The data point to several treatment implications. For one, the finding of possible immune exhaustion suggests that immune checkpoint inhibitors may be therapeutic by promoting clearance of foreign antigens. Immune dysfunction leads to neurochemical alterations that affect neuronal circuits, which may be another point of intervention, the authors suggested.

On the other hand, “attempting to target downstream mechanisms with exercise, cognitive behavioral therapy, or autonomic directed therapies may have limited impact on symptom burden, as it would not address the root cause of PI-ME/CFS,” they noted.

Combination therapy targeting multiple pathways along with a personalized medicine approach should be considered, they said.

“I think the most important thing is not to discount these patients,” Dr. Nath told this news organization. “They have a real disease, and we need to be empathetic towards them. We also need to make sure that they don’t have something underlying that is treatable, and then treat them symptomatically the best that you can. If not, then refer them to ME/CFS studies or clinics where people specialize in these conditions and work with them.”

The study authors and Dr. VanElzakker reported no relevant financial relationships. Dr. Bonilla consults for United Health and Resverlogix.
 

A version of this article appeared on Medscape.com.

Postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a distinct, centrally mediated condition, with evidence of autonomic, immune, and metabolic dysfunction, new "deep phenotyping" data suggested.

The study was initiated in 2016 at the US National Institutes of Health. Its aim was to better elucidate the underlying pathophysiology of ME/CFS, a multisystem disorder characterized by persistent and disabling fatigue, post-exertional malaise, cognitive complaints, and other physical symptoms. A total of 17 carefully selected individuals with PI-ME/CFS onset within the prior 5 years were compared with 21 healthy volunteers on a more extensive set of biologic measurements than has been examined in any prior study of the condition.

Overall, the findings suggested that ME/CFS is “a distinct entity characterized by somatic and cognitive complaints that are centrally mediated,” with fatigue that is “defined by effort preferences and central autonomic dysfunction,” Brian T. Walitt, MD, of the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland, and colleagues wrote in the paper, published on February 21 in Nature Communications.

In addition, “there are distinct sex signatures of immune and metabolic dysregulation which suggest persistent antigenic stimulation.” Physical deconditioning over time, while not the source of the condition, “is an important consequence,” the authors added.

Asked to comment, Hector Bonilla, MD, director of the ME/CFS Clinic and codirector of the Stanford Post-Acute COVID-19 Syndrome Clinic, Atherton, California, pointed out that the sample was small and the study was cross-sectional and therefore likely missed dynamic changes in the patients.

Nonetheless, Dr. Bonilla told this news organization, “they have shown clear objective changes in patients with ME/CFS not seen in the controls. These are present in the microbiome, in the immune system, and in metabolites, especially in spinal fluid, that lead to a neuroinflammatory condition. And these are linked with autonomic dysfunction that can explain many of the symptoms that patients experience ... The symptoms are not manufactured by them.”

Thus far, the only treatments for ME/CFS are symptomatic. Understanding the pathophysiology is essential to identifying disease-modifying therapy, study lead author Avindra Nath, MD, Senior Investigator and Clinical Director of Intramural Research at NINDS, told this news organization.

“The disease is real. But our medical profession is limited in what they can do to diagnose or impact them ... The first thing we need to do is try to understand the pathophysiology. So that’s why the study was put together,” Dr. Nath said.

Postinfectious syndromes including ME/CFS have been given many names, including post-Lyme disease, Gulf War illness, and more recently, long COVID. With ME/CFS, the Epstein-Barr virus has historically been one of the most commonly associated triggers, although several other viral, bacterial, and environmental toxins have been implicated.

“There are a whole host of these things that have very similar symptoms or overlapping symptoms ... It’s quite possible that the underlying pathophysiology overlaps between all these syndromes,” Dr. Nath noted.

Another ME/CFS expert not involved in the study, researcher Michael VanElzakker, PhD, of the Neurotherapeutics Division at Harvard Medical School and Massachusetts General Hospital, Boston, said that the possibility of antigen persistence of the infectious pathogen arising from the immune system profiling conducted in the study is noteworthy and merits further study.

“To me, the obvious next step would be techniques like tissue-based assays and T-cell sequencing to try and understand what exactly those antigens are and what their source might be. Importantly, it is probably not the same antigen or pathogen source in all patients, but that’s a question that needs an answer,” Dr. VanElzakker said.

Of note, the 17 study participants had been adjudicated by an expert panel from an initial 484 inquiries and 217 who underwent detailed case reviews. They had to meet at least one of three published ME/CFS criteria and to have moderate to severe clinical symptom severity as determined by several fatigue scores. None met the criteria for psychiatric diagnoses.

Yet, even in the cases that met study criteria, underlying causes emerged in 20% of the participants over time, suggesting diagnostic misattribution. “This misclassification bias has important ramifications on the interpretation of the existing ME/CFS research literature,” the authors wrote.

Dr. VanElzakker noted, “The fact that this research study was probably the most detailed workup many of these patients had ever gotten is a serious indictment of our current profit-based healthcare system’s prioritization of 15-minute doctor’s appointments. It is almost certain that other patients would also benefit from an intensive detailed workup.”
 

Multiple Abnormalities Identified

There were no differences between the PI-ME/CFS and control groups in ventilatory function, muscle oxygenation, mechanical efficiency, resting energy expenditure, basal mitochondrial function of immune cells, muscle fiber composition, or body composition, suggesting the absence of a resting low-energy state, the authors said.

In 40-minute head-up tilt-table testing, there were no differences between the ME/CFS and control groups in frequency or orthostatic hypotension or extensive orthostatic tachycardia. However, a 24-hour ambulatory electrocardiogram showed that the patients with PI-ME/CFS had diminished heart rate variability. They also showed increased heart rate throughout the day, suggesting increased sympathetic activity, and a diminished drop in nighttime heart rate, suggesting decreased parasympathetic activity.

“Considered together, these data suggest that there is an alteration in autonomic tone, implying central nervous system regulatory change,” Dr. Walitt and colleagues wrote.

On the “Effort-Expenditure for Rewards Task,” the participants with PI-ME/CFS showed significant differences in “effort preference,” or a tendency to avoid the harder tasks, as well as a slowing of button-pushing over time, compared with the controls, even with easier tasks. This pattern suggests that those with PI-ME/CFS were “pacing to limit exertion and associated feelings of discomfort,” the authors wrote.

Dr. Nath describes this behavior as akin to “if you develop a flu, you feel that you just want to lay down in bed and not hurt yourself. It’s not that you’re not capable of doing [the task], but your body tells you don’t do it. Your body just wants to fight the infection ... these people just never bounce back.”

Compared with the controls, the participants with PI-ME/CFS failed to maintain a moderate grip force even though there was no difference in maximum grip strength or arm muscle mass. This performance difference correlated with decreased activity of the right temporal-parietal junction, a novel observation suggesting that the fatigue in the PI-ME/CFS group “is due to dysfunction of integrative brain regions that drive the motor cortex, the cause of which needs to be further explored,” Dr. Walitt and colleagues wrote.

On cardiopulmonary testing, peak power, peak respiratory rate, peak heart rate, and peak VO₂ were all lower in the PI-ME/CFS group, correlating to a difference of approximately 3.3 metabolic equivalent of task units. The differential cardiorespiratory performance relates to “autonomic function, hypothalamic-pituitary-adrenal axis hyporesponsiveness, and muscular deconditioning from disuse that clinically impacts activities of daily life,” they said.

In the participants with PI-ME/CFS, catechol levels in cerebrospinal fluid correlated with grip strength and effort preference, and several metabolites of the dopamine pathway correlated with several cognitive symptoms.

“This suggests that central nervous system catechol pathways are dysregulated in PI-ME/CFS and may play a role in effort preference and cognitive complaints,” as well as decreased central catecholamine biosynthesis. Similar findings have been seen in patients with long COVID, the authors noted.

There were increased naive B cells and decreased switched memory B cells in blood of participants with PI-ME/CFS. Contrary to prior studies, there was no consistent pattern of autoimmunity across all participants with PI-ME/CFS, and no previously undescribed antibodies were identified.

However, programmed cell death protein 1, a marker of T-cell exhaustion and activation, was elevated in the cerebrospinal fluid of the patients with PI-ME/CFS.

Several sex-based differences were noted, including in immune cell expression in cerebrospinal fluid, peripheral blood mononuclear cell gene expression, and muscle gene expression. Males and females also differed in the cerebrospinal metabolomics that distinguished the participants with PI-ME/CFS from controls.
 

What Do These Findings Suggest About Treatment?

The data point to several treatment implications. For one, the finding of possible immune exhaustion suggests that immune checkpoint inhibitors may be therapeutic by promoting clearance of foreign antigens. Immune dysfunction leads to neurochemical alterations that affect neuronal circuits, which may be another point of intervention, the authors suggested.

On the other hand, “attempting to target downstream mechanisms with exercise, cognitive behavioral therapy, or autonomic directed therapies may have limited impact on symptom burden, as it would not address the root cause of PI-ME/CFS,” they noted.

Combination therapy targeting multiple pathways along with a personalized medicine approach should be considered, they said.

“I think the most important thing is not to discount these patients,” Dr. Nath told this news organization. “They have a real disease, and we need to be empathetic towards them. We also need to make sure that they don’t have something underlying that is treatable, and then treat them symptomatically the best that you can. If not, then refer them to ME/CFS studies or clinics where people specialize in these conditions and work with them.”

The study authors and Dr. VanElzakker reported no relevant financial relationships. Dr. Bonilla consults for United Health and Resverlogix.
 

A version of this article appeared on Medscape.com.

Poor communication between physician and patient can cause a lot of harm, according to Joseph N. Cappella, PhD, Gerald R. Miller Professor Emeritus of Communication at the University of Pennsylvania in Philadelphia, and Richard N. Street Jr, PhD, professor of communication and media science at Texas A&M University in Houston, Texas. When a physician and patient talk past each other, it may impair the patient’s compliance with preventive measures, screening, and treatment; undermine the physician-patient relationship; exacerbate fears and concerns; and possibly lead patients to rely on misleading, incomplete, or simply incorrect information, turning away from evidence-based medicine.

Drs. Cappella and Street made these points in an essay recently published in JAMA. The essay marks the beginning of the JAMA series Communicating Medicine.

“Helping clinicians deliver accurate information more effectively can lead to better-informed patients,” wrote Anne R. Cappola, MD, professor of endocrinology, diabetes, and metabolism at the University of Pennsylvania, and Kirsten Bibbins-Domingo, MD, PhD, professor of medicine at the University of California, San Francisco, in an accompanying editorial. Drs. Cappola and Bibbins-Domingo also are editors of JAMA.

To establish a common understanding between physician and patient, Drs. Cappella and Street identified the following four responsibilities of the physician:

• Discover what the patient understands and why
• Provide accurate information in an understandable manner
• Promote the credibility of the information
• Verify whether the patient has understood.

“Research has shown that although medical facts need to be the basis for the clinician’s core message, those facts are more effectively communicated in a patient-clinician relationship characterized by trust and cooperation and when the information is presented in a manner that fosters patient understanding,” wrote Drs. Cappella and Street. This approach includes using interpreters for patients who do not fluently speak the physician’s language and supplementing explanations with simple written information, images, and videos.

Patients generally believe their physician’s information, and most patients view their physicians as a trustworthy source. Trust is based on the belief that the physician has the patient’s best interests at heart.

However, patients may be distrustful of their physician’s information if it contradicts their own belief system or personal experiences or because they inherently distrust the medical profession.

In addition, patients are less willing to accept explanations and recommendations if they feel misunderstood, judged, discriminated against, or rushed by the physician. The basis for effective communication is a relationship with patients that is built on trust and respect. Empirically supported strategies for expressing respect and building trust include the following:

• Affirming the patient’s values
• Anticipating and addressing false or misleading information
• Using simple, jargon-free language
• Embedding facts into a story, rather than presenting the scientific evidence dryly.

“Conveying factual material using these techniques makes facts more engaging and memorable,” wrote Drs. Cappella and Street. It is crucial to inquire about and consider the patient’s perspective, health beliefs, assumptions, concerns, needs, and stories in the conversation.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Poor communication between physician and patient can cause a lot of harm, according to Joseph N. Cappella, PhD, Gerald R. Miller Professor Emeritus of Communication at the University of Pennsylvania in Philadelphia, and Richard N. Street Jr, PhD, professor of communication and media science at Texas A&M University in Houston, Texas. When a physician and patient talk past each other, it may impair the patient’s compliance with preventive measures, screening, and treatment; undermine the physician-patient relationship; exacerbate fears and concerns; and possibly lead patients to rely on misleading, incomplete, or simply incorrect information, turning away from evidence-based medicine.

Drs. Cappella and Street made these points in an essay recently published in JAMA. The essay marks the beginning of the JAMA series Communicating Medicine.

“Helping clinicians deliver accurate information more effectively can lead to better-informed patients,” wrote Anne R. Cappola, MD, professor of endocrinology, diabetes, and metabolism at the University of Pennsylvania, and Kirsten Bibbins-Domingo, MD, PhD, professor of medicine at the University of California, San Francisco, in an accompanying editorial. Drs. Cappola and Bibbins-Domingo also are editors of JAMA.

To establish a common understanding between physician and patient, Drs. Cappella and Street identified the following four responsibilities of the physician:

• Discover what the patient understands and why
• Provide accurate information in an understandable manner
• Promote the credibility of the information
• Verify whether the patient has understood.

“Research has shown that although medical facts need to be the basis for the clinician’s core message, those facts are more effectively communicated in a patient-clinician relationship characterized by trust and cooperation and when the information is presented in a manner that fosters patient understanding,” wrote Drs. Cappella and Street. This approach includes using interpreters for patients who do not fluently speak the physician’s language and supplementing explanations with simple written information, images, and videos.

Patients generally believe their physician’s information, and most patients view their physicians as a trustworthy source. Trust is based on the belief that the physician has the patient’s best interests at heart.

However, patients may be distrustful of their physician’s information if it contradicts their own belief system or personal experiences or because they inherently distrust the medical profession.

In addition, patients are less willing to accept explanations and recommendations if they feel misunderstood, judged, discriminated against, or rushed by the physician. The basis for effective communication is a relationship with patients that is built on trust and respect. Empirically supported strategies for expressing respect and building trust include the following:

• Affirming the patient’s values
• Anticipating and addressing false or misleading information
• Using simple, jargon-free language
• Embedding facts into a story, rather than presenting the scientific evidence dryly.

“Conveying factual material using these techniques makes facts more engaging and memorable,” wrote Drs. Cappella and Street. It is crucial to inquire about and consider the patient’s perspective, health beliefs, assumptions, concerns, needs, and stories in the conversation.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Poor communication between physician and patient can cause a lot of harm, according to Joseph N. Cappella, PhD, Gerald R. Miller Professor Emeritus of Communication at the University of Pennsylvania in Philadelphia, and Richard N. Street Jr, PhD, professor of communication and media science at Texas A&M University in Houston, Texas. When a physician and patient talk past each other, it may impair the patient’s compliance with preventive measures, screening, and treatment; undermine the physician-patient relationship; exacerbate fears and concerns; and possibly lead patients to rely on misleading, incomplete, or simply incorrect information, turning away from evidence-based medicine.

Drs. Cappella and Street made these points in an essay recently published in JAMA. The essay marks the beginning of the JAMA series Communicating Medicine.

“Helping clinicians deliver accurate information more effectively can lead to better-informed patients,” wrote Anne R. Cappola, MD, professor of endocrinology, diabetes, and metabolism at the University of Pennsylvania, and Kirsten Bibbins-Domingo, MD, PhD, professor of medicine at the University of California, San Francisco, in an accompanying editorial. Drs. Cappola and Bibbins-Domingo also are editors of JAMA.

To establish a common understanding between physician and patient, Drs. Cappella and Street identified the following four responsibilities of the physician:

• Discover what the patient understands and why
• Provide accurate information in an understandable manner
• Promote the credibility of the information
• Verify whether the patient has understood.

“Research has shown that although medical facts need to be the basis for the clinician’s core message, those facts are more effectively communicated in a patient-clinician relationship characterized by trust and cooperation and when the information is presented in a manner that fosters patient understanding,” wrote Drs. Cappella and Street. This approach includes using interpreters for patients who do not fluently speak the physician’s language and supplementing explanations with simple written information, images, and videos.

Patients generally believe their physician’s information, and most patients view their physicians as a trustworthy source. Trust is based on the belief that the physician has the patient’s best interests at heart.

However, patients may be distrustful of their physician’s information if it contradicts their own belief system or personal experiences or because they inherently distrust the medical profession.

In addition, patients are less willing to accept explanations and recommendations if they feel misunderstood, judged, discriminated against, or rushed by the physician. The basis for effective communication is a relationship with patients that is built on trust and respect. Empirically supported strategies for expressing respect and building trust include the following:

• Affirming the patient’s values
• Anticipating and addressing false or misleading information
• Using simple, jargon-free language
• Embedding facts into a story, rather than presenting the scientific evidence dryly.

“Conveying factual material using these techniques makes facts more engaging and memorable,” wrote Drs. Cappella and Street. It is crucial to inquire about and consider the patient’s perspective, health beliefs, assumptions, concerns, needs, and stories in the conversation.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Inflammatory arthritis (IA) occurred in one-third of patients with systemic sclerosis (SSc) in a large observational study and was significantly associated with poor quality of life and physical function, as well as diffuse disease, musculoskeletal manifestations, myositis, and sicca.

METHODOLOGY:

• Researchers reviewed data from 1717 adults with SSc who were enrolled in the Australian  Cohort Study to identify those with IA, defined as the presence of synovitis in one or more joints on clinical examination documented by the treating physician.
• The primary outcome was health-related quality of life (HRQoL) based on patient reports using the Medical Outcomes Short Form 36 and Patient-Reported Outcomes Measurement Information System, and physical function measured with the Health Assessment Questionnaire.

TAKEAWAY:

• IA was identified in 33.3% of the study participants over a median of 4.3 years’ follow-up. IA occurred at a median age of about 60 years and after a median SSc disease duration of 7.9 years. No significant differences in baseline demographics appeared between patients with and without IA.
• Patients with IA had significantly increased risk for diffuse cutaneous SSc (odds ratio [OR], 1.33), concurrent musculoskeletal manifestations such as tendon friction rubs and joint contractures (OR, 1.70), myositis (OR, 2.11), and sicca symptoms (OR, 1.57), compared with those without.
• Patients with IA reported significantly lower HRQoL scores and significantly greater physical disability, compared with those who did not have IA (P < .001 for both).
• IA was significantly less common among patients with , compared with those without pulmonary arterial hypertension (7.2% vs 11.3%; P = .007).

IN PRACTICE:

“Recognizing the presence of IA in SSc is an important first step, as its treatment and monitoring may alleviate some of the associated morbidity,” the researchers wrote.

SOURCE:

The lead author of the study was Eric Schwender, a medical student at the Royal College of Surgeons in Ireland, Dublin, Ireland. The study was published online in Arthritis Care & Research.

LIMITATIONS:

The inability to assess distribution and severity of IA limited the results, as did the inability to assess the impact of disease-modifying antirheumatic drugs in patients with IA.

DISCLOSURES:

The study was supported by Scleroderma Australia, Arthritis Australia, Actelion Australia, Bayer, CSL Biotherapies, GlaxoSmithKline Australia, and Pfizer, as well as grants to several researchers from the National Health and Medical Research Council of Australia. Lead author Mr. Schwender had no financial conflicts to disclose.

A version of this article appeared on Medscape.com.

TOPLINE:

Inflammatory arthritis (IA) occurred in one-third of patients with systemic sclerosis (SSc) in a large observational study and was significantly associated with poor quality of life and physical function, as well as diffuse disease, musculoskeletal manifestations, myositis, and sicca.

METHODOLOGY:

• Researchers reviewed data from 1717 adults with SSc who were enrolled in the Australian  Cohort Study to identify those with IA, defined as the presence of synovitis in one or more joints on clinical examination documented by the treating physician.
• The primary outcome was health-related quality of life (HRQoL) based on patient reports using the Medical Outcomes Short Form 36 and Patient-Reported Outcomes Measurement Information System, and physical function measured with the Health Assessment Questionnaire.

TAKEAWAY:

• IA was identified in 33.3% of the study participants over a median of 4.3 years’ follow-up. IA occurred at a median age of about 60 years and after a median SSc disease duration of 7.9 years. No significant differences in baseline demographics appeared between patients with and without IA.
• Patients with IA had significantly increased risk for diffuse cutaneous SSc (odds ratio [OR], 1.33), concurrent musculoskeletal manifestations such as tendon friction rubs and joint contractures (OR, 1.70), myositis (OR, 2.11), and sicca symptoms (OR, 1.57), compared with those without.
• Patients with IA reported significantly lower HRQoL scores and significantly greater physical disability, compared with those who did not have IA (P < .001 for both).
• IA was significantly less common among patients with , compared with those without pulmonary arterial hypertension (7.2% vs 11.3%; P = .007).

IN PRACTICE:

“Recognizing the presence of IA in SSc is an important first step, as its treatment and monitoring may alleviate some of the associated morbidity,” the researchers wrote.

SOURCE:

The lead author of the study was Eric Schwender, a medical student at the Royal College of Surgeons in Ireland, Dublin, Ireland. The study was published online in Arthritis Care & Research.

LIMITATIONS:

The inability to assess distribution and severity of IA limited the results, as did the inability to assess the impact of disease-modifying antirheumatic drugs in patients with IA.

DISCLOSURES:

The study was supported by Scleroderma Australia, Arthritis Australia, Actelion Australia, Bayer, CSL Biotherapies, GlaxoSmithKline Australia, and Pfizer, as well as grants to several researchers from the National Health and Medical Research Council of Australia. Lead author Mr. Schwender had no financial conflicts to disclose.

A version of this article appeared on Medscape.com.

TOPLINE:

Inflammatory arthritis (IA) occurred in one-third of patients with systemic sclerosis (SSc) in a large observational study and was significantly associated with poor quality of life and physical function, as well as diffuse disease, musculoskeletal manifestations, myositis, and sicca.

METHODOLOGY:

• Researchers reviewed data from 1717 adults with SSc who were enrolled in the Australian  Cohort Study to identify those with IA, defined as the presence of synovitis in one or more joints on clinical examination documented by the treating physician.
• The primary outcome was health-related quality of life (HRQoL) based on patient reports using the Medical Outcomes Short Form 36 and Patient-Reported Outcomes Measurement Information System, and physical function measured with the Health Assessment Questionnaire.

TAKEAWAY:

• IA was identified in 33.3% of the study participants over a median of 4.3 years’ follow-up. IA occurred at a median age of about 60 years and after a median SSc disease duration of 7.9 years. No significant differences in baseline demographics appeared between patients with and without IA.
• Patients with IA had significantly increased risk for diffuse cutaneous SSc (odds ratio [OR], 1.33), concurrent musculoskeletal manifestations such as tendon friction rubs and joint contractures (OR, 1.70), myositis (OR, 2.11), and sicca symptoms (OR, 1.57), compared with those without.
• Patients with IA reported significantly lower HRQoL scores and significantly greater physical disability, compared with those who did not have IA (P < .001 for both).
• IA was significantly less common among patients with , compared with those without pulmonary arterial hypertension (7.2% vs 11.3%; P = .007).

IN PRACTICE:

“Recognizing the presence of IA in SSc is an important first step, as its treatment and monitoring may alleviate some of the associated morbidity,” the researchers wrote.

SOURCE:

The lead author of the study was Eric Schwender, a medical student at the Royal College of Surgeons in Ireland, Dublin, Ireland. The study was published online in Arthritis Care & Research.

LIMITATIONS:

The inability to assess distribution and severity of IA limited the results, as did the inability to assess the impact of disease-modifying antirheumatic drugs in patients with IA.

DISCLOSURES:

The study was supported by Scleroderma Australia, Arthritis Australia, Actelion Australia, Bayer, CSL Biotherapies, GlaxoSmithKline Australia, and Pfizer, as well as grants to several researchers from the National Health and Medical Research Council of Australia. Lead author Mr. Schwender had no financial conflicts to disclose.

A version of this article appeared on Medscape.com.

I recently received an email from a distraught physician. Several months previously, he had sold his practice to a large private equity-funded group. The terms spelled out in the group’s letter of intent (LOI) seemed ideal. He could continue running his office any way he wished, set his own hours and fees, and keep his employees. All his overhead expenses would disappear. His income would remain the same, maybe even increase. He signed it eagerly.

When he received the actual sale and employment contracts, none of the details promised in the LOI were included; but he figured that since they were spelled out in the LOI, which both he and the buyer had signed, he was covered. His attorney — a family friend with no experience in medical practice transactions — approved the documents.

The deal seemed too good to be true, and it was. The day after the sale closed, all his employees received termination notices. The group offered to rehire some of them, but at lower salaries and reduced benefits. (Most declined.) The new staffers he received were inadequately trained and unfamiliar with his standard office procedures. Patients complained that fees had increased substantially. His own compensation was contingent on meeting strict billing and performance goals. Malpractice premiums remained his responsibility. His office hours were lengthened to include evenings and Saturday mornings.

When he complained to the group that none of the things promised in the LOI had been delivered, he was informed that the LOI was not legally binding. In fact, the sale and employment contracts both clearly specified that they “replaced any previous written or oral agreements between the parties.”

There are some valuable lessons to be learned here. First, whether you are a young physician seeking a new job with a hospital or large practice, or an older one looking to sell an established practice, retain an attorney experienced in medical transactions early, before you sign anything, binding or not. Second, recognize that any promises made in an LOI must be spelled out in the employment and/or sale contract as well.

You might ask, if the terms in an LOI are not binding, why bother with one at all? For one thing, you want to make sure that you and your potential employer or buyer are on the same page with respect to major terms before you get down to details in the employment agreement and/or the medical practice sale agreement. For another, in most states certain LOI provisions are legally binding. For example, the document will most likely provide that each party is responsible for its own attorneys’ fees and for maintaining confidentiality during the negotiations, and that you will not negotiate with any other parties for some specified period of time. In most cases, such provisions are binding whether you go on to sign a formal contract or not.

When you receive an LOI, go through it carefully and identify areas of concern. The offering party will likely be in a rush to sign you up; but once you sign, you won’t be able to negotiate with anyone else for a while, which weakens your negotiating position. Regardless of what is said about time being “of the essence,” proceed slowly and with caution.

Bear in mind that employers and buyers never begin with their best offer. Unless you have been through this before, it is unlikely that you will know your value as an employee or the value of your practice, or what exactly you are entitled to ask for. Rather than signing something you don’t completely understand, explain to the offering party that you need time to consider and evaluate their offer.

This is the time to hire a competent medical attorney to do some due diligence on the offering party and review their offer, and to educate yourself about practice value and compensation benchmarks in your area. You and your counsel should assemble a list of things that you want changed in the LOI, then present them to the other side. They should be amenable to negotiation. If they are not (as was the case in the example presented earlier), you should reconsider whether you really want to be associated with that particular buyer or employer.

Once you have signed the LOI, experts say speed then works to your advantage. “Time kills all deals,” as one lawyer put it. “The longer it takes to close the transaction, the more that can go wrong.” The prospective employer or buyer could uncover information about you or your practice that decreases their perception of value, or economic conditions might change.

While speed is now important, and most of the core issues should already have been resolved in the LOI, don’t be afraid to ask for everything you want, whether it’s a better sale price, higher compensation, a favorable call schedule, more vacation time, or anything else. You won’t know what you can get if you don’t ask for it.

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

I recently received an email from a distraught physician. Several months previously, he had sold his practice to a large private equity-funded group. The terms spelled out in the group’s letter of intent (LOI) seemed ideal. He could continue running his office any way he wished, set his own hours and fees, and keep his employees. All his overhead expenses would disappear. His income would remain the same, maybe even increase. He signed it eagerly.

When he received the actual sale and employment contracts, none of the details promised in the LOI were included; but he figured that since they were spelled out in the LOI, which both he and the buyer had signed, he was covered. His attorney — a family friend with no experience in medical practice transactions — approved the documents.

The deal seemed too good to be true, and it was. The day after the sale closed, all his employees received termination notices. The group offered to rehire some of them, but at lower salaries and reduced benefits. (Most declined.) The new staffers he received were inadequately trained and unfamiliar with his standard office procedures. Patients complained that fees had increased substantially. His own compensation was contingent on meeting strict billing and performance goals. Malpractice premiums remained his responsibility. His office hours were lengthened to include evenings and Saturday mornings.

When he complained to the group that none of the things promised in the LOI had been delivered, he was informed that the LOI was not legally binding. In fact, the sale and employment contracts both clearly specified that they “replaced any previous written or oral agreements between the parties.”

There are some valuable lessons to be learned here. First, whether you are a young physician seeking a new job with a hospital or large practice, or an older one looking to sell an established practice, retain an attorney experienced in medical transactions early, before you sign anything, binding or not. Second, recognize that any promises made in an LOI must be spelled out in the employment and/or sale contract as well.

You might ask, if the terms in an LOI are not binding, why bother with one at all? For one thing, you want to make sure that you and your potential employer or buyer are on the same page with respect to major terms before you get down to details in the employment agreement and/or the medical practice sale agreement. For another, in most states certain LOI provisions are legally binding. For example, the document will most likely provide that each party is responsible for its own attorneys’ fees and for maintaining confidentiality during the negotiations, and that you will not negotiate with any other parties for some specified period of time. In most cases, such provisions are binding whether you go on to sign a formal contract or not.

When you receive an LOI, go through it carefully and identify areas of concern. The offering party will likely be in a rush to sign you up; but once you sign, you won’t be able to negotiate with anyone else for a while, which weakens your negotiating position. Regardless of what is said about time being “of the essence,” proceed slowly and with caution.

Bear in mind that employers and buyers never begin with their best offer. Unless you have been through this before, it is unlikely that you will know your value as an employee or the value of your practice, or what exactly you are entitled to ask for. Rather than signing something you don’t completely understand, explain to the offering party that you need time to consider and evaluate their offer.

This is the time to hire a competent medical attorney to do some due diligence on the offering party and review their offer, and to educate yourself about practice value and compensation benchmarks in your area. You and your counsel should assemble a list of things that you want changed in the LOI, then present them to the other side. They should be amenable to negotiation. If they are not (as was the case in the example presented earlier), you should reconsider whether you really want to be associated with that particular buyer or employer.

Once you have signed the LOI, experts say speed then works to your advantage. “Time kills all deals,” as one lawyer put it. “The longer it takes to close the transaction, the more that can go wrong.” The prospective employer or buyer could uncover information about you or your practice that decreases their perception of value, or economic conditions might change.

While speed is now important, and most of the core issues should already have been resolved in the LOI, don’t be afraid to ask for everything you want, whether it’s a better sale price, higher compensation, a favorable call schedule, more vacation time, or anything else. You won’t know what you can get if you don’t ask for it.

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

I recently received an email from a distraught physician. Several months previously, he had sold his practice to a large private equity-funded group. The terms spelled out in the group’s letter of intent (LOI) seemed ideal. He could continue running his office any way he wished, set his own hours and fees, and keep his employees. All his overhead expenses would disappear. His income would remain the same, maybe even increase. He signed it eagerly.

When he received the actual sale and employment contracts, none of the details promised in the LOI were included; but he figured that since they were spelled out in the LOI, which both he and the buyer had signed, he was covered. His attorney — a family friend with no experience in medical practice transactions — approved the documents.

The deal seemed too good to be true, and it was. The day after the sale closed, all his employees received termination notices. The group offered to rehire some of them, but at lower salaries and reduced benefits. (Most declined.) The new staffers he received were inadequately trained and unfamiliar with his standard office procedures. Patients complained that fees had increased substantially. His own compensation was contingent on meeting strict billing and performance goals. Malpractice premiums remained his responsibility. His office hours were lengthened to include evenings and Saturday mornings.

When he complained to the group that none of the things promised in the LOI had been delivered, he was informed that the LOI was not legally binding. In fact, the sale and employment contracts both clearly specified that they “replaced any previous written or oral agreements between the parties.”

There are some valuable lessons to be learned here. First, whether you are a young physician seeking a new job with a hospital or large practice, or an older one looking to sell an established practice, retain an attorney experienced in medical transactions early, before you sign anything, binding or not. Second, recognize that any promises made in an LOI must be spelled out in the employment and/or sale contract as well.

You might ask, if the terms in an LOI are not binding, why bother with one at all? For one thing, you want to make sure that you and your potential employer or buyer are on the same page with respect to major terms before you get down to details in the employment agreement and/or the medical practice sale agreement. For another, in most states certain LOI provisions are legally binding. For example, the document will most likely provide that each party is responsible for its own attorneys’ fees and for maintaining confidentiality during the negotiations, and that you will not negotiate with any other parties for some specified period of time. In most cases, such provisions are binding whether you go on to sign a formal contract or not.

When you receive an LOI, go through it carefully and identify areas of concern. The offering party will likely be in a rush to sign you up; but once you sign, you won’t be able to negotiate with anyone else for a while, which weakens your negotiating position. Regardless of what is said about time being “of the essence,” proceed slowly and with caution.

Bear in mind that employers and buyers never begin with their best offer. Unless you have been through this before, it is unlikely that you will know your value as an employee or the value of your practice, or what exactly you are entitled to ask for. Rather than signing something you don’t completely understand, explain to the offering party that you need time to consider and evaluate their offer.

This is the time to hire a competent medical attorney to do some due diligence on the offering party and review their offer, and to educate yourself about practice value and compensation benchmarks in your area. You and your counsel should assemble a list of things that you want changed in the LOI, then present them to the other side. They should be amenable to negotiation. If they are not (as was the case in the example presented earlier), you should reconsider whether you really want to be associated with that particular buyer or employer.

Once you have signed the LOI, experts say speed then works to your advantage. “Time kills all deals,” as one lawyer put it. “The longer it takes to close the transaction, the more that can go wrong.” The prospective employer or buyer could uncover information about you or your practice that decreases their perception of value, or economic conditions might change.

While speed is now important, and most of the core issues should already have been resolved in the LOI, don’t be afraid to ask for everything you want, whether it’s a better sale price, higher compensation, a favorable call schedule, more vacation time, or anything else. You won’t know what you can get if you don’t ask for it.

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

Pretreatment testing of patients starting systemic immunomodulatory therapies for chronic skin diseases fell short of recommendations, based on an analysis of more than 120,000 individuals in a national commercial insurance claims database.

Because of concerns for the potential reactivation of tuberculosis or hepatitis B or C, or for an increased risk for infections, myelosuppression, and hepatoxicity in the wake of immunomodulator use, some medical societies recommend screening patients for hepatitis B, hepatitis C, and tuberculosis before starting these medications, wrote Maria C. Schneeweiss, MD, of Brigham and Women’s Hospital, Boston, Massachusetts, and colleagues.

“Conducting this study was crucial because of the increasing use of systemic immunomodulatory agents for chronic inflammatory skin diseases and the recognized need for pretreatment testing to prevent complications,” coauthor Denys Shay, a PhD candidate in population health sciences at Harvard University, Cambridge, Massachusetts, said in an interview.

“Despite recommendations from professional societies, there was a lack of clarity on how consistently these guidelines were being followed in the United States. This study aimed to fill that gap in knowledge, providing a comprehensive view of current practices and highlighting areas for improvement,” he said.

In the study, published online in JAMA Dermatology, he and his coauthors identified 122,308 adults in the United States with psoriasis, hidradenitis suppurativa, or atopic dermatitis who started an immunomodulatory agent, including methotrexate (28,684 patients), tumor necrosis factor (TNF)–alpha inhibitors (40,965), ustekinumab (12,841), interleukin (IL)-23 inhibitors (6116), IL-17A inhibitors (9799), dupilumab (7787), and apremilast (16,116). The data were from a commercial insurance claims database from December 31, 2002, to December 31, 2020.

The primary outcome was the proportion of patients who underwent recommended screening lab tests including tuberculosis, hepatitis, liver function, complete blood cell counts (CBCs), and lipid panels within 6 months before treatment initiation and during the first 2 years of treatment. The median age of the study population was 49 years, and 52.1% were male.

A CBC was the most common pretreatment test across treatments, performed in 41%-69% of patients before starting treatment. Tuberculosis screening occurred in 11%-59% of patients within 6 months of initiating treatment, and 3%-26% had updated tests after 1 year. Similarly, 13%-41% of patients underwent hepatitis screening prior to treatment.

The highest levels of pretreatment testing occurred for TNF-alpha inhibitors, ustekinumab, IL-17A inhibitors, and IL-23 inhibitors, with similar patterns, while the lowest levels of testing occurred with apremilast and dupilumab.

Testing prevalence before starting apremilast and after a year of treatment was 15%-45% and 9%-36%, respectively. Testing before initiation and a year into treatment with dupilumab was 11%-41% and 3%-25%, respectively.

The findings were limited by several factors including the descriptive design, which does not allow for evaluation of the testing practices, the researchers said.

However, the results show the extent of patients with chronic inflammatory skin diseases (CISDs) who do not undergo pretreatment testing, and research is needed to create testing practices on the basis of recommendations for each agent and incorporating each patient’s history and clinical profile, they concluded.

“The finding that less than 60% of patients received recommended pretreatment testing was initially somewhat surprising,” Shay said in the interview. “However, the context provided by higher rates of baseline testing within the 6-12 months before treatment initiation and the potential for additional testing not captured by the dataset — such as hospital stays — suggests that the gap may not be as large as this estimate,” he said.

“The key message for clinicians is that there are considerable variations in laboratory testing practices with regard to the initiation of systemic immunomodulatory agents in patients with CISDs,” Shay said. “This represents a divergence from existing testing guidelines.”

“Further research is needed to understand the reasons for the variations in pretreatment testing practices and whether this heterogeneity affects patient outcomes,” he added.

Resist Routine Testing

The study findings represent a call to action in the form of ongoing assessment of the safety, clinical utility, and cost-effectiveness of pretreatment testing, wrote Clinton W. Enos, MD, Ana Ormaza Vera, MD, and Abby S. Van Voorhees, MD, of the Department of Dermatology, Eastern Virginia Medical School, Norfolk, Virginia, in an accompanying editorial.

The data in the current study suggesting less frequent laboratory testing compared with current guidelines could stem from a high comfort level with many of the therapies that have been available and in use for many years, they noted. Clinicians’ lack of knowledge of the laboratory screening and monitoring guidelines also may play a role, they said.

However, the authors cautioned against routine checking of laboratory results “without purpose” and without attention to their clinical utility and cost. “A thorough medical history is essential and can serve as a sensitive indicator of which patients are more at risk for diseases such as TB or hepatitis, thereby allowing for more meaningful laboratory screening use,” they said.

Evidence supporting prescreening labs for the spectrum of systemic agents used in dermatology varies considerably, “some trapped in time and carried forward for decades until finally questioned, others rooted in treatment mechanism and clinical data,” Adam Friedman, MD, professor and chief of dermatology at George Washington University, Washington, DC, said in an interview.

The study elucidated the current state of clinical practice, said Friedman, who was not involved with the study. This includes screening even if the label says it is not necessary and letting screening slide when guidelines say otherwise — even if the guidelines are outdated and insurance requires certain metrics prior to approval, he said.

Looking ahead, “we need better consensus and even better communication/education on said guidance,” Dr. Friedman said. “Clear, concise, evidenced-based, and expert-validated guidance to ensure we are meaningfully using medical resources” is what is needed, he added. “It will certainly take a village, and close collaboration between the industry and practitioners is key to success.”

The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Shay had no financial conflicts to disclose. Lead author Dr. Schneeweiss disclosed grants from UCB Pharma and AbbVie to Brigham and Women’s Hospital outside the submitted work. Other authors disclosed receiving personal fees from Aetion and grants from UCB Pharma and Takeda outside the submitted work; grants from Amarin, Kowa, Novartis, and Pfizer outside the submitted work; and personal fees from Hims & Hers, AbbVie, Sun Pharmaceuticals, Pfizer, Digital Diagnostics, Lilly, Equillium, ASLAN, Boehringer Ingelheim, ACOM, Olaplex, and Legacy Healthcare during the study. No other disclosures were reported.

Editorial author Dr. Enos disclosed serving as an investigator for Amgen and Castle Biosciences and receiving grants from Arcutis Biotherapeutics outside the submitted work. Dr. Van Voorhees disclosed an honorarium outside the submitted work.

Dr. Friedman had no relevant financial conflicts to disclose.

A version of this article appeared on Medscape.com.

Pretreatment testing of patients starting systemic immunomodulatory therapies for chronic skin diseases fell short of recommendations, based on an analysis of more than 120,000 individuals in a national commercial insurance claims database.

Because of concerns for the potential reactivation of tuberculosis or hepatitis B or C, or for an increased risk for infections, myelosuppression, and hepatoxicity in the wake of immunomodulator use, some medical societies recommend screening patients for hepatitis B, hepatitis C, and tuberculosis before starting these medications, wrote Maria C. Schneeweiss, MD, of Brigham and Women’s Hospital, Boston, Massachusetts, and colleagues.

“Conducting this study was crucial because of the increasing use of systemic immunomodulatory agents for chronic inflammatory skin diseases and the recognized need for pretreatment testing to prevent complications,” coauthor Denys Shay, a PhD candidate in population health sciences at Harvard University, Cambridge, Massachusetts, said in an interview.

“Despite recommendations from professional societies, there was a lack of clarity on how consistently these guidelines were being followed in the United States. This study aimed to fill that gap in knowledge, providing a comprehensive view of current practices and highlighting areas for improvement,” he said.

In the study, published online in JAMA Dermatology, he and his coauthors identified 122,308 adults in the United States with psoriasis, hidradenitis suppurativa, or atopic dermatitis who started an immunomodulatory agent, including methotrexate (28,684 patients), tumor necrosis factor (TNF)–alpha inhibitors (40,965), ustekinumab (12,841), interleukin (IL)-23 inhibitors (6116), IL-17A inhibitors (9799), dupilumab (7787), and apremilast (16,116). The data were from a commercial insurance claims database from December 31, 2002, to December 31, 2020.

The primary outcome was the proportion of patients who underwent recommended screening lab tests including tuberculosis, hepatitis, liver function, complete blood cell counts (CBCs), and lipid panels within 6 months before treatment initiation and during the first 2 years of treatment. The median age of the study population was 49 years, and 52.1% were male.

A CBC was the most common pretreatment test across treatments, performed in 41%-69% of patients before starting treatment. Tuberculosis screening occurred in 11%-59% of patients within 6 months of initiating treatment, and 3%-26% had updated tests after 1 year. Similarly, 13%-41% of patients underwent hepatitis screening prior to treatment.

The highest levels of pretreatment testing occurred for TNF-alpha inhibitors, ustekinumab, IL-17A inhibitors, and IL-23 inhibitors, with similar patterns, while the lowest levels of testing occurred with apremilast and dupilumab.

Testing prevalence before starting apremilast and after a year of treatment was 15%-45% and 9%-36%, respectively. Testing before initiation and a year into treatment with dupilumab was 11%-41% and 3%-25%, respectively.

The findings were limited by several factors including the descriptive design, which does not allow for evaluation of the testing practices, the researchers said.

However, the results show the extent of patients with chronic inflammatory skin diseases (CISDs) who do not undergo pretreatment testing, and research is needed to create testing practices on the basis of recommendations for each agent and incorporating each patient’s history and clinical profile, they concluded.

“The finding that less than 60% of patients received recommended pretreatment testing was initially somewhat surprising,” Shay said in the interview. “However, the context provided by higher rates of baseline testing within the 6-12 months before treatment initiation and the potential for additional testing not captured by the dataset — such as hospital stays — suggests that the gap may not be as large as this estimate,” he said.

“The key message for clinicians is that there are considerable variations in laboratory testing practices with regard to the initiation of systemic immunomodulatory agents in patients with CISDs,” Shay said. “This represents a divergence from existing testing guidelines.”

“Further research is needed to understand the reasons for the variations in pretreatment testing practices and whether this heterogeneity affects patient outcomes,” he added.

Resist Routine Testing

The study findings represent a call to action in the form of ongoing assessment of the safety, clinical utility, and cost-effectiveness of pretreatment testing, wrote Clinton W. Enos, MD, Ana Ormaza Vera, MD, and Abby S. Van Voorhees, MD, of the Department of Dermatology, Eastern Virginia Medical School, Norfolk, Virginia, in an accompanying editorial.

The data in the current study suggesting less frequent laboratory testing compared with current guidelines could stem from a high comfort level with many of the therapies that have been available and in use for many years, they noted. Clinicians’ lack of knowledge of the laboratory screening and monitoring guidelines also may play a role, they said.

However, the authors cautioned against routine checking of laboratory results “without purpose” and without attention to their clinical utility and cost. “A thorough medical history is essential and can serve as a sensitive indicator of which patients are more at risk for diseases such as TB or hepatitis, thereby allowing for more meaningful laboratory screening use,” they said.

Evidence supporting prescreening labs for the spectrum of systemic agents used in dermatology varies considerably, “some trapped in time and carried forward for decades until finally questioned, others rooted in treatment mechanism and clinical data,” Adam Friedman, MD, professor and chief of dermatology at George Washington University, Washington, DC, said in an interview.

The study elucidated the current state of clinical practice, said Friedman, who was not involved with the study. This includes screening even if the label says it is not necessary and letting screening slide when guidelines say otherwise — even if the guidelines are outdated and insurance requires certain metrics prior to approval, he said.

Looking ahead, “we need better consensus and even better communication/education on said guidance,” Dr. Friedman said. “Clear, concise, evidenced-based, and expert-validated guidance to ensure we are meaningfully using medical resources” is what is needed, he added. “It will certainly take a village, and close collaboration between the industry and practitioners is key to success.”

The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Shay had no financial conflicts to disclose. Lead author Dr. Schneeweiss disclosed grants from UCB Pharma and AbbVie to Brigham and Women’s Hospital outside the submitted work. Other authors disclosed receiving personal fees from Aetion and grants from UCB Pharma and Takeda outside the submitted work; grants from Amarin, Kowa, Novartis, and Pfizer outside the submitted work; and personal fees from Hims & Hers, AbbVie, Sun Pharmaceuticals, Pfizer, Digital Diagnostics, Lilly, Equillium, ASLAN, Boehringer Ingelheim, ACOM, Olaplex, and Legacy Healthcare during the study. No other disclosures were reported.

Editorial author Dr. Enos disclosed serving as an investigator for Amgen and Castle Biosciences and receiving grants from Arcutis Biotherapeutics outside the submitted work. Dr. Van Voorhees disclosed an honorarium outside the submitted work.

Dr. Friedman had no relevant financial conflicts to disclose.

A version of this article appeared on Medscape.com.

Pretreatment testing of patients starting systemic immunomodulatory therapies for chronic skin diseases fell short of recommendations, based on an analysis of more than 120,000 individuals in a national commercial insurance claims database.

Because of concerns for the potential reactivation of tuberculosis or hepatitis B or C, or for an increased risk for infections, myelosuppression, and hepatoxicity in the wake of immunomodulator use, some medical societies recommend screening patients for hepatitis B, hepatitis C, and tuberculosis before starting these medications, wrote Maria C. Schneeweiss, MD, of Brigham and Women’s Hospital, Boston, Massachusetts, and colleagues.

“Conducting this study was crucial because of the increasing use of systemic immunomodulatory agents for chronic inflammatory skin diseases and the recognized need for pretreatment testing to prevent complications,” coauthor Denys Shay, a PhD candidate in population health sciences at Harvard University, Cambridge, Massachusetts, said in an interview.

“Despite recommendations from professional societies, there was a lack of clarity on how consistently these guidelines were being followed in the United States. This study aimed to fill that gap in knowledge, providing a comprehensive view of current practices and highlighting areas for improvement,” he said.

In the study, published online in JAMA Dermatology, he and his coauthors identified 122,308 adults in the United States with psoriasis, hidradenitis suppurativa, or atopic dermatitis who started an immunomodulatory agent, including methotrexate (28,684 patients), tumor necrosis factor (TNF)–alpha inhibitors (40,965), ustekinumab (12,841), interleukin (IL)-23 inhibitors (6116), IL-17A inhibitors (9799), dupilumab (7787), and apremilast (16,116). The data were from a commercial insurance claims database from December 31, 2002, to December 31, 2020.

The primary outcome was the proportion of patients who underwent recommended screening lab tests including tuberculosis, hepatitis, liver function, complete blood cell counts (CBCs), and lipid panels within 6 months before treatment initiation and during the first 2 years of treatment. The median age of the study population was 49 years, and 52.1% were male.

A CBC was the most common pretreatment test across treatments, performed in 41%-69% of patients before starting treatment. Tuberculosis screening occurred in 11%-59% of patients within 6 months of initiating treatment, and 3%-26% had updated tests after 1 year. Similarly, 13%-41% of patients underwent hepatitis screening prior to treatment.

The highest levels of pretreatment testing occurred for TNF-alpha inhibitors, ustekinumab, IL-17A inhibitors, and IL-23 inhibitors, with similar patterns, while the lowest levels of testing occurred with apremilast and dupilumab.

Testing prevalence before starting apremilast and after a year of treatment was 15%-45% and 9%-36%, respectively. Testing before initiation and a year into treatment with dupilumab was 11%-41% and 3%-25%, respectively.

The findings were limited by several factors including the descriptive design, which does not allow for evaluation of the testing practices, the researchers said.

However, the results show the extent of patients with chronic inflammatory skin diseases (CISDs) who do not undergo pretreatment testing, and research is needed to create testing practices on the basis of recommendations for each agent and incorporating each patient’s history and clinical profile, they concluded.

“The finding that less than 60% of patients received recommended pretreatment testing was initially somewhat surprising,” Shay said in the interview. “However, the context provided by higher rates of baseline testing within the 6-12 months before treatment initiation and the potential for additional testing not captured by the dataset — such as hospital stays — suggests that the gap may not be as large as this estimate,” he said.

“The key message for clinicians is that there are considerable variations in laboratory testing practices with regard to the initiation of systemic immunomodulatory agents in patients with CISDs,” Shay said. “This represents a divergence from existing testing guidelines.”

“Further research is needed to understand the reasons for the variations in pretreatment testing practices and whether this heterogeneity affects patient outcomes,” he added.

Resist Routine Testing

The study findings represent a call to action in the form of ongoing assessment of the safety, clinical utility, and cost-effectiveness of pretreatment testing, wrote Clinton W. Enos, MD, Ana Ormaza Vera, MD, and Abby S. Van Voorhees, MD, of the Department of Dermatology, Eastern Virginia Medical School, Norfolk, Virginia, in an accompanying editorial.

The data in the current study suggesting less frequent laboratory testing compared with current guidelines could stem from a high comfort level with many of the therapies that have been available and in use for many years, they noted. Clinicians’ lack of knowledge of the laboratory screening and monitoring guidelines also may play a role, they said.

However, the authors cautioned against routine checking of laboratory results “without purpose” and without attention to their clinical utility and cost. “A thorough medical history is essential and can serve as a sensitive indicator of which patients are more at risk for diseases such as TB or hepatitis, thereby allowing for more meaningful laboratory screening use,” they said.

Evidence supporting prescreening labs for the spectrum of systemic agents used in dermatology varies considerably, “some trapped in time and carried forward for decades until finally questioned, others rooted in treatment mechanism and clinical data,” Adam Friedman, MD, professor and chief of dermatology at George Washington University, Washington, DC, said in an interview.

The study elucidated the current state of clinical practice, said Friedman, who was not involved with the study. This includes screening even if the label says it is not necessary and letting screening slide when guidelines say otherwise — even if the guidelines are outdated and insurance requires certain metrics prior to approval, he said.

Looking ahead, “we need better consensus and even better communication/education on said guidance,” Dr. Friedman said. “Clear, concise, evidenced-based, and expert-validated guidance to ensure we are meaningfully using medical resources” is what is needed, he added. “It will certainly take a village, and close collaboration between the industry and practitioners is key to success.”

The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Shay had no financial conflicts to disclose. Lead author Dr. Schneeweiss disclosed grants from UCB Pharma and AbbVie to Brigham and Women’s Hospital outside the submitted work. Other authors disclosed receiving personal fees from Aetion and grants from UCB Pharma and Takeda outside the submitted work; grants from Amarin, Kowa, Novartis, and Pfizer outside the submitted work; and personal fees from Hims & Hers, AbbVie, Sun Pharmaceuticals, Pfizer, Digital Diagnostics, Lilly, Equillium, ASLAN, Boehringer Ingelheim, ACOM, Olaplex, and Legacy Healthcare during the study. No other disclosures were reported.

Editorial author Dr. Enos disclosed serving as an investigator for Amgen and Castle Biosciences and receiving grants from Arcutis Biotherapeutics outside the submitted work. Dr. Van Voorhees disclosed an honorarium outside the submitted work.

Dr. Friedman had no relevant financial conflicts to disclose.

A version of this article appeared on Medscape.com.

The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) has issued a reminder to healthcare professionals regarding the potential serious adverse reactions associated with Paxlovid when administered in combination with specific immunosuppressants.

These immunosuppressants, encompassing calcineurin inhibitors (tacrolimus and ciclosporin) and mTOR inhibitors (everolimus and sirolimus), possess a narrow safe dosage range. They are recognized for their role in diminishing the activity of the immune system and are typically prescribed for autoimmune conditions and organ transplant recipients.

The highlighted risk arises due to drug-drug interactions, which can compromise the body’s ability to eliminate these medicines effectively.

Paxlovid, also known as nirmatrelvir with ritonavir, is an antiviral medication used to treat COVID-19 in adults who do not require supplemental oxygen and who are at an increased risk of progressing to severe COVID-19. It should be administered as soon as possible after a diagnosis of COVID-19 has been made and within 5 days of symptom onset.

Conditional marketing authorization for Paxlovid was granted across the European Union (EU) on January 28, 2022, and subsequently transitioned to full marketing authorization on February 24, 2023.

Developed by Pfizer, Paxlovid exhibited an 89% reduction in the risk for hospitalization or death among unvaccinated individuals in a phase 2-3 clinical trial. This led the National Institutes of Health to prioritize Paxlovid over other COVID-19 treatments. Subsequent real-world studies have affirmed its effectiveness, even among the vaccinated.

When combining Paxlovid with tacrolimus, ciclosporin, everolimus, or sirolimus, healthcare professionals need to actively monitor their blood levels. This proactive approach is essential to mitigate the risk for drug-drug interactions and potential serious reactions. They should collaborate with a multidisciplinary team of specialists to navigate the complexities of administering these medications concurrently.

Further, Paxlovid must not be coadministered with medications highly reliant on CYP3A liver enzymes for elimination, such as the immunosuppressant voclosporin. When administered together, there is a risk for these drugs interfering with each other’s metabolism, potentially leading to altered blood levels, reduced effectiveness, or an increased risk for adverse reactions.

After a thorough review, PRAC has highlighted potential serious adverse reactions, including fatal cases, due to drug interactions between Paxlovid and specified immunosuppressants. Thus, it issued a direct healthcare professional communication (DHPC) to emphasize the recognized risk for these interactions, as previously outlined in Paxlovid’s product information.

The DHPC for Paxlovid will undergo further evaluation by EMA’s Committee for Medicinal Products for Human Use and, upon adoption, will be disseminated to healthcare professionals. The communication plan will include publication on the DHPCs page and in national registers across EU Member States.

A version of this article appeared on Medscape.com.

The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) has issued a reminder to healthcare professionals regarding the potential serious adverse reactions associated with Paxlovid when administered in combination with specific immunosuppressants.

These immunosuppressants, encompassing calcineurin inhibitors (tacrolimus and ciclosporin) and mTOR inhibitors (everolimus and sirolimus), possess a narrow safe dosage range. They are recognized for their role in diminishing the activity of the immune system and are typically prescribed for autoimmune conditions and organ transplant recipients.

The highlighted risk arises due to drug-drug interactions, which can compromise the body’s ability to eliminate these medicines effectively.

Paxlovid, also known as nirmatrelvir with ritonavir, is an antiviral medication used to treat COVID-19 in adults who do not require supplemental oxygen and who are at an increased risk of progressing to severe COVID-19. It should be administered as soon as possible after a diagnosis of COVID-19 has been made and within 5 days of symptom onset.

Conditional marketing authorization for Paxlovid was granted across the European Union (EU) on January 28, 2022, and subsequently transitioned to full marketing authorization on February 24, 2023.

Developed by Pfizer, Paxlovid exhibited an 89% reduction in the risk for hospitalization or death among unvaccinated individuals in a phase 2-3 clinical trial. This led the National Institutes of Health to prioritize Paxlovid over other COVID-19 treatments. Subsequent real-world studies have affirmed its effectiveness, even among the vaccinated.

When combining Paxlovid with tacrolimus, ciclosporin, everolimus, or sirolimus, healthcare professionals need to actively monitor their blood levels. This proactive approach is essential to mitigate the risk for drug-drug interactions and potential serious reactions. They should collaborate with a multidisciplinary team of specialists to navigate the complexities of administering these medications concurrently.

Further, Paxlovid must not be coadministered with medications highly reliant on CYP3A liver enzymes for elimination, such as the immunosuppressant voclosporin. When administered together, there is a risk for these drugs interfering with each other’s metabolism, potentially leading to altered blood levels, reduced effectiveness, or an increased risk for adverse reactions.

After a thorough review, PRAC has highlighted potential serious adverse reactions, including fatal cases, due to drug interactions between Paxlovid and specified immunosuppressants. Thus, it issued a direct healthcare professional communication (DHPC) to emphasize the recognized risk for these interactions, as previously outlined in Paxlovid’s product information.

The DHPC for Paxlovid will undergo further evaluation by EMA’s Committee for Medicinal Products for Human Use and, upon adoption, will be disseminated to healthcare professionals. The communication plan will include publication on the DHPCs page and in national registers across EU Member States.

A version of this article appeared on Medscape.com.

The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) has issued a reminder to healthcare professionals regarding the potential serious adverse reactions associated with Paxlovid when administered in combination with specific immunosuppressants.

These immunosuppressants, encompassing calcineurin inhibitors (tacrolimus and ciclosporin) and mTOR inhibitors (everolimus and sirolimus), possess a narrow safe dosage range. They are recognized for their role in diminishing the activity of the immune system and are typically prescribed for autoimmune conditions and organ transplant recipients.

The highlighted risk arises due to drug-drug interactions, which can compromise the body’s ability to eliminate these medicines effectively.

Paxlovid, also known as nirmatrelvir with ritonavir, is an antiviral medication used to treat COVID-19 in adults who do not require supplemental oxygen and who are at an increased risk of progressing to severe COVID-19. It should be administered as soon as possible after a diagnosis of COVID-19 has been made and within 5 days of symptom onset.

Conditional marketing authorization for Paxlovid was granted across the European Union (EU) on January 28, 2022, and subsequently transitioned to full marketing authorization on February 24, 2023.

Developed by Pfizer, Paxlovid exhibited an 89% reduction in the risk for hospitalization or death among unvaccinated individuals in a phase 2-3 clinical trial. This led the National Institutes of Health to prioritize Paxlovid over other COVID-19 treatments. Subsequent real-world studies have affirmed its effectiveness, even among the vaccinated.

When combining Paxlovid with tacrolimus, ciclosporin, everolimus, or sirolimus, healthcare professionals need to actively monitor their blood levels. This proactive approach is essential to mitigate the risk for drug-drug interactions and potential serious reactions. They should collaborate with a multidisciplinary team of specialists to navigate the complexities of administering these medications concurrently.

Further, Paxlovid must not be coadministered with medications highly reliant on CYP3A liver enzymes for elimination, such as the immunosuppressant voclosporin. When administered together, there is a risk for these drugs interfering with each other’s metabolism, potentially leading to altered blood levels, reduced effectiveness, or an increased risk for adverse reactions.

After a thorough review, PRAC has highlighted potential serious adverse reactions, including fatal cases, due to drug interactions between Paxlovid and specified immunosuppressants. Thus, it issued a direct healthcare professional communication (DHPC) to emphasize the recognized risk for these interactions, as previously outlined in Paxlovid’s product information.

The DHPC for Paxlovid will undergo further evaluation by EMA’s Committee for Medicinal Products for Human Use and, upon adoption, will be disseminated to healthcare professionals. The communication plan will include publication on the DHPCs page and in national registers across EU Member States.

A version of this article appeared on Medscape.com.

“You’ll never walk alone.” — Nettie Fowler, Carousel

A few winters ago, a young man and his fiancée were driving on the 91 freeway in southern California during a torrential downpour when their Honda Civic hydroplaned, slamming into the jersey barrier. They were both unhurt. Unsure what to do next, they made the catastrophic decision to exit the vehicle. As the man walked around the back of the car he was nearly hit by a black sedan sliding out of control trying to avoid them. When he came around the car, his fiancé was nowhere to be found. She had been struck at highway speed and lay crushed under the sedan hundreds of feet away.

I know this poor man because he was referred to me. Not as a dermatologist, but as a fellow human healing from trauma. On January 1, 2019, at about 9:30 PM, while we were home together, my beloved wife of 24 years took her own life. Even 5 years on it is difficult to believe that she isn’t proofing this paragraph like she had done for every one of my Derm News columns for years. We had been together since teenagers and had lived a joy-filled life. As anyone who has lost a loved one to suicide knows, it is an unknowable, fatal disease. Very few of my patients know my story. There isn’t any medical reason to share. But that day I joined the community of those who have carried unbearable heaviness of grief and survived. Sometimes others seek me out for help.

Kaiser Permanente

At first, my instinct was to guide them, to give advice, to tell them what to do and where to go. But I’ve learned that people in this dark valley don’t need a guide. They need someone to accompany them. To walk with them for a few minutes on their lonely journey. I recently read David Brooks’s new book, How to Know a Person. I’ve been a fan of his since he joined the New York Times in 2003 and have read almost everything he’s written. I sometimes even imagine how he might approach a column whenever I’m stuck (thank you, David). His The Road to Character book is in my canon of literature for self-growth. This latest book is an interesting digression from that central theme. He argues that our society is in acute need of forming better connections and that an important way we can be moral is to learn, and to practice, how to know each other. He shares an emotional experience of losing a close friend to suicide and writes a poignant explanation of what it means to accompany someone in need. It particularly resonated with me. We are doctors and are wired to find the source of a problem, like quickly rotating through the 4X, 10X, 40X on a microscope. Once identified, we spend most of our time creating and explaining treatments. I see how this makes me a great dermatologist but just an average human.

Brooks tells the story of a woman with a brain tumor who often finds herself on the ground surrounded by well-meaning people trying to help. She explains later that what she really needs in those moments is just for someone to get on the ground and lie with her. To accompany her.

Having crossed the midpoint of life, I see with the benefit of perspective how suffering has afforded me wisdom: I am more sensitive and attuned to others. It also gave me credibility: I know how it feels to walk life’s loneliest journey. I’ve also learned to make myself vulnerable for someone to share their story with me. I won’t be afraid to hear the details. I won’t judge them for weeping too little or for sobbing too much. I don’t answer whys. I won’t say what they should do next. But for a few minutes I can walk beside them as a person who cares.

Courtesy Jeffrey Benabio, MD

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

“You’ll never walk alone.” — Nettie Fowler, Carousel

A few winters ago, a young man and his fiancée were driving on the 91 freeway in southern California during a torrential downpour when their Honda Civic hydroplaned, slamming into the jersey barrier. They were both unhurt. Unsure what to do next, they made the catastrophic decision to exit the vehicle. As the man walked around the back of the car he was nearly hit by a black sedan sliding out of control trying to avoid them. When he came around the car, his fiancé was nowhere to be found. She had been struck at highway speed and lay crushed under the sedan hundreds of feet away.

I know this poor man because he was referred to me. Not as a dermatologist, but as a fellow human healing from trauma. On January 1, 2019, at about 9:30 PM, while we were home together, my beloved wife of 24 years took her own life. Even 5 years on it is difficult to believe that she isn’t proofing this paragraph like she had done for every one of my Derm News columns for years. We had been together since teenagers and had lived a joy-filled life. As anyone who has lost a loved one to suicide knows, it is an unknowable, fatal disease. Very few of my patients know my story. There isn’t any medical reason to share. But that day I joined the community of those who have carried unbearable heaviness of grief and survived. Sometimes others seek me out for help.

Kaiser Permanente

At first, my instinct was to guide them, to give advice, to tell them what to do and where to go. But I’ve learned that people in this dark valley don’t need a guide. They need someone to accompany them. To walk with them for a few minutes on their lonely journey. I recently read David Brooks’s new book, How to Know a Person. I’ve been a fan of his since he joined the New York Times in 2003 and have read almost everything he’s written. I sometimes even imagine how he might approach a column whenever I’m stuck (thank you, David). His The Road to Character book is in my canon of literature for self-growth. This latest book is an interesting digression from that central theme. He argues that our society is in acute need of forming better connections and that an important way we can be moral is to learn, and to practice, how to know each other. He shares an emotional experience of losing a close friend to suicide and writes a poignant explanation of what it means to accompany someone in need. It particularly resonated with me. We are doctors and are wired to find the source of a problem, like quickly rotating through the 4X, 10X, 40X on a microscope. Once identified, we spend most of our time creating and explaining treatments. I see how this makes me a great dermatologist but just an average human.

Brooks tells the story of a woman with a brain tumor who often finds herself on the ground surrounded by well-meaning people trying to help. She explains later that what she really needs in those moments is just for someone to get on the ground and lie with her. To accompany her.

Having crossed the midpoint of life, I see with the benefit of perspective how suffering has afforded me wisdom: I am more sensitive and attuned to others. It also gave me credibility: I know how it feels to walk life’s loneliest journey. I’ve also learned to make myself vulnerable for someone to share their story with me. I won’t be afraid to hear the details. I won’t judge them for weeping too little or for sobbing too much. I don’t answer whys. I won’t say what they should do next. But for a few minutes I can walk beside them as a person who cares.

Courtesy Jeffrey Benabio, MD

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

“You’ll never walk alone.” — Nettie Fowler, Carousel

A few winters ago, a young man and his fiancée were driving on the 91 freeway in southern California during a torrential downpour when their Honda Civic hydroplaned, slamming into the jersey barrier. They were both unhurt. Unsure what to do next, they made the catastrophic decision to exit the vehicle. As the man walked around the back of the car he was nearly hit by a black sedan sliding out of control trying to avoid them. When he came around the car, his fiancé was nowhere to be found. She had been struck at highway speed and lay crushed under the sedan hundreds of feet away.

I know this poor man because he was referred to me. Not as a dermatologist, but as a fellow human healing from trauma. On January 1, 2019, at about 9:30 PM, while we were home together, my beloved wife of 24 years took her own life. Even 5 years on it is difficult to believe that she isn’t proofing this paragraph like she had done for every one of my Derm News columns for years. We had been together since teenagers and had lived a joy-filled life. As anyone who has lost a loved one to suicide knows, it is an unknowable, fatal disease. Very few of my patients know my story. There isn’t any medical reason to share. But that day I joined the community of those who have carried unbearable heaviness of grief and survived. Sometimes others seek me out for help.

Kaiser Permanente

At first, my instinct was to guide them, to give advice, to tell them what to do and where to go. But I’ve learned that people in this dark valley don’t need a guide. They need someone to accompany them. To walk with them for a few minutes on their lonely journey. I recently read David Brooks’s new book, How to Know a Person. I’ve been a fan of his since he joined the New York Times in 2003 and have read almost everything he’s written. I sometimes even imagine how he might approach a column whenever I’m stuck (thank you, David). His The Road to Character book is in my canon of literature for self-growth. This latest book is an interesting digression from that central theme. He argues that our society is in acute need of forming better connections and that an important way we can be moral is to learn, and to practice, how to know each other. He shares an emotional experience of losing a close friend to suicide and writes a poignant explanation of what it means to accompany someone in need. It particularly resonated with me. We are doctors and are wired to find the source of a problem, like quickly rotating through the 4X, 10X, 40X on a microscope. Once identified, we spend most of our time creating and explaining treatments. I see how this makes me a great dermatologist but just an average human.

Brooks tells the story of a woman with a brain tumor who often finds herself on the ground surrounded by well-meaning people trying to help. She explains later that what she really needs in those moments is just for someone to get on the ground and lie with her. To accompany her.

Having crossed the midpoint of life, I see with the benefit of perspective how suffering has afforded me wisdom: I am more sensitive and attuned to others. It also gave me credibility: I know how it feels to walk life’s loneliest journey. I’ve also learned to make myself vulnerable for someone to share their story with me. I won’t be afraid to hear the details. I won’t judge them for weeping too little or for sobbing too much. I don’t answer whys. I won’t say what they should do next. But for a few minutes I can walk beside them as a person who cares.

Courtesy Jeffrey Benabio, MD

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

Obesity and diabetes increase the risk for complications following joint surgeries like total hip replacement, but can semaglutide and related drugs help?

The question has massive implications. More than 450,000 total hip arthroplasty (THA) procedures are performed annually in the United States, with the number expected to grow to 850,000 by 2030. Obesity is the leading reason for the increase. Semaglutide and other glucagon-like peptide 1 (GLP-1) receptor agonists can lead to dramatic and rapid weight loss, in addition to controlling diabetes, so researchers have wondered if the medications might improve outcomes in patients undergoing joint surgery. 

Two studies presented at the 2024 annual meeting of the American Academy of Orthopaedic Surgeons (AAOS) sought to answer the question — but reached different conclusions. 

One study of THA patients taking semaglutide found fewer 90-day readmissions for diabetes and fewer prosthetic joint infections at the 2-year mark. Another found similar outcomes on the need for revision surgery, infections, and many other postsurgery metrics in people who took the GLP-1 receptor agonist and those who did not. Neither study had outside funding.
 

Study: Fewer Infections, Readmissions

For their study, Matthew Magruder, MD, a third-year orthopedic resident at Maimonides Medical Center’s Department of Orthopaedic Surgery and Rehabilitation in New York City, and his colleagues used an administrative claim database (PearlDiver) to identify THA patients who underwent the surgery between January 1, 2020, to October 31, 2021, when semaglutide was approved for the treatment of diabetes but not yet for obesity. The researchers found 9465 patients who had had a primary THA, of whom 1653 had received a prescription for semaglutide.

In total, 84.9% of those on semaglutide had obesity, as did 85.2% of those not on the medication.

Dr. Magruder’s group looked at medical complications such as deep vein thrombosis, myocardial infarction, hypoglycemia, and pulmonary embolism within 90 days of surgery, implant-related complications 2 years after the procedure, rates of readmission within 90 days of the procedure, length of stay in the hospital, and costs of care. 

They found that patients taking semaglutide were less likely to be readmitted to the hospital within 90 days of THA (6.2% vs 8.8%; P <.01) and experienced fewer joint infections (1.6% vs 2.9%; P <.01). No significant differences were found in the other outcomes.

Among the potential concerns involving the use of GLP-1 receptor agonists in patients undergoing surgery are their potential to cause hypoglycemia and the risk for aspiration during anesthesia. But those issues did not emerge in the analysis.

“We concluded that this was preliminary evidence that using semaglutide at the time of surgery was safe and potentially effective at reducing complications,” said Dr. Magruder, whose team published their findings in The Journal of Arthroplasty.
 

Study: Semaglutide Has No Effect on Postop Complications

In another study presented at the AAOS meeting, researchers found that rates of complications after THA were similar in patients with obesity who took semaglutide and those who did not. That information could be helpful for clinicians who have been reluctant to perform THA procedures in patients who also have had bariatric surgery, said Daniel E. Pereira, MD, a resident at Washington University in St. Louis and the first author of the study.

A recent retrospective review found that patients who had bariatric surgery have worse implant survivorship and higher rates of dislocation than do those with a naturally low or high body mass index (BMI). 

Pereira and his colleagues used a national database, with deidentified patient records, originally finding 42,410 patients. After matching, they evaluated 616 in each cohort: those who took semaglutide and those who did not. The average age was 62.7 years; average BMI was 35.5. 

Both groups had a similar risk for a range of complications including revision surgery, infection of the new joint and surgical site, opioid-related disorders, pulmonary embolism, deep vein thrombosis, and mortality. 

“We didn’t observe anything significant [between groups] in terms of the complications,” said David Momtaz, MPH, a fourth-year medical student at the University of Texas Health Science Center at San Antonio, who helped conduct the research. 

Dr. Pereira said he hoped the results would end the hesitation he observes, partly due to a lack of research, among some physicians about prescribing semaglutide before THA in appropriate patients. “Our preliminary evidence suggests there is no need to withhold THA in patients who successfully lost weight on semaglutide,” he said.
 

Expert Perspective: Not Unexpected

Peter Hanson, MD, an orthopedic surgeon and orthopedic medical director at Sharp Grossmont Hospital in La Mesa, California, who specializes in hip and knee replacement, said he was unsurprised by the findings. 

The patients he has observed on GLP-1 receptor agonists lose weight, he said, and a few even to the point of not needing a replacement. A recent study found that every 1% decrease in weight was associated with a 2% reduced risk for knee replacement in those with knee osteoarthritis or at risk for it, and every 1% drop in weight was associated with a 3% reduced risk for THA.

“I always advise my overweight patient to lose at least 30 pounds, even if their BMI is less than 40, like many in these studies,” Dr. Hanson said. If a patient’s doctor prescribes semaglutide or another GLP-1 receptor agonist, “I am very supportive, and we postpone surgery until the weight loss is maximized,” he added.

Drs. Magruder, Pereira, Momtaz, and Hanson have no disclosures.

A version of this article appeared on Medscape.com.