Rheumatology

TOPLINE:

Continued denosumab treatment is associated with a lower risk for diabetes in adults with osteoporosis older than 65 years, found a large-scale cohort study in Taiwan.

METHODOLOGY:

• Denosumab, used in osteoporosis treatment, has been suggested to improve glycemic parameters, but clinical evidence of its effects on diabetes risk is limited and inconsistent.
• Using data from Taiwan’s National Health Insurance Research Database (NHIRD), the study asked if continued denosumab treatment (60 mg) for osteoporosis reduced the risk for diabetes compared to those who discontinued denosumab.
• Researchers included all new users of denosumab between 2012 and 2019 who had no prior history of malignant neoplasms, Paget disease, or diabetes requiring antidiabetic medication.
• Patients in the treatment group (n = 34,255), who received a second dose of denosumab within 225 days, were 1:1 propensity matched with a control group (n = 34,255) of patients who had discontinued denosumab after the first dose.
• The 68,510 patients (mean age, 77.7 years; 84.3% women) were followed up for a mean of 1.9 years. The primary outcome was new-onset diabetes that required treatment with any antidiabetic drug.

TAKEAWAY:

• Continued denosumab treatment vs its discontinuation was associated with a lower risk for incident diabetes (hazard ratio [HR], 0.84; 95% CI, 0.78-0.90).
• In patients aged 65 years or older who were on continued treatment of denosumab, the risk for diabetes was lower (HR, 0.80; 95% CI, 0.75-0.85) but not among those younger than 65 years.
• A reduced risk for diabetes with continued denosumab treatment was observed in both men (HR, 0.85; 95% CI, 0.73-0.97) and women (HR, 0.81; 95% CI, 0.76-0.86).
• Lower diabetes risk with continued denosumab treatment was observed regardless of comorbidities, such as dyslipidemia, hypertension, ischemic heart disease, or kidney failure.

IN PRACTICE:

“Given the high osteoporosis prevalence, the extensive use of antiosteoporosis medications, and the negative effect of diabetes on both patient health and healthcare system burdens in the global aging population, our findings possess substantial clinical and public health significance,” the authors wrote.

SOURCE:

This study was led by Huei-Kai Huang, MD, Department of Family Medicine and Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, and published online in JAMA Network Open.

LIMITATIONS:

The research used claims-based data, so some clinical details, such as lifestyle, substance use, prediabetes weight status, and laboratory results, were not included. Owing to the anonymity policy of the NHIRD, patients could not be directly evaluated to validate incident diabetes. The study included the Taiwanese population, so the findings may not be generalizable to other populations. In Taiwan, the threshold for reimbursement of initiating denosumab treatment for osteoporosis includes below-normal bone density scores and a hip or vertebral fracture.

DISCLOSURES:

This study was supported by grants from the National Science and Technology Council of Taiwan and the National Health Research Institutes of Taiwan and a grant from the Buddhist Tzu Chi Medical Foundation. The corresponding author and a coauthor disclosed receiving funds from Amgen, Novartis, Pfizer, Sanofi, Takeda, and AbbVie, all outside the submitted work.

A version of this article appeared on Medscape.com.

TOPLINE:

Continued denosumab treatment is associated with a lower risk for diabetes in adults with osteoporosis older than 65 years, found a large-scale cohort study in Taiwan.

METHODOLOGY:

• Denosumab, used in osteoporosis treatment, has been suggested to improve glycemic parameters, but clinical evidence of its effects on diabetes risk is limited and inconsistent.
• Using data from Taiwan’s National Health Insurance Research Database (NHIRD), the study asked if continued denosumab treatment (60 mg) for osteoporosis reduced the risk for diabetes compared to those who discontinued denosumab.
• Researchers included all new users of denosumab between 2012 and 2019 who had no prior history of malignant neoplasms, Paget disease, or diabetes requiring antidiabetic medication.
• Patients in the treatment group (n = 34,255), who received a second dose of denosumab within 225 days, were 1:1 propensity matched with a control group (n = 34,255) of patients who had discontinued denosumab after the first dose.
• The 68,510 patients (mean age, 77.7 years; 84.3% women) were followed up for a mean of 1.9 years. The primary outcome was new-onset diabetes that required treatment with any antidiabetic drug.

TAKEAWAY:

• Continued denosumab treatment vs its discontinuation was associated with a lower risk for incident diabetes (hazard ratio [HR], 0.84; 95% CI, 0.78-0.90).
• In patients aged 65 years or older who were on continued treatment of denosumab, the risk for diabetes was lower (HR, 0.80; 95% CI, 0.75-0.85) but not among those younger than 65 years.
• A reduced risk for diabetes with continued denosumab treatment was observed in both men (HR, 0.85; 95% CI, 0.73-0.97) and women (HR, 0.81; 95% CI, 0.76-0.86).
• Lower diabetes risk with continued denosumab treatment was observed regardless of comorbidities, such as dyslipidemia, hypertension, ischemic heart disease, or kidney failure.

IN PRACTICE:

“Given the high osteoporosis prevalence, the extensive use of antiosteoporosis medications, and the negative effect of diabetes on both patient health and healthcare system burdens in the global aging population, our findings possess substantial clinical and public health significance,” the authors wrote.

SOURCE:

This study was led by Huei-Kai Huang, MD, Department of Family Medicine and Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, and published online in JAMA Network Open.

LIMITATIONS:

The research used claims-based data, so some clinical details, such as lifestyle, substance use, prediabetes weight status, and laboratory results, were not included. Owing to the anonymity policy of the NHIRD, patients could not be directly evaluated to validate incident diabetes. The study included the Taiwanese population, so the findings may not be generalizable to other populations. In Taiwan, the threshold for reimbursement of initiating denosumab treatment for osteoporosis includes below-normal bone density scores and a hip or vertebral fracture.

DISCLOSURES:

This study was supported by grants from the National Science and Technology Council of Taiwan and the National Health Research Institutes of Taiwan and a grant from the Buddhist Tzu Chi Medical Foundation. The corresponding author and a coauthor disclosed receiving funds from Amgen, Novartis, Pfizer, Sanofi, Takeda, and AbbVie, all outside the submitted work.

A version of this article appeared on Medscape.com.

TOPLINE:

Continued denosumab treatment is associated with a lower risk for diabetes in adults with osteoporosis older than 65 years, found a large-scale cohort study in Taiwan.

METHODOLOGY:

• Denosumab, used in osteoporosis treatment, has been suggested to improve glycemic parameters, but clinical evidence of its effects on diabetes risk is limited and inconsistent.
• Using data from Taiwan’s National Health Insurance Research Database (NHIRD), the study asked if continued denosumab treatment (60 mg) for osteoporosis reduced the risk for diabetes compared to those who discontinued denosumab.
• Researchers included all new users of denosumab between 2012 and 2019 who had no prior history of malignant neoplasms, Paget disease, or diabetes requiring antidiabetic medication.
• Patients in the treatment group (n = 34,255), who received a second dose of denosumab within 225 days, were 1:1 propensity matched with a control group (n = 34,255) of patients who had discontinued denosumab after the first dose.
• The 68,510 patients (mean age, 77.7 years; 84.3% women) were followed up for a mean of 1.9 years. The primary outcome was new-onset diabetes that required treatment with any antidiabetic drug.

TAKEAWAY:

• Continued denosumab treatment vs its discontinuation was associated with a lower risk for incident diabetes (hazard ratio [HR], 0.84; 95% CI, 0.78-0.90).
• In patients aged 65 years or older who were on continued treatment of denosumab, the risk for diabetes was lower (HR, 0.80; 95% CI, 0.75-0.85) but not among those younger than 65 years.
• A reduced risk for diabetes with continued denosumab treatment was observed in both men (HR, 0.85; 95% CI, 0.73-0.97) and women (HR, 0.81; 95% CI, 0.76-0.86).
• Lower diabetes risk with continued denosumab treatment was observed regardless of comorbidities, such as dyslipidemia, hypertension, ischemic heart disease, or kidney failure.

IN PRACTICE:

“Given the high osteoporosis prevalence, the extensive use of antiosteoporosis medications, and the negative effect of diabetes on both patient health and healthcare system burdens in the global aging population, our findings possess substantial clinical and public health significance,” the authors wrote.

SOURCE:

This study was led by Huei-Kai Huang, MD, Department of Family Medicine and Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, and published online in JAMA Network Open.

LIMITATIONS:

The research used claims-based data, so some clinical details, such as lifestyle, substance use, prediabetes weight status, and laboratory results, were not included. Owing to the anonymity policy of the NHIRD, patients could not be directly evaluated to validate incident diabetes. The study included the Taiwanese population, so the findings may not be generalizable to other populations. In Taiwan, the threshold for reimbursement of initiating denosumab treatment for osteoporosis includes below-normal bone density scores and a hip or vertebral fracture.

DISCLOSURES:

This study was supported by grants from the National Science and Technology Council of Taiwan and the National Health Research Institutes of Taiwan and a grant from the Buddhist Tzu Chi Medical Foundation. The corresponding author and a coauthor disclosed receiving funds from Amgen, Novartis, Pfizer, Sanofi, Takeda, and AbbVie, all outside the submitted work.

A version of this article appeared on Medscape.com.

TOPLINE:

Many factors may influence fatigue in patients with psoriasis and psoriatic arthritis (PsA), researchers report.

METHODOLOGY:

• The individual components of fatigue in psoriasis and PsA have not been examined thoroughly.
• Researchers drew from the nationwide prospective Danish Skin Cohort to identify 2741 adults with dermatologist-diagnosed psoriasis (of which 593 also had PsA) and 3788 controls in the general population.
• All adults in the analysis completed the multidimensional fatigue inventory (MIF-20), a validated 20-item tool that measures five dimensions of fatigue: General fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue. A higher score indicates more severe fatigue.
• All adults were also asked about their current intensity of joint pain over the previous 7 days, severity of pruritus and skin pain over the previous 24 hours, and sleep problems over the previous 72 hours on a numerical rating scale (NRS). The researchers applied linear regression models to continuous outcomes and adjusted for age, sex, socioeconomic status, psoriasis severity, and joint pain intensity, and beta coefficients (β) for the slopes were estimated with 95% CIs.

TAKEAWAY:

• Compared with the general population, higher total MFI-20 scores were observed for psoriasis and PsA, respectively. However, on the adjusted analysis, the impact on total fatigue was greatest for those with PsA (β = 5.23; 95% CI, 3.55-6.90), followed by psoriasis (β = 2.10; 95% CI, 0.96-3.25) compared with the general population (P trend < .0001).
• Increasing age was associated with a lower impact on total fatigue in psoriasis (β = −0.13; 95% CI, −0.18 to −0.08) and in PsA (β = −0.10; 95% CI, −0.19 to −0.01).
• Among patients with psoriasis with or without PsA, increasing joint pain intensity was associated with overall fatigue (β = 2.23; 95% CI, 2.03-2.44) for each one-point increase in joint pain on the NRS.
• In other findings, greater intensity of itch was associated with higher fatigue scores for both psoriasis and PsA, while skin pain was significantly associated with fatigue in PsA (β = 0.65; 95% CI, 0.08-1.22) but not in psoriasis without PsA (P = .2043).

IN PRACTICE:

“The observation that joint pain and itch, rather than psoriasis severity, appear to be major drivers of fatigue in psoriasis and PsA highlights the importance of a symptom-based approach when treating psoriasis, rather than focusing on objective severity measures alone,” the authors wrote.

SOURCE:

Corresponding author Alexander Egeberg, MD, of the Department of Dermatology at Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark, and colleagues conducted the research, which was published in the Journal of the American Academy of Dermatology.

LIMITATIONS:

The researchers were unable to assess whether the pain was inflammatory or noninflammatory or the number of affected joints. They also lacked information about the use of methotrexate, which commonly causes fatigue.

DISCLOSURES:

Dr. Egeberg is now an employee at LEO Pharma. He has received research funding from Pfizer, Eli Lilly, the Danish National Psoriasis Foundation, and the Royal Hofbundtmager Aage Bang Foundation, and honoraria as a consultant and/or speaker from AbbVie, Almirall, Bristol-Myers Squibb, Leo Pharma, Samsung Bioepis Co., Ltd., Pfizer, Eli Lilly, Novartis, UCB, Union Therapeutics, Horizon Therapeutics, Galderma, and Janssen Pharmaceuticals. Three of the coauthors reported being a consultant to, an adviser for, and/or having received research support from many pharmaceutical companies.

A version of this article appeared on Medscape.com.

TOPLINE:

Many factors may influence fatigue in patients with psoriasis and psoriatic arthritis (PsA), researchers report.

METHODOLOGY:

• The individual components of fatigue in psoriasis and PsA have not been examined thoroughly.
• Researchers drew from the nationwide prospective Danish Skin Cohort to identify 2741 adults with dermatologist-diagnosed psoriasis (of which 593 also had PsA) and 3788 controls in the general population.
• All adults in the analysis completed the multidimensional fatigue inventory (MIF-20), a validated 20-item tool that measures five dimensions of fatigue: General fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue. A higher score indicates more severe fatigue.
• All adults were also asked about their current intensity of joint pain over the previous 7 days, severity of pruritus and skin pain over the previous 24 hours, and sleep problems over the previous 72 hours on a numerical rating scale (NRS). The researchers applied linear regression models to continuous outcomes and adjusted for age, sex, socioeconomic status, psoriasis severity, and joint pain intensity, and beta coefficients (β) for the slopes were estimated with 95% CIs.

TAKEAWAY:

• Compared with the general population, higher total MFI-20 scores were observed for psoriasis and PsA, respectively. However, on the adjusted analysis, the impact on total fatigue was greatest for those with PsA (β = 5.23; 95% CI, 3.55-6.90), followed by psoriasis (β = 2.10; 95% CI, 0.96-3.25) compared with the general population (P trend < .0001).
• Increasing age was associated with a lower impact on total fatigue in psoriasis (β = −0.13; 95% CI, −0.18 to −0.08) and in PsA (β = −0.10; 95% CI, −0.19 to −0.01).
• Among patients with psoriasis with or without PsA, increasing joint pain intensity was associated with overall fatigue (β = 2.23; 95% CI, 2.03-2.44) for each one-point increase in joint pain on the NRS.
• In other findings, greater intensity of itch was associated with higher fatigue scores for both psoriasis and PsA, while skin pain was significantly associated with fatigue in PsA (β = 0.65; 95% CI, 0.08-1.22) but not in psoriasis without PsA (P = .2043).

IN PRACTICE:

“The observation that joint pain and itch, rather than psoriasis severity, appear to be major drivers of fatigue in psoriasis and PsA highlights the importance of a symptom-based approach when treating psoriasis, rather than focusing on objective severity measures alone,” the authors wrote.

SOURCE:

Corresponding author Alexander Egeberg, MD, of the Department of Dermatology at Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark, and colleagues conducted the research, which was published in the Journal of the American Academy of Dermatology.

LIMITATIONS:

The researchers were unable to assess whether the pain was inflammatory or noninflammatory or the number of affected joints. They also lacked information about the use of methotrexate, which commonly causes fatigue.

DISCLOSURES:

Dr. Egeberg is now an employee at LEO Pharma. He has received research funding from Pfizer, Eli Lilly, the Danish National Psoriasis Foundation, and the Royal Hofbundtmager Aage Bang Foundation, and honoraria as a consultant and/or speaker from AbbVie, Almirall, Bristol-Myers Squibb, Leo Pharma, Samsung Bioepis Co., Ltd., Pfizer, Eli Lilly, Novartis, UCB, Union Therapeutics, Horizon Therapeutics, Galderma, and Janssen Pharmaceuticals. Three of the coauthors reported being a consultant to, an adviser for, and/or having received research support from many pharmaceutical companies.

A version of this article appeared on Medscape.com.

TOPLINE:

Many factors may influence fatigue in patients with psoriasis and psoriatic arthritis (PsA), researchers report.

METHODOLOGY:

• The individual components of fatigue in psoriasis and PsA have not been examined thoroughly.
• Researchers drew from the nationwide prospective Danish Skin Cohort to identify 2741 adults with dermatologist-diagnosed psoriasis (of which 593 also had PsA) and 3788 controls in the general population.
• All adults in the analysis completed the multidimensional fatigue inventory (MIF-20), a validated 20-item tool that measures five dimensions of fatigue: General fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue. A higher score indicates more severe fatigue.
• All adults were also asked about their current intensity of joint pain over the previous 7 days, severity of pruritus and skin pain over the previous 24 hours, and sleep problems over the previous 72 hours on a numerical rating scale (NRS). The researchers applied linear regression models to continuous outcomes and adjusted for age, sex, socioeconomic status, psoriasis severity, and joint pain intensity, and beta coefficients (β) for the slopes were estimated with 95% CIs.

TAKEAWAY:

• Compared with the general population, higher total MFI-20 scores were observed for psoriasis and PsA, respectively. However, on the adjusted analysis, the impact on total fatigue was greatest for those with PsA (β = 5.23; 95% CI, 3.55-6.90), followed by psoriasis (β = 2.10; 95% CI, 0.96-3.25) compared with the general population (P trend < .0001).
• Increasing age was associated with a lower impact on total fatigue in psoriasis (β = −0.13; 95% CI, −0.18 to −0.08) and in PsA (β = −0.10; 95% CI, −0.19 to −0.01).
• Among patients with psoriasis with or without PsA, increasing joint pain intensity was associated with overall fatigue (β = 2.23; 95% CI, 2.03-2.44) for each one-point increase in joint pain on the NRS.
• In other findings, greater intensity of itch was associated with higher fatigue scores for both psoriasis and PsA, while skin pain was significantly associated with fatigue in PsA (β = 0.65; 95% CI, 0.08-1.22) but not in psoriasis without PsA (P = .2043).

IN PRACTICE:

“The observation that joint pain and itch, rather than psoriasis severity, appear to be major drivers of fatigue in psoriasis and PsA highlights the importance of a symptom-based approach when treating psoriasis, rather than focusing on objective severity measures alone,” the authors wrote.

SOURCE:

Corresponding author Alexander Egeberg, MD, of the Department of Dermatology at Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark, and colleagues conducted the research, which was published in the Journal of the American Academy of Dermatology.

LIMITATIONS:

The researchers were unable to assess whether the pain was inflammatory or noninflammatory or the number of affected joints. They also lacked information about the use of methotrexate, which commonly causes fatigue.

DISCLOSURES:

Dr. Egeberg is now an employee at LEO Pharma. He has received research funding from Pfizer, Eli Lilly, the Danish National Psoriasis Foundation, and the Royal Hofbundtmager Aage Bang Foundation, and honoraria as a consultant and/or speaker from AbbVie, Almirall, Bristol-Myers Squibb, Leo Pharma, Samsung Bioepis Co., Ltd., Pfizer, Eli Lilly, Novartis, UCB, Union Therapeutics, Horizon Therapeutics, Galderma, and Janssen Pharmaceuticals. Three of the coauthors reported being a consultant to, an adviser for, and/or having received research support from many pharmaceutical companies.

A version of this article appeared on Medscape.com.

A 73-year-old man with hypertension is evaluated for right great toe pain. A tap of the toe reveals uric acid crystals. He has a history of hypertension and hyperlipidemia. His current medications are hydrochlorothiazide, amlodipine, and atorvastatin.

Which blood pressure medication would you recommend to replace his hydrochlorothiazide?

A. Furosemide

B. Chlorthalidone

C. Lisinopril

D. Losartan

E. Irbesartan

Losartan

Diuretics should be avoided if possible in a patient with gout, as they increase uric acid levels. Of the other three options, losartan offers the added benefit of lowering uric acid levels. Losartan has uricosuric effects — a property that is unique to losartan of the angiotensin receptor blockers (ARBs) that have been studied.^1,2 The uric acid lowering appears to be a probenecid-like effect.

Losartan has also been evaluated to see whether using it in combination with a thiazide diuretic can reduce the rise in uric acid that occurs with thiazides. Matsumura and colleagues looked at data from the COMFORT trial, focusing on the effect of combining losartan with hydrochlorothiazide on uric acid levels.³ They looked at a group of 118 patients on an ARB other than losartan plus a diuretic, who were then randomly assigned to losartan 50 mg/hydrochlorothiazide 12.5 mg or continuation of another ARB plus a diuretic. Blood pressure control was the same between groups, but the patients who received the losartan combination had lower uric acid levels (P = .01).

Ferreira and colleagues looked at the difference in uric acid lowering between high-dose (150 mg/day) vs low-dose losartan (50 mg/day).⁴ Compared with low-dose, high-dose losartan reduced serum uric acid by 0.27 (0.34 to 0.21) mg/dL, P < .001.
 

SGLT2 inhibitors

SGLT2 inhibitors also lower uric acid. Suijik and colleagues conducted an analysis of two randomized trials of SGLT2 inhibitors (empagliflozin and dapagliflozin), and concluded that SGLT2 inhibitors induce uric acid excretion, which is strongly linked to urinary glucose excretion.⁵

Metformin

Metformin is used as a firstline drug for the treatment of diabetes. It also has evidence for decreasing colonic polyps. Cho and colleagues looked at over 12,000 patients with diabetes over a 12-year period; 3775 underwent colonoscopies.⁶ They compared frequency of polyps in patients who were using metformin with those who were not treated with metformin. The polyp detection rate was lower in the metformin group than in the no metformin group (39.4% vs. 62.4%, P < .01).

Higurashi and colleagues performed a double-blind, placebo-controlled trial of metformin in nondiabetic patients for the prevention of colon polyps.⁷ The dose of metformin used in this study was very low (250 mg/day). There were significantly fewer adenomas in the metformin group (22 of 71 patients) than in the placebo group (32 of 62) (relative risk, 0.60; 95% confidence interval, 0.39-0.92, P = .016).
 

Thiazide diuretics

Thiazide diuretics have long been used to help prevent kidney stones in addition to treating hypertension. They decrease urinary calcium excretion, which may reduce kidney stones. Could this reduction in calcium excretion be good for bones?

Xiao and colleagues did a meta-analysis of 11 prospective studies involving 2,193,160 participants.⁸ Thiazide diuretic users had a significant 14% reduction in the risk of all fractures (RR, 0.86; 95% CI, 0.80-0.93; P = .009) and an 18% reduction in the risk of hip fracture (RR, 0.82; 95% CI, 0.80-0.93; P = .009). Kruse and colleagues found that long duration and continuity of thiazide exposure seemed to be important to obtain this protective effect on fracture risk.⁹

Pearls:

• Losartan, but not other ARBs, lowers uric acid levels and may be helpful in managing hypertension in gout patients; higher doses lower uric acid more.
• Metformin use appears to decrease colon polyp formation.
• Thiazide diuretics may reduce fracture risk while patients are taking them.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Würzner G et al. Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia and gout. J Hypertens. 2001 Oct;19(10):1855-60.

2. Puig JG et al. Effect of eprosartan and losartan on uric acid metabolism in patients with essential hypertension. J Hypertens. 1999 Jul;17(7):1033-9.

3. Matsumura K et al. Effect of losartan on serum uric acid in hypertension treated with a diuretic: The COMFORT study. Clin Exp Hypertens. 2015;37(3):192-6.

4. Ferreira JP et al. High- versus low-dose losartan and uric acid: An analysis from HEAAL. J Cardiol. 2023 Jul;82(1):57-61.

5. Suijk DLS et al. SGLT2 inhibition and uric acid excretion in patients with type 2 diabetes and normal kidney function. Soc Nephrol. 2022 May;17(5):663-71.

6. Youn Hee Cho et al. Does metformin affect the incidence of colonic polyps and adenomas in patients with type 2 diabetes mellitus? Intestinal Res. 2014 Apr;12(2):139-45.

7. Higurashi T et al. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: A multicentre double-blind, placebo-controlled, randomised phase 3 trial. Lancet Oncol. 2016;17:475-83.

8. Xiao X et al. Thiazide diuretic usage and risk of fracture: a meta-analysis of cohort studies. Osteoporos Int. 2018 Jul;29(7):1515-24.

9. Kruse C et al. Continuous and long-term treatment is more important than dosage for the protective effect of thiazide use on bone metabolism and fracture risk. J Intern Med. 2016 Jan;279(1):110-22.

A 73-year-old man with hypertension is evaluated for right great toe pain. A tap of the toe reveals uric acid crystals. He has a history of hypertension and hyperlipidemia. His current medications are hydrochlorothiazide, amlodipine, and atorvastatin.

Which blood pressure medication would you recommend to replace his hydrochlorothiazide?

A. Furosemide

B. Chlorthalidone

C. Lisinopril

D. Losartan

E. Irbesartan

Losartan

Diuretics should be avoided if possible in a patient with gout, as they increase uric acid levels. Of the other three options, losartan offers the added benefit of lowering uric acid levels. Losartan has uricosuric effects — a property that is unique to losartan of the angiotensin receptor blockers (ARBs) that have been studied.^1,2 The uric acid lowering appears to be a probenecid-like effect.

Losartan has also been evaluated to see whether using it in combination with a thiazide diuretic can reduce the rise in uric acid that occurs with thiazides. Matsumura and colleagues looked at data from the COMFORT trial, focusing on the effect of combining losartan with hydrochlorothiazide on uric acid levels.³ They looked at a group of 118 patients on an ARB other than losartan plus a diuretic, who were then randomly assigned to losartan 50 mg/hydrochlorothiazide 12.5 mg or continuation of another ARB plus a diuretic. Blood pressure control was the same between groups, but the patients who received the losartan combination had lower uric acid levels (P = .01).

Ferreira and colleagues looked at the difference in uric acid lowering between high-dose (150 mg/day) vs low-dose losartan (50 mg/day).⁴ Compared with low-dose, high-dose losartan reduced serum uric acid by 0.27 (0.34 to 0.21) mg/dL, P < .001.
 

SGLT2 inhibitors

SGLT2 inhibitors also lower uric acid. Suijik and colleagues conducted an analysis of two randomized trials of SGLT2 inhibitors (empagliflozin and dapagliflozin), and concluded that SGLT2 inhibitors induce uric acid excretion, which is strongly linked to urinary glucose excretion.⁵

Metformin

Metformin is used as a firstline drug for the treatment of diabetes. It also has evidence for decreasing colonic polyps. Cho and colleagues looked at over 12,000 patients with diabetes over a 12-year period; 3775 underwent colonoscopies.⁶ They compared frequency of polyps in patients who were using metformin with those who were not treated with metformin. The polyp detection rate was lower in the metformin group than in the no metformin group (39.4% vs. 62.4%, P < .01).

Higurashi and colleagues performed a double-blind, placebo-controlled trial of metformin in nondiabetic patients for the prevention of colon polyps.⁷ The dose of metformin used in this study was very low (250 mg/day). There were significantly fewer adenomas in the metformin group (22 of 71 patients) than in the placebo group (32 of 62) (relative risk, 0.60; 95% confidence interval, 0.39-0.92, P = .016).
 

Thiazide diuretics

Thiazide diuretics have long been used to help prevent kidney stones in addition to treating hypertension. They decrease urinary calcium excretion, which may reduce kidney stones. Could this reduction in calcium excretion be good for bones?

Xiao and colleagues did a meta-analysis of 11 prospective studies involving 2,193,160 participants.⁸ Thiazide diuretic users had a significant 14% reduction in the risk of all fractures (RR, 0.86; 95% CI, 0.80-0.93; P = .009) and an 18% reduction in the risk of hip fracture (RR, 0.82; 95% CI, 0.80-0.93; P = .009). Kruse and colleagues found that long duration and continuity of thiazide exposure seemed to be important to obtain this protective effect on fracture risk.⁹

Pearls:

• Losartan, but not other ARBs, lowers uric acid levels and may be helpful in managing hypertension in gout patients; higher doses lower uric acid more.
• Metformin use appears to decrease colon polyp formation.
• Thiazide diuretics may reduce fracture risk while patients are taking them.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Würzner G et al. Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia and gout. J Hypertens. 2001 Oct;19(10):1855-60.

2. Puig JG et al. Effect of eprosartan and losartan on uric acid metabolism in patients with essential hypertension. J Hypertens. 1999 Jul;17(7):1033-9.

3. Matsumura K et al. Effect of losartan on serum uric acid in hypertension treated with a diuretic: The COMFORT study. Clin Exp Hypertens. 2015;37(3):192-6.

4. Ferreira JP et al. High- versus low-dose losartan and uric acid: An analysis from HEAAL. J Cardiol. 2023 Jul;82(1):57-61.

5. Suijk DLS et al. SGLT2 inhibition and uric acid excretion in patients with type 2 diabetes and normal kidney function. Soc Nephrol. 2022 May;17(5):663-71.

6. Youn Hee Cho et al. Does metformin affect the incidence of colonic polyps and adenomas in patients with type 2 diabetes mellitus? Intestinal Res. 2014 Apr;12(2):139-45.

7. Higurashi T et al. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: A multicentre double-blind, placebo-controlled, randomised phase 3 trial. Lancet Oncol. 2016;17:475-83.

8. Xiao X et al. Thiazide diuretic usage and risk of fracture: a meta-analysis of cohort studies. Osteoporos Int. 2018 Jul;29(7):1515-24.

9. Kruse C et al. Continuous and long-term treatment is more important than dosage for the protective effect of thiazide use on bone metabolism and fracture risk. J Intern Med. 2016 Jan;279(1):110-22.

A 73-year-old man with hypertension is evaluated for right great toe pain. A tap of the toe reveals uric acid crystals. He has a history of hypertension and hyperlipidemia. His current medications are hydrochlorothiazide, amlodipine, and atorvastatin.

Which blood pressure medication would you recommend to replace his hydrochlorothiazide?

A. Furosemide

B. Chlorthalidone

C. Lisinopril

D. Losartan

E. Irbesartan

Losartan

Diuretics should be avoided if possible in a patient with gout, as they increase uric acid levels. Of the other three options, losartan offers the added benefit of lowering uric acid levels. Losartan has uricosuric effects — a property that is unique to losartan of the angiotensin receptor blockers (ARBs) that have been studied.^1,2 The uric acid lowering appears to be a probenecid-like effect.

Losartan has also been evaluated to see whether using it in combination with a thiazide diuretic can reduce the rise in uric acid that occurs with thiazides. Matsumura and colleagues looked at data from the COMFORT trial, focusing on the effect of combining losartan with hydrochlorothiazide on uric acid levels.³ They looked at a group of 118 patients on an ARB other than losartan plus a diuretic, who were then randomly assigned to losartan 50 mg/hydrochlorothiazide 12.5 mg or continuation of another ARB plus a diuretic. Blood pressure control was the same between groups, but the patients who received the losartan combination had lower uric acid levels (P = .01).

Ferreira and colleagues looked at the difference in uric acid lowering between high-dose (150 mg/day) vs low-dose losartan (50 mg/day).⁴ Compared with low-dose, high-dose losartan reduced serum uric acid by 0.27 (0.34 to 0.21) mg/dL, P < .001.
 

SGLT2 inhibitors

SGLT2 inhibitors also lower uric acid. Suijik and colleagues conducted an analysis of two randomized trials of SGLT2 inhibitors (empagliflozin and dapagliflozin), and concluded that SGLT2 inhibitors induce uric acid excretion, which is strongly linked to urinary glucose excretion.⁵

Metformin

Metformin is used as a firstline drug for the treatment of diabetes. It also has evidence for decreasing colonic polyps. Cho and colleagues looked at over 12,000 patients with diabetes over a 12-year period; 3775 underwent colonoscopies.⁶ They compared frequency of polyps in patients who were using metformin with those who were not treated with metformin. The polyp detection rate was lower in the metformin group than in the no metformin group (39.4% vs. 62.4%, P < .01).

Higurashi and colleagues performed a double-blind, placebo-controlled trial of metformin in nondiabetic patients for the prevention of colon polyps.⁷ The dose of metformin used in this study was very low (250 mg/day). There were significantly fewer adenomas in the metformin group (22 of 71 patients) than in the placebo group (32 of 62) (relative risk, 0.60; 95% confidence interval, 0.39-0.92, P = .016).
 

Thiazide diuretics

Thiazide diuretics have long been used to help prevent kidney stones in addition to treating hypertension. They decrease urinary calcium excretion, which may reduce kidney stones. Could this reduction in calcium excretion be good for bones?

Xiao and colleagues did a meta-analysis of 11 prospective studies involving 2,193,160 participants.⁸ Thiazide diuretic users had a significant 14% reduction in the risk of all fractures (RR, 0.86; 95% CI, 0.80-0.93; P = .009) and an 18% reduction in the risk of hip fracture (RR, 0.82; 95% CI, 0.80-0.93; P = .009). Kruse and colleagues found that long duration and continuity of thiazide exposure seemed to be important to obtain this protective effect on fracture risk.⁹

Pearls:

• Losartan, but not other ARBs, lowers uric acid levels and may be helpful in managing hypertension in gout patients; higher doses lower uric acid more.
• Metformin use appears to decrease colon polyp formation.
• Thiazide diuretics may reduce fracture risk while patients are taking them.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Würzner G et al. Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia and gout. J Hypertens. 2001 Oct;19(10):1855-60.

2. Puig JG et al. Effect of eprosartan and losartan on uric acid metabolism in patients with essential hypertension. J Hypertens. 1999 Jul;17(7):1033-9.

3. Matsumura K et al. Effect of losartan on serum uric acid in hypertension treated with a diuretic: The COMFORT study. Clin Exp Hypertens. 2015;37(3):192-6.

4. Ferreira JP et al. High- versus low-dose losartan and uric acid: An analysis from HEAAL. J Cardiol. 2023 Jul;82(1):57-61.

5. Suijk DLS et al. SGLT2 inhibition and uric acid excretion in patients with type 2 diabetes and normal kidney function. Soc Nephrol. 2022 May;17(5):663-71.

6. Youn Hee Cho et al. Does metformin affect the incidence of colonic polyps and adenomas in patients with type 2 diabetes mellitus? Intestinal Res. 2014 Apr;12(2):139-45.

7. Higurashi T et al. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: A multicentre double-blind, placebo-controlled, randomised phase 3 trial. Lancet Oncol. 2016;17:475-83.

8. Xiao X et al. Thiazide diuretic usage and risk of fracture: a meta-analysis of cohort studies. Osteoporos Int. 2018 Jul;29(7):1515-24.

9. Kruse C et al. Continuous and long-term treatment is more important than dosage for the protective effect of thiazide use on bone metabolism and fracture risk. J Intern Med. 2016 Jan;279(1):110-22.

People with gout are 58% more likely to develop cardiovascular disease (CVD), according to a new analysis. This increased risk was observed across 12 different cardiovascular conditions, including heart failure, arrhythmias, and valve diseases.

“These findings suggest that the organ damage associated with gout is likely to be much broader than originally thought,” Nathalie Conrad, PhD, senior author of the research and cardiovascular epidemiologist at KU Leuven, Leuven, Belgium, said in an email. This could be useful for future research on underlying biological mechanisms driving CVD risk in gout, she added.

While previous research has tied gout to increased cardiovascular risk, these studies “largely focused on coronary heart disease, stroke, and thromboembolic outcomes,” she explained, and have been smaller in size.

This new study included more than 862,000 individuals, which permitted researchers to investigate rarer CVD outcomes such as myocarditis and pericarditis.

For the study, researchers used electronic health records from the UK Clinical Practice Research Datalink, a primary care database that contains anonymized health data for about 22 million individuals. Using these data, they identified more than 152,600 individuals with gout. Patients included in the analysis were diagnosed between 2000 and 2017, younger than 80 years at diagnosis, and free of CVD for at least 12 months after their gout diagnosis.

Patients with gout were compared with nearly 710,000 controls, matched on demographic factors such as age, sex, and geographic region.

Researchers then investigated the incidence of 12 CVDs, including atherosclerotic diseases, degenerative and thromboembolic diseases, and arrythmias, between the two groups from January 1, 2000, to June 30, 2019.

The findings were published in the March 2024 issue of The Lancet Rheumatology. Overall, patients with gout were 58% more likely to develop any CVD than their matched comparators without gout. There was a higher disease incidence among patients with gout for each of the 12 conditions. This association was more pronounced in women (hazard ratio [HR], 1.88) than in men (HR, 1.49), and gout amplified the risk for CVD in younger individuals to a greater extent.

Individuals younger than 45 years with gout were more than twice as likely to develop CVD compared with similarly aged individuals without gout. For comparison, individuals aged 45-54 years with gout were 84% more likely to develop CVD, and individuals aged 55-64 years were 57% more likely to develop CVD than matched controls.

Conduction system disease had the highest incident risk (HR, 1.88), followed by heart failure and valve disease (HR, 1.85 for both).

Individuals with gout had higher rates of comorbidities than the controls, including hypertension, obesity, and dyslipidemia. Overall, CVD risk was slightly attenuated after adjustment for traditional CVD risk factors such as smoking, blood pressure, and body mass index but still significant: Patients with gout had a 31% higher risk for CVD than comparators.

This shows “that known CVD risk factors only explain part of the CVD risks seen in patients with gout,” Dr. Conrad said. Other factors such as inflammation and other disease activity factors could be at play, she explained, which would need to be explored in future research.

The study “shows the whole landscape” of CVD and gout, Michael H. Pillinger, MD, rheumatologist and professor of medicine, biochemistry, and molecular pharmacology at NYU Grossman School of Medicine in New York City, said in an interview. He was not involved with the research.

“Every possible cardiovascular disease that they could think of was something that gout patients had more of than the non-gout patients,” he added. “I think this is going to be a paper that gets cited a lot, at minimum when describing the background of risk when we look at gout patients.”

The study had some limitations, including that researchers were unable to account for how medications such as nonsteroidal anti-inflammatory drugs, corticosteroids, colchicine, or allopurinol may have affected the association between gout and CVD.

“This is because analyses of nonrandomized treatment can be confounded by indication, wherein it is difficult to differentiate the effects of the treatment from underlying disease severity,” the authors wrote.

There was also a large amount of missing data on blood pressure, body mass index, smoking status, and other health information relevant to cardiovascular risk, so sensitivity analyses adjusting for these factors “should be interpreted with caution,” they added.

Dr. Pillinger also noted that the rates of comorbidities in the gout study population were lower than what have been found in US study populations. For example, about 40% of patients with gout in the analysis had hypertension, while other studies have suggested higher rates of 60%-70%, he said. However, it’s not clear if these differences could have affected outcomes. He added that these limitations do not “in any way weaken [the authors’] conclusion.”

The findings call for better strategies to reduce CVD risk in patients with gout, Dr. Conrad noted.

“Further improvements could come from better recognition and intervention on CVD risk factors (eg, through lifestyle changes or drug therapies where they are indicated), as well as proactive screening for heart disease in patients with gout, which could allow early diagnosis and interventions to delay more severe outcomes,” she added.

This study was funded by Research Foundation Flanders. Dr. Conrad was funded by a personal fellowship from the Research Foundation Flanders and a European Society of Cardiology research grant. She received royalties from Oxford University Innovation. Four of Dr. Conrad’s eight coauthors also reported financial relationships with pharmaceutical companies. Dr. Pillinger served as a consultant to Amgen, Federation Bio, Fortress Biotech, and Scilex, and he holds an investigator-initiated grant from Hikma.

A version of this article appeared on Medscape.com.

People with gout are 58% more likely to develop cardiovascular disease (CVD), according to a new analysis. This increased risk was observed across 12 different cardiovascular conditions, including heart failure, arrhythmias, and valve diseases.

“These findings suggest that the organ damage associated with gout is likely to be much broader than originally thought,” Nathalie Conrad, PhD, senior author of the research and cardiovascular epidemiologist at KU Leuven, Leuven, Belgium, said in an email. This could be useful for future research on underlying biological mechanisms driving CVD risk in gout, she added.

While previous research has tied gout to increased cardiovascular risk, these studies “largely focused on coronary heart disease, stroke, and thromboembolic outcomes,” she explained, and have been smaller in size.

This new study included more than 862,000 individuals, which permitted researchers to investigate rarer CVD outcomes such as myocarditis and pericarditis.

For the study, researchers used electronic health records from the UK Clinical Practice Research Datalink, a primary care database that contains anonymized health data for about 22 million individuals. Using these data, they identified more than 152,600 individuals with gout. Patients included in the analysis were diagnosed between 2000 and 2017, younger than 80 years at diagnosis, and free of CVD for at least 12 months after their gout diagnosis.

Patients with gout were compared with nearly 710,000 controls, matched on demographic factors such as age, sex, and geographic region.

Researchers then investigated the incidence of 12 CVDs, including atherosclerotic diseases, degenerative and thromboembolic diseases, and arrythmias, between the two groups from January 1, 2000, to June 30, 2019.

The findings were published in the March 2024 issue of The Lancet Rheumatology. Overall, patients with gout were 58% more likely to develop any CVD than their matched comparators without gout. There was a higher disease incidence among patients with gout for each of the 12 conditions. This association was more pronounced in women (hazard ratio [HR], 1.88) than in men (HR, 1.49), and gout amplified the risk for CVD in younger individuals to a greater extent.

Individuals younger than 45 years with gout were more than twice as likely to develop CVD compared with similarly aged individuals without gout. For comparison, individuals aged 45-54 years with gout were 84% more likely to develop CVD, and individuals aged 55-64 years were 57% more likely to develop CVD than matched controls.

Conduction system disease had the highest incident risk (HR, 1.88), followed by heart failure and valve disease (HR, 1.85 for both).

Individuals with gout had higher rates of comorbidities than the controls, including hypertension, obesity, and dyslipidemia. Overall, CVD risk was slightly attenuated after adjustment for traditional CVD risk factors such as smoking, blood pressure, and body mass index but still significant: Patients with gout had a 31% higher risk for CVD than comparators.

This shows “that known CVD risk factors only explain part of the CVD risks seen in patients with gout,” Dr. Conrad said. Other factors such as inflammation and other disease activity factors could be at play, she explained, which would need to be explored in future research.

The study “shows the whole landscape” of CVD and gout, Michael H. Pillinger, MD, rheumatologist and professor of medicine, biochemistry, and molecular pharmacology at NYU Grossman School of Medicine in New York City, said in an interview. He was not involved with the research.

“Every possible cardiovascular disease that they could think of was something that gout patients had more of than the non-gout patients,” he added. “I think this is going to be a paper that gets cited a lot, at minimum when describing the background of risk when we look at gout patients.”

The study had some limitations, including that researchers were unable to account for how medications such as nonsteroidal anti-inflammatory drugs, corticosteroids, colchicine, or allopurinol may have affected the association between gout and CVD.

“This is because analyses of nonrandomized treatment can be confounded by indication, wherein it is difficult to differentiate the effects of the treatment from underlying disease severity,” the authors wrote.

There was also a large amount of missing data on blood pressure, body mass index, smoking status, and other health information relevant to cardiovascular risk, so sensitivity analyses adjusting for these factors “should be interpreted with caution,” they added.

Dr. Pillinger also noted that the rates of comorbidities in the gout study population were lower than what have been found in US study populations. For example, about 40% of patients with gout in the analysis had hypertension, while other studies have suggested higher rates of 60%-70%, he said. However, it’s not clear if these differences could have affected outcomes. He added that these limitations do not “in any way weaken [the authors’] conclusion.”

The findings call for better strategies to reduce CVD risk in patients with gout, Dr. Conrad noted.

“Further improvements could come from better recognition and intervention on CVD risk factors (eg, through lifestyle changes or drug therapies where they are indicated), as well as proactive screening for heart disease in patients with gout, which could allow early diagnosis and interventions to delay more severe outcomes,” she added.

This study was funded by Research Foundation Flanders. Dr. Conrad was funded by a personal fellowship from the Research Foundation Flanders and a European Society of Cardiology research grant. She received royalties from Oxford University Innovation. Four of Dr. Conrad’s eight coauthors also reported financial relationships with pharmaceutical companies. Dr. Pillinger served as a consultant to Amgen, Federation Bio, Fortress Biotech, and Scilex, and he holds an investigator-initiated grant from Hikma.

A version of this article appeared on Medscape.com.

People with gout are 58% more likely to develop cardiovascular disease (CVD), according to a new analysis. This increased risk was observed across 12 different cardiovascular conditions, including heart failure, arrhythmias, and valve diseases.

“These findings suggest that the organ damage associated with gout is likely to be much broader than originally thought,” Nathalie Conrad, PhD, senior author of the research and cardiovascular epidemiologist at KU Leuven, Leuven, Belgium, said in an email. This could be useful for future research on underlying biological mechanisms driving CVD risk in gout, she added.

While previous research has tied gout to increased cardiovascular risk, these studies “largely focused on coronary heart disease, stroke, and thromboembolic outcomes,” she explained, and have been smaller in size.

This new study included more than 862,000 individuals, which permitted researchers to investigate rarer CVD outcomes such as myocarditis and pericarditis.

For the study, researchers used electronic health records from the UK Clinical Practice Research Datalink, a primary care database that contains anonymized health data for about 22 million individuals. Using these data, they identified more than 152,600 individuals with gout. Patients included in the analysis were diagnosed between 2000 and 2017, younger than 80 years at diagnosis, and free of CVD for at least 12 months after their gout diagnosis.

Patients with gout were compared with nearly 710,000 controls, matched on demographic factors such as age, sex, and geographic region.

Researchers then investigated the incidence of 12 CVDs, including atherosclerotic diseases, degenerative and thromboembolic diseases, and arrythmias, between the two groups from January 1, 2000, to June 30, 2019.

The findings were published in the March 2024 issue of The Lancet Rheumatology. Overall, patients with gout were 58% more likely to develop any CVD than their matched comparators without gout. There was a higher disease incidence among patients with gout for each of the 12 conditions. This association was more pronounced in women (hazard ratio [HR], 1.88) than in men (HR, 1.49), and gout amplified the risk for CVD in younger individuals to a greater extent.

Individuals younger than 45 years with gout were more than twice as likely to develop CVD compared with similarly aged individuals without gout. For comparison, individuals aged 45-54 years with gout were 84% more likely to develop CVD, and individuals aged 55-64 years were 57% more likely to develop CVD than matched controls.

Conduction system disease had the highest incident risk (HR, 1.88), followed by heart failure and valve disease (HR, 1.85 for both).

Individuals with gout had higher rates of comorbidities than the controls, including hypertension, obesity, and dyslipidemia. Overall, CVD risk was slightly attenuated after adjustment for traditional CVD risk factors such as smoking, blood pressure, and body mass index but still significant: Patients with gout had a 31% higher risk for CVD than comparators.

This shows “that known CVD risk factors only explain part of the CVD risks seen in patients with gout,” Dr. Conrad said. Other factors such as inflammation and other disease activity factors could be at play, she explained, which would need to be explored in future research.

The study “shows the whole landscape” of CVD and gout, Michael H. Pillinger, MD, rheumatologist and professor of medicine, biochemistry, and molecular pharmacology at NYU Grossman School of Medicine in New York City, said in an interview. He was not involved with the research.

“Every possible cardiovascular disease that they could think of was something that gout patients had more of than the non-gout patients,” he added. “I think this is going to be a paper that gets cited a lot, at minimum when describing the background of risk when we look at gout patients.”

The study had some limitations, including that researchers were unable to account for how medications such as nonsteroidal anti-inflammatory drugs, corticosteroids, colchicine, or allopurinol may have affected the association between gout and CVD.

“This is because analyses of nonrandomized treatment can be confounded by indication, wherein it is difficult to differentiate the effects of the treatment from underlying disease severity,” the authors wrote.

There was also a large amount of missing data on blood pressure, body mass index, smoking status, and other health information relevant to cardiovascular risk, so sensitivity analyses adjusting for these factors “should be interpreted with caution,” they added.

Dr. Pillinger also noted that the rates of comorbidities in the gout study population were lower than what have been found in US study populations. For example, about 40% of patients with gout in the analysis had hypertension, while other studies have suggested higher rates of 60%-70%, he said. However, it’s not clear if these differences could have affected outcomes. He added that these limitations do not “in any way weaken [the authors’] conclusion.”

The findings call for better strategies to reduce CVD risk in patients with gout, Dr. Conrad noted.

“Further improvements could come from better recognition and intervention on CVD risk factors (eg, through lifestyle changes or drug therapies where they are indicated), as well as proactive screening for heart disease in patients with gout, which could allow early diagnosis and interventions to delay more severe outcomes,” she added.

This study was funded by Research Foundation Flanders. Dr. Conrad was funded by a personal fellowship from the Research Foundation Flanders and a European Society of Cardiology research grant. She received royalties from Oxford University Innovation. Four of Dr. Conrad’s eight coauthors also reported financial relationships with pharmaceutical companies. Dr. Pillinger served as a consultant to Amgen, Federation Bio, Fortress Biotech, and Scilex, and he holds an investigator-initiated grant from Hikma.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration has approved the first interchangeable, high-concentration, citrate-free adalimumab biosimilar, adalimumab-ryvk (Simlandi).

This is the 10th adalimumab biosimilar approved by the regulatory agency and the first biosimilar approval in the US market for the Icelandic pharmaceutical company Alvotech in partnership with Teva Pharmaceuticals.

“An interchangeable citrate-free, high-concentration biosimilar adalimumab has the potential to change the market dynamics in a rapidly evolving environment for biosimilars in the U.S.,” said Robert Wessman, chairman and CEO of Alvotech, in a company press release on February 23.

Adalimumab-ryvk was approved in the European Union in 2021 and in Australia and Canada in 2022. 

Adalimumab-ryvk is indicated for adults with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, Crohn’s disease, plaque psoriasis, hidradenitis suppurativa, and noninfectious intermediate and posterior uveitis and panuveitis. In pediatric patients, it is indicated for polyarticular juvenile idiopathic arthritis in children 2 years of age and older and Crohn’s disease in children 6 years of age and older.

Adalimumab-ryvk is the third Humira biosimilar overall granted interchangeability status, which allows pharmacists (depending on state law) to substitute the biosimilar for the reference product without involving the prescribing clinician. Adalimumab-adbm (Cyltezo), manufactured by Boehringer Ingelheim, and adalimumab-afzb (Abrilada), manufactured by Pfizer, were previously granted interchangeability status; however, they both are interchangeable with the low-concentration formulation of Humira, which make up only an estimated 15% of Humira prescriptions, according to a report by Goodroot. 

Adalimumab-ryvk will be launched “imminently” in the United States, according to the press release, but no specific dates were provided. It is also not yet known how the biosimilar will be priced compared with Humira. Other adalimumab biosimilars have launched with discounts from 5% to 85% of Humira’s list price.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration has approved the first interchangeable, high-concentration, citrate-free adalimumab biosimilar, adalimumab-ryvk (Simlandi).

This is the 10th adalimumab biosimilar approved by the regulatory agency and the first biosimilar approval in the US market for the Icelandic pharmaceutical company Alvotech in partnership with Teva Pharmaceuticals.

“An interchangeable citrate-free, high-concentration biosimilar adalimumab has the potential to change the market dynamics in a rapidly evolving environment for biosimilars in the U.S.,” said Robert Wessman, chairman and CEO of Alvotech, in a company press release on February 23.

Adalimumab-ryvk was approved in the European Union in 2021 and in Australia and Canada in 2022. 

Adalimumab-ryvk is indicated for adults with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, Crohn’s disease, plaque psoriasis, hidradenitis suppurativa, and noninfectious intermediate and posterior uveitis and panuveitis. In pediatric patients, it is indicated for polyarticular juvenile idiopathic arthritis in children 2 years of age and older and Crohn’s disease in children 6 years of age and older.

Adalimumab-ryvk is the third Humira biosimilar overall granted interchangeability status, which allows pharmacists (depending on state law) to substitute the biosimilar for the reference product without involving the prescribing clinician. Adalimumab-adbm (Cyltezo), manufactured by Boehringer Ingelheim, and adalimumab-afzb (Abrilada), manufactured by Pfizer, were previously granted interchangeability status; however, they both are interchangeable with the low-concentration formulation of Humira, which make up only an estimated 15% of Humira prescriptions, according to a report by Goodroot. 

Adalimumab-ryvk will be launched “imminently” in the United States, according to the press release, but no specific dates were provided. It is also not yet known how the biosimilar will be priced compared with Humira. Other adalimumab biosimilars have launched with discounts from 5% to 85% of Humira’s list price.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration has approved the first interchangeable, high-concentration, citrate-free adalimumab biosimilar, adalimumab-ryvk (Simlandi).

This is the 10th adalimumab biosimilar approved by the regulatory agency and the first biosimilar approval in the US market for the Icelandic pharmaceutical company Alvotech in partnership with Teva Pharmaceuticals.

“An interchangeable citrate-free, high-concentration biosimilar adalimumab has the potential to change the market dynamics in a rapidly evolving environment for biosimilars in the U.S.,” said Robert Wessman, chairman and CEO of Alvotech, in a company press release on February 23.

Adalimumab-ryvk was approved in the European Union in 2021 and in Australia and Canada in 2022. 

Adalimumab-ryvk is indicated for adults with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, Crohn’s disease, plaque psoriasis, hidradenitis suppurativa, and noninfectious intermediate and posterior uveitis and panuveitis. In pediatric patients, it is indicated for polyarticular juvenile idiopathic arthritis in children 2 years of age and older and Crohn’s disease in children 6 years of age and older.

Adalimumab-ryvk is the third Humira biosimilar overall granted interchangeability status, which allows pharmacists (depending on state law) to substitute the biosimilar for the reference product without involving the prescribing clinician. Adalimumab-adbm (Cyltezo), manufactured by Boehringer Ingelheim, and adalimumab-afzb (Abrilada), manufactured by Pfizer, were previously granted interchangeability status; however, they both are interchangeable with the low-concentration formulation of Humira, which make up only an estimated 15% of Humira prescriptions, according to a report by Goodroot. 

Adalimumab-ryvk will be launched “imminently” in the United States, according to the press release, but no specific dates were provided. It is also not yet known how the biosimilar will be priced compared with Humira. Other adalimumab biosimilars have launched with discounts from 5% to 85% of Humira’s list price.

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.

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.

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.

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.

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.

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.

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.

It’s no secret that regular exercise is important. But for patients with painful joints, it can be the last thing they want to do. Exercise is one of the cornerstones of managing arthritis, yet nearly one third of patients with arthritis are inactive.

Guidelines recommend that clinicians encourage their patients to engage in physical activity, but it can be difficult to know where to start.

This news organization recently spoke to experts on what resources are available, how much exercise is ideal, and how to motivate patients to move more.
 

What Are the Benefits of Exercise in Osteoarthritis?

Nearly all professional societies agree that exercise is one of the hallmarks of managing osteoarthritis (OA). According to two Cochrane reviews, there is high-equality evidence that exercise can help reduce pain as well as improve physical function in both hip and knee OA. In fact, physical activity can decrease pain and improve function by 40% in adults with arthritis, according to the Centers for Disease Control and Prevention.

Exercise also plays a large role in preventing disability by improving joint range of motion as well as maintaining muscle mass that supports joints.

There is also preliminary evidence that exercise could have a structural benefit to osteoarthritic joints. In a study of about 1200 individuals with knee OA, those who walked for exercise not only had reduced frequent knee pain, compared with non-walkers, but also were 20% less likely to have worsening of medial joint space narrowing.

Beyond symptom and impairment improvements, exercise can also play a role in staving off other chronic diseases linked to OA, such as cardiovascular disease and type 2 diabetes. Physical activity and exercise “are effective in preventing at least 35 chronic conditions and treating at least 26 chronic conditions, with one of the potential working mechanisms being exercise-induced anti-inflammatory effects,” wrote the authors of a commentary in the Journal of Orthopaedic & Sports Physical Therapy.

The known mental health benefits of exercise can also be beneficial for patients, as rates of depression and anxiety can be higher in people with arthritis than in the general population.
 

What Is the Ideal Amount of Exercise for Patients?

Current guidelines recommend that adults should get 150 minutes of moderate physical activity each week. But for patients with chronic pain, that may seem unachievable, Kelli Allen, PhD, professor of medicine and exercise physiologist at the University of North Carolina School of Medicine in Chapel Hill, said during a presentation at the American College of Rheumatology 2023 annual meeting in San Diego. Promisingly, research has shown that some exercise is better than none.

One study looking at over 1500 adults with lower extremity joint symptoms suggested that approximately 1 hour of physical activity per week increased the likelihood that participants remained disability-free over 4 years. In another analysis looking at 280 studies, researchers concluded that resistance training programs lasting 3-6 months resulted in moderate improvements in pain and physical function, but these benefits did not depend on exercise volume or participant adherence.

“These findings highlight the flexibility available for clinicians in the prescription of resistance exercise for knee and hip OA without compromising improvements in pain and physical function,” the authors wrote.

Step counts can be another way to measure activity, with 10,000 steps being a common target. But fewer steps a day can also yield health benefits. One study found that among nearly 1800 participants with knee OA, each additional 1000 steps per day was associated with a 16%-18% reduced risk of developing functional limitations 2 years later. Walking 6000 steps a day was the threshold that best determined who would develop functional limitations and who would not.

“I think it’s really a helpful message to encourage people with chronic pain that if you can get to 6000, maybe that’s a good goal,” Dr. Allen said.

Going for a 20-minute walk three times a week can be a good place to start, said Grace H. Lo, MD, associate professor in the Division of Immunology, Allergy, and Rheumatology at Baylor College of Medicine in Houston, Texas. For people who currently do not do any activity, Dr. Lo recommends starting small, like walking to get the mail every day. “Do something practical that is something they can sustain and keep in their daily activities that will help to increase their function and hopefully lessen some of their symptoms.”
 

Are Certain Types of Exercise More Beneficial?

There is no specific type of exercise that is best for OA, so it comes down to patient preference. The best exercise is “whatever somebody is actually going to do,” Dr. Allen noted.

Una Makris, MD, associate professor of internal medicine in the Division of Rheumatic Disease at the University of Texas Southwestern Medical Center and rheumatologist at the North Texas VA Health Care System in Dallas, Texas, said that her practice focuses on a combination of aerobic activity, functional balance, and strength training, as recommended by the World Health Organization.

“It’s not clear to me that one type of exercise is better than another; it’s more about what does this patient enjoy, and how can we make this a routine, so it is a sustainable behavior,” she told this news organization.

Generally, lower-impact exercises like biking, walking, or swimming tend to be better for OA, Dr. Lo added. Several studies have also shown tai chi to be beneficial in patients with OA, she said. More recently, Dr. Lo has conducted research on gardening as an exercise intervention for OA.

“It’s a great way to encourage people to exercise,” she said in an interview. “Besides the fact that they’re physically active, they can also be outside. There are a lot of mental health benefits to doing gardening as well.”

Dr. Allen added that certain exercises should be considered on the basis of an individual’s goals and physical needs. If someone has balance issues, for example, then yoga or tai chi could be useful to add to their exercise program, she said.
 

What Resources Are Available?

The Osteoarthritis Action Alliance has a list of 23 evidence-based exercise programs that have been shown to improve arthritis symptoms. These arthritis-appropriate, evidence-based interventions vary from instructor-led, in-person sessions to self-directed programs.

Walk with Ease (or Camine Con Gusto in Spanish) is one popular program, noted Dr. Allen. The program can be in-person or self-directed, with a required booklet that costs $11.95. However, there are discounted books for community-based organizations. The My Knee Exercise program, created by the University of Melbourne, Australia, provides a free, self-directed, 6-month strengthening program. The availability and cost of other programs are dependent on the format and location, the guide noted.

But understanding what programs are available in certain communities takes time, which can be a barrier to clinician referrals, noted Katie Huffman, director of education and outreach at OA Action Alliance.

“We would love to see these programs being covered by payers and health plans so that there’s incentive for providers to refer and patients to participate in the programs,” she noted.

While some states do cover a limited number of programs under Medicaid, coverage across states and payers is not yet universal.

In addition to these programs, the alliance has a simple guide to help plan workouts based on current activity level. The guide links to free exercises from CreakyJoints, an online community for people with arthritis, and the Arthritis Foundation.

Dr. Lo noted that the Veterans Affairs program, “VA Whole Health,” has free resources that are available to anyone. The provided videos offer tai chi, chair exercises, and guided meditations.

“It’s thoughtful to people who have some limitations in their physical activity,” she said.

Because the program is online, it could be difficult to access for those who are not comfortable with electronics, she said, “but if you can find a way to pass that, I think that this is an amazing resource,” she said.
 

How Do You Motivate Patients to Move?

“When it comes to motivation, I don’t think there is a one-size-fits-all approach,” said Dr. Makris. She tries to identify what matters most for each patient as a starting point. “When they can identify something in their day-to-day life that they value, then I like to link a physical activity-based goal to that,” she said. Setting physical activity goals using the mnemonic SMART (Specific, Measurable, Attainable, Realistic, and Timely) can be useful, she advised.

The OA Action Alliance also provides additional tools for clinicians on how to counsel patients on behavior change.

Understanding the patient’s lifestyle is also crucial when discussing physical activity, Dr. Lo added. “You have to give them practical solutions that they can actually incorporate into their lives,” she said.

Discussions around physical activity should be an ongoing part of clinic visits, both Dr. Lo and Dr. Makris agreed, to celebrate achievements and revise goals.

“I’m kind of notorious for being really slow in clinic because I just let people talk,” Dr. Lo said. “I do feel like these extra moments, when you spend time talking about these things, allow your recommendations to be more customized for the patients” and make the biggest impact.

Dr. Allen, Dr. Lo, and Dr. Makris reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

It’s no secret that regular exercise is important. But for patients with painful joints, it can be the last thing they want to do. Exercise is one of the cornerstones of managing arthritis, yet nearly one third of patients with arthritis are inactive.

Guidelines recommend that clinicians encourage their patients to engage in physical activity, but it can be difficult to know where to start.

This news organization recently spoke to experts on what resources are available, how much exercise is ideal, and how to motivate patients to move more.
 

What Are the Benefits of Exercise in Osteoarthritis?

Nearly all professional societies agree that exercise is one of the hallmarks of managing osteoarthritis (OA). According to two Cochrane reviews, there is high-equality evidence that exercise can help reduce pain as well as improve physical function in both hip and knee OA. In fact, physical activity can decrease pain and improve function by 40% in adults with arthritis, according to the Centers for Disease Control and Prevention.

Exercise also plays a large role in preventing disability by improving joint range of motion as well as maintaining muscle mass that supports joints.

There is also preliminary evidence that exercise could have a structural benefit to osteoarthritic joints. In a study of about 1200 individuals with knee OA, those who walked for exercise not only had reduced frequent knee pain, compared with non-walkers, but also were 20% less likely to have worsening of medial joint space narrowing.

Beyond symptom and impairment improvements, exercise can also play a role in staving off other chronic diseases linked to OA, such as cardiovascular disease and type 2 diabetes. Physical activity and exercise “are effective in preventing at least 35 chronic conditions and treating at least 26 chronic conditions, with one of the potential working mechanisms being exercise-induced anti-inflammatory effects,” wrote the authors of a commentary in the Journal of Orthopaedic & Sports Physical Therapy.

The known mental health benefits of exercise can also be beneficial for patients, as rates of depression and anxiety can be higher in people with arthritis than in the general population.
 

What Is the Ideal Amount of Exercise for Patients?

Current guidelines recommend that adults should get 150 minutes of moderate physical activity each week. But for patients with chronic pain, that may seem unachievable, Kelli Allen, PhD, professor of medicine and exercise physiologist at the University of North Carolina School of Medicine in Chapel Hill, said during a presentation at the American College of Rheumatology 2023 annual meeting in San Diego. Promisingly, research has shown that some exercise is better than none.

One study looking at over 1500 adults with lower extremity joint symptoms suggested that approximately 1 hour of physical activity per week increased the likelihood that participants remained disability-free over 4 years. In another analysis looking at 280 studies, researchers concluded that resistance training programs lasting 3-6 months resulted in moderate improvements in pain and physical function, but these benefits did not depend on exercise volume or participant adherence.

“These findings highlight the flexibility available for clinicians in the prescription of resistance exercise for knee and hip OA without compromising improvements in pain and physical function,” the authors wrote.

Step counts can be another way to measure activity, with 10,000 steps being a common target. But fewer steps a day can also yield health benefits. One study found that among nearly 1800 participants with knee OA, each additional 1000 steps per day was associated with a 16%-18% reduced risk of developing functional limitations 2 years later. Walking 6000 steps a day was the threshold that best determined who would develop functional limitations and who would not.

“I think it’s really a helpful message to encourage people with chronic pain that if you can get to 6000, maybe that’s a good goal,” Dr. Allen said.

Going for a 20-minute walk three times a week can be a good place to start, said Grace H. Lo, MD, associate professor in the Division of Immunology, Allergy, and Rheumatology at Baylor College of Medicine in Houston, Texas. For people who currently do not do any activity, Dr. Lo recommends starting small, like walking to get the mail every day. “Do something practical that is something they can sustain and keep in their daily activities that will help to increase their function and hopefully lessen some of their symptoms.”
 

Are Certain Types of Exercise More Beneficial?

There is no specific type of exercise that is best for OA, so it comes down to patient preference. The best exercise is “whatever somebody is actually going to do,” Dr. Allen noted.

Una Makris, MD, associate professor of internal medicine in the Division of Rheumatic Disease at the University of Texas Southwestern Medical Center and rheumatologist at the North Texas VA Health Care System in Dallas, Texas, said that her practice focuses on a combination of aerobic activity, functional balance, and strength training, as recommended by the World Health Organization.

“It’s not clear to me that one type of exercise is better than another; it’s more about what does this patient enjoy, and how can we make this a routine, so it is a sustainable behavior,” she told this news organization.

Generally, lower-impact exercises like biking, walking, or swimming tend to be better for OA, Dr. Lo added. Several studies have also shown tai chi to be beneficial in patients with OA, she said. More recently, Dr. Lo has conducted research on gardening as an exercise intervention for OA.

“It’s a great way to encourage people to exercise,” she said in an interview. “Besides the fact that they’re physically active, they can also be outside. There are a lot of mental health benefits to doing gardening as well.”

Dr. Allen added that certain exercises should be considered on the basis of an individual’s goals and physical needs. If someone has balance issues, for example, then yoga or tai chi could be useful to add to their exercise program, she said.
 

What Resources Are Available?

The Osteoarthritis Action Alliance has a list of 23 evidence-based exercise programs that have been shown to improve arthritis symptoms. These arthritis-appropriate, evidence-based interventions vary from instructor-led, in-person sessions to self-directed programs.

Walk with Ease (or Camine Con Gusto in Spanish) is one popular program, noted Dr. Allen. The program can be in-person or self-directed, with a required booklet that costs $11.95. However, there are discounted books for community-based organizations. The My Knee Exercise program, created by the University of Melbourne, Australia, provides a free, self-directed, 6-month strengthening program. The availability and cost of other programs are dependent on the format and location, the guide noted.

But understanding what programs are available in certain communities takes time, which can be a barrier to clinician referrals, noted Katie Huffman, director of education and outreach at OA Action Alliance.

“We would love to see these programs being covered by payers and health plans so that there’s incentive for providers to refer and patients to participate in the programs,” she noted.

While some states do cover a limited number of programs under Medicaid, coverage across states and payers is not yet universal.

In addition to these programs, the alliance has a simple guide to help plan workouts based on current activity level. The guide links to free exercises from CreakyJoints, an online community for people with arthritis, and the Arthritis Foundation.

Dr. Lo noted that the Veterans Affairs program, “VA Whole Health,” has free resources that are available to anyone. The provided videos offer tai chi, chair exercises, and guided meditations.

“It’s thoughtful to people who have some limitations in their physical activity,” she said.

Because the program is online, it could be difficult to access for those who are not comfortable with electronics, she said, “but if you can find a way to pass that, I think that this is an amazing resource,” she said.
 

How Do You Motivate Patients to Move?

“When it comes to motivation, I don’t think there is a one-size-fits-all approach,” said Dr. Makris. She tries to identify what matters most for each patient as a starting point. “When they can identify something in their day-to-day life that they value, then I like to link a physical activity-based goal to that,” she said. Setting physical activity goals using the mnemonic SMART (Specific, Measurable, Attainable, Realistic, and Timely) can be useful, she advised.

The OA Action Alliance also provides additional tools for clinicians on how to counsel patients on behavior change.

Understanding the patient’s lifestyle is also crucial when discussing physical activity, Dr. Lo added. “You have to give them practical solutions that they can actually incorporate into their lives,” she said.

Discussions around physical activity should be an ongoing part of clinic visits, both Dr. Lo and Dr. Makris agreed, to celebrate achievements and revise goals.

“I’m kind of notorious for being really slow in clinic because I just let people talk,” Dr. Lo said. “I do feel like these extra moments, when you spend time talking about these things, allow your recommendations to be more customized for the patients” and make the biggest impact.

Dr. Allen, Dr. Lo, and Dr. Makris reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

It’s no secret that regular exercise is important. But for patients with painful joints, it can be the last thing they want to do. Exercise is one of the cornerstones of managing arthritis, yet nearly one third of patients with arthritis are inactive.

Guidelines recommend that clinicians encourage their patients to engage in physical activity, but it can be difficult to know where to start.

This news organization recently spoke to experts on what resources are available, how much exercise is ideal, and how to motivate patients to move more.
 

What Are the Benefits of Exercise in Osteoarthritis?

Nearly all professional societies agree that exercise is one of the hallmarks of managing osteoarthritis (OA). According to two Cochrane reviews, there is high-equality evidence that exercise can help reduce pain as well as improve physical function in both hip and knee OA. In fact, physical activity can decrease pain and improve function by 40% in adults with arthritis, according to the Centers for Disease Control and Prevention.

Exercise also plays a large role in preventing disability by improving joint range of motion as well as maintaining muscle mass that supports joints.

There is also preliminary evidence that exercise could have a structural benefit to osteoarthritic joints. In a study of about 1200 individuals with knee OA, those who walked for exercise not only had reduced frequent knee pain, compared with non-walkers, but also were 20% less likely to have worsening of medial joint space narrowing.

Beyond symptom and impairment improvements, exercise can also play a role in staving off other chronic diseases linked to OA, such as cardiovascular disease and type 2 diabetes. Physical activity and exercise “are effective in preventing at least 35 chronic conditions and treating at least 26 chronic conditions, with one of the potential working mechanisms being exercise-induced anti-inflammatory effects,” wrote the authors of a commentary in the Journal of Orthopaedic & Sports Physical Therapy.

The known mental health benefits of exercise can also be beneficial for patients, as rates of depression and anxiety can be higher in people with arthritis than in the general population.
 

What Is the Ideal Amount of Exercise for Patients?

Current guidelines recommend that adults should get 150 minutes of moderate physical activity each week. But for patients with chronic pain, that may seem unachievable, Kelli Allen, PhD, professor of medicine and exercise physiologist at the University of North Carolina School of Medicine in Chapel Hill, said during a presentation at the American College of Rheumatology 2023 annual meeting in San Diego. Promisingly, research has shown that some exercise is better than none.

One study looking at over 1500 adults with lower extremity joint symptoms suggested that approximately 1 hour of physical activity per week increased the likelihood that participants remained disability-free over 4 years. In another analysis looking at 280 studies, researchers concluded that resistance training programs lasting 3-6 months resulted in moderate improvements in pain and physical function, but these benefits did not depend on exercise volume or participant adherence.

“These findings highlight the flexibility available for clinicians in the prescription of resistance exercise for knee and hip OA without compromising improvements in pain and physical function,” the authors wrote.

Step counts can be another way to measure activity, with 10,000 steps being a common target. But fewer steps a day can also yield health benefits. One study found that among nearly 1800 participants with knee OA, each additional 1000 steps per day was associated with a 16%-18% reduced risk of developing functional limitations 2 years later. Walking 6000 steps a day was the threshold that best determined who would develop functional limitations and who would not.

“I think it’s really a helpful message to encourage people with chronic pain that if you can get to 6000, maybe that’s a good goal,” Dr. Allen said.

Going for a 20-minute walk three times a week can be a good place to start, said Grace H. Lo, MD, associate professor in the Division of Immunology, Allergy, and Rheumatology at Baylor College of Medicine in Houston, Texas. For people who currently do not do any activity, Dr. Lo recommends starting small, like walking to get the mail every day. “Do something practical that is something they can sustain and keep in their daily activities that will help to increase their function and hopefully lessen some of their symptoms.”
 

Are Certain Types of Exercise More Beneficial?

There is no specific type of exercise that is best for OA, so it comes down to patient preference. The best exercise is “whatever somebody is actually going to do,” Dr. Allen noted.

Una Makris, MD, associate professor of internal medicine in the Division of Rheumatic Disease at the University of Texas Southwestern Medical Center and rheumatologist at the North Texas VA Health Care System in Dallas, Texas, said that her practice focuses on a combination of aerobic activity, functional balance, and strength training, as recommended by the World Health Organization.

“It’s not clear to me that one type of exercise is better than another; it’s more about what does this patient enjoy, and how can we make this a routine, so it is a sustainable behavior,” she told this news organization.

Generally, lower-impact exercises like biking, walking, or swimming tend to be better for OA, Dr. Lo added. Several studies have also shown tai chi to be beneficial in patients with OA, she said. More recently, Dr. Lo has conducted research on gardening as an exercise intervention for OA.

“It’s a great way to encourage people to exercise,” she said in an interview. “Besides the fact that they’re physically active, they can also be outside. There are a lot of mental health benefits to doing gardening as well.”

Dr. Allen added that certain exercises should be considered on the basis of an individual’s goals and physical needs. If someone has balance issues, for example, then yoga or tai chi could be useful to add to their exercise program, she said.
 

What Resources Are Available?

The Osteoarthritis Action Alliance has a list of 23 evidence-based exercise programs that have been shown to improve arthritis symptoms. These arthritis-appropriate, evidence-based interventions vary from instructor-led, in-person sessions to self-directed programs.

Walk with Ease (or Camine Con Gusto in Spanish) is one popular program, noted Dr. Allen. The program can be in-person or self-directed, with a required booklet that costs $11.95. However, there are discounted books for community-based organizations. The My Knee Exercise program, created by the University of Melbourne, Australia, provides a free, self-directed, 6-month strengthening program. The availability and cost of other programs are dependent on the format and location, the guide noted.

But understanding what programs are available in certain communities takes time, which can be a barrier to clinician referrals, noted Katie Huffman, director of education and outreach at OA Action Alliance.

“We would love to see these programs being covered by payers and health plans so that there’s incentive for providers to refer and patients to participate in the programs,” she noted.

While some states do cover a limited number of programs under Medicaid, coverage across states and payers is not yet universal.

In addition to these programs, the alliance has a simple guide to help plan workouts based on current activity level. The guide links to free exercises from CreakyJoints, an online community for people with arthritis, and the Arthritis Foundation.

Dr. Lo noted that the Veterans Affairs program, “VA Whole Health,” has free resources that are available to anyone. The provided videos offer tai chi, chair exercises, and guided meditations.

“It’s thoughtful to people who have some limitations in their physical activity,” she said.

Because the program is online, it could be difficult to access for those who are not comfortable with electronics, she said, “but if you can find a way to pass that, I think that this is an amazing resource,” she said.
 

How Do You Motivate Patients to Move?

“When it comes to motivation, I don’t think there is a one-size-fits-all approach,” said Dr. Makris. She tries to identify what matters most for each patient as a starting point. “When they can identify something in their day-to-day life that they value, then I like to link a physical activity-based goal to that,” she said. Setting physical activity goals using the mnemonic SMART (Specific, Measurable, Attainable, Realistic, and Timely) can be useful, she advised.

The OA Action Alliance also provides additional tools for clinicians on how to counsel patients on behavior change.

Understanding the patient’s lifestyle is also crucial when discussing physical activity, Dr. Lo added. “You have to give them practical solutions that they can actually incorporate into their lives,” she said.

Discussions around physical activity should be an ongoing part of clinic visits, both Dr. Lo and Dr. Makris agreed, to celebrate achievements and revise goals.

“I’m kind of notorious for being really slow in clinic because I just let people talk,” Dr. Lo said. “I do feel like these extra moments, when you spend time talking about these things, allow your recommendations to be more customized for the patients” and make the biggest impact.

Dr. Allen, Dr. Lo, and Dr. Makris reported no relevant financial relationships.

A version of this article appeared on Medscape.com.