Steve Cimino

A new study has found that older men with high levels of abdominal aortic calcification (AAC) and a prevalent vertebral fracture – both of which can be assessed via lateral spine radiographs – are at increased risk of hip, clinical vertebral, and major osteoporotic fractures.

“The results of this study and others suggest that it may be appropriate to expand lateral spine imaging to include those with a significant pre-test probability of higher AAC being present,” wrote John T. Schousboe, MD, of the Park Nicollet Clinic and HealthPartners Institute in Bloomington, Minn. The study was published in the Journal of Bone and Mineral Research.

To determine the impact of prevalent vertebral fractures and AAC on fracture risk, the researchers assessed the lateral spine radiographs of 5,365 men who were enrolled in the Osteoporotic Fractures in Men (MrOS) study. All participants were 65 years or older, community dwelling, able to walk without assistance, and without bilateral hip arthroplasties. They split patients’ 24-point AAC (ACC-24) scores at the baseline visit into four levels: 0-1, 2-4, 5-8, and greater than 9. Self-reports of fractures were solicited from the cohort every 4 months.

Of all participants, 7.6% (n = 407) had a prevalent vertebral fracture at baseline. They were, on average, 1.5 years older than participants without a fracture; they were also more likely to be white and to have a prior nonspine fracture, along with having a lower femoral neck BMD (0.718 g/cm², compared with 0.787 g/cm²; P < .001). In addition, significantly more men with a prevalent vertebral fracture had an AAC score greater than 9 (27% vs. 21.2%).

After an average follow-up period of 12.4 years (standard deviation, 5.2), 634 men had a major osteoporotic fracture, 283 had a hip fracture, 206 had a clinical vertebral fracture, and 2,626 died without having any of the three. After adjustment for risk factors such as age, prior nonspine fracture, and prevalent vertebral fracture, men with higher AAC-24 scores had a higher risk of major osteoporotic fracture, compared with men who had scores of 0-1: a hazard ratio of 1.38 (95% confidence interval, 1.10-1.73; P < .001) for scores 2-4, a HR of 1.45 (95% CI, 1.14-1.84; P < .001) for scores 5-8, and a HR of 1.65 (95% CI, 1.29-2.10; P < .001) for scores greater than 9.

Similar findings were reported regarding risk of hip fractures: a HR of 1.54 (95% CI, 1.07-2.20; P < .001) for men with AAC-24 scores 2-4, a HR of 1.40 (95% CI, 0.96-2.06; P < .001) for scores 5-8, and a HR of 2.17 (95% CI, 1.50-3.13; P < .001) for scores greater than 9. AAC-24 score severity was not associated with a higher risk of clinical vertebral fractures.

After adjustment for risk factors and AAC-24 score, men with prevalent vertebral fractures had an increased risk of all three fracture outcomes, compared with men without any fractures at baseline: a HR of 1.56 (95% CI, 1.12-2.16; P < .001) for hip fracture, a HR of 1.85 (95% CI, 1.48-2.31; P < .001) for major osteoporotic fracture, and a HR of 2.76 (95% CI, 1.94-3.91; P < .001) for clinical vertebral fracture.

Adjusting for competing mortality produced similar results: men with higher levels of AAC had increased risk of major osteoporotic fracture and hip fracture, although AAC-24 score was not associated with higher risk of clinical vertebral fractures. Prevalent vertebral fractures were also still associated with higher risk of hip (subdistribution HR, 1.42; 95% CI, 1.01-2.00; P = .004), major osteoporotic fracture (SHR, 1.71; 95% CI, 1.36-2.14; P < .001), and clinical vertebral fracture (SHR, 2.46; 95% CI, 1.72-3.52; P < .001).

Fracture risk assessment proves to be “a nice proof of concept”

“It’s well known that prevalent fractures predict future fractures,” said Thomas M. Link, MD, PhD, chief of the musculoskeletal imaging section in the department of radiology and biomedical imaging at the University of California, San Francisco, in an interview. “The new finding is that aortic calcifications combined with prevalent fractures perform better in predicting major osteoporotic fractures. Traditionally on radiographs, we note that patients who have more calcifications in vessels have less density or calcium in the bone, so this is a nice proof of concept.”

“While the study shows excellent reproducibility, it is not clear how the AAC-24 score was validated,” he added. “Theoretically, abdominal CT could be used for this.”

Along with validation of the AAC-24 score on lateral spine radiographs, he expressed a desire that future research would be “clearer regarding how this would potentially impact patient management. Prevalent fractures already are an indication to treat patients with osteoporosis-specific drugs. How would the results of this study impact management beyond that?”

The authors acknowledged their study’s other potential limitations, including limits in their ability to estimate absolute and relative hip fracture risk in men with low AAC scores but a prevalent vertebral fracture. In addition, they noted that their cohort was “mostly white, healthy, community-dwelling older men” and therefore may not be generalizable to other populations.

The study was supported by the National Institutes of Health, including grants from the National Institute on Aging, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Center for Advancing Translational Sciences, and the NIH Roadmap for Medical Research. One author reported being supported by a National Heart Foundation of Australia Future Leader Fellowship. The others disclosed no potential conflicts of interest.

A new study has found that older men with high levels of abdominal aortic calcification (AAC) and a prevalent vertebral fracture – both of which can be assessed via lateral spine radiographs – are at increased risk of hip, clinical vertebral, and major osteoporotic fractures.

“The results of this study and others suggest that it may be appropriate to expand lateral spine imaging to include those with a significant pre-test probability of higher AAC being present,” wrote John T. Schousboe, MD, of the Park Nicollet Clinic and HealthPartners Institute in Bloomington, Minn. The study was published in the Journal of Bone and Mineral Research.

To determine the impact of prevalent vertebral fractures and AAC on fracture risk, the researchers assessed the lateral spine radiographs of 5,365 men who were enrolled in the Osteoporotic Fractures in Men (MrOS) study. All participants were 65 years or older, community dwelling, able to walk without assistance, and without bilateral hip arthroplasties. They split patients’ 24-point AAC (ACC-24) scores at the baseline visit into four levels: 0-1, 2-4, 5-8, and greater than 9. Self-reports of fractures were solicited from the cohort every 4 months.

Of all participants, 7.6% (n = 407) had a prevalent vertebral fracture at baseline. They were, on average, 1.5 years older than participants without a fracture; they were also more likely to be white and to have a prior nonspine fracture, along with having a lower femoral neck BMD (0.718 g/cm², compared with 0.787 g/cm²; P < .001). In addition, significantly more men with a prevalent vertebral fracture had an AAC score greater than 9 (27% vs. 21.2%).

After an average follow-up period of 12.4 years (standard deviation, 5.2), 634 men had a major osteoporotic fracture, 283 had a hip fracture, 206 had a clinical vertebral fracture, and 2,626 died without having any of the three. After adjustment for risk factors such as age, prior nonspine fracture, and prevalent vertebral fracture, men with higher AAC-24 scores had a higher risk of major osteoporotic fracture, compared with men who had scores of 0-1: a hazard ratio of 1.38 (95% confidence interval, 1.10-1.73; P < .001) for scores 2-4, a HR of 1.45 (95% CI, 1.14-1.84; P < .001) for scores 5-8, and a HR of 1.65 (95% CI, 1.29-2.10; P < .001) for scores greater than 9.

Similar findings were reported regarding risk of hip fractures: a HR of 1.54 (95% CI, 1.07-2.20; P < .001) for men with AAC-24 scores 2-4, a HR of 1.40 (95% CI, 0.96-2.06; P < .001) for scores 5-8, and a HR of 2.17 (95% CI, 1.50-3.13; P < .001) for scores greater than 9. AAC-24 score severity was not associated with a higher risk of clinical vertebral fractures.

After adjustment for risk factors and AAC-24 score, men with prevalent vertebral fractures had an increased risk of all three fracture outcomes, compared with men without any fractures at baseline: a HR of 1.56 (95% CI, 1.12-2.16; P < .001) for hip fracture, a HR of 1.85 (95% CI, 1.48-2.31; P < .001) for major osteoporotic fracture, and a HR of 2.76 (95% CI, 1.94-3.91; P < .001) for clinical vertebral fracture.

Adjusting for competing mortality produced similar results: men with higher levels of AAC had increased risk of major osteoporotic fracture and hip fracture, although AAC-24 score was not associated with higher risk of clinical vertebral fractures. Prevalent vertebral fractures were also still associated with higher risk of hip (subdistribution HR, 1.42; 95% CI, 1.01-2.00; P = .004), major osteoporotic fracture (SHR, 1.71; 95% CI, 1.36-2.14; P < .001), and clinical vertebral fracture (SHR, 2.46; 95% CI, 1.72-3.52; P < .001).

Fracture risk assessment proves to be “a nice proof of concept”

“It’s well known that prevalent fractures predict future fractures,” said Thomas M. Link, MD, PhD, chief of the musculoskeletal imaging section in the department of radiology and biomedical imaging at the University of California, San Francisco, in an interview. “The new finding is that aortic calcifications combined with prevalent fractures perform better in predicting major osteoporotic fractures. Traditionally on radiographs, we note that patients who have more calcifications in vessels have less density or calcium in the bone, so this is a nice proof of concept.”

“While the study shows excellent reproducibility, it is not clear how the AAC-24 score was validated,” he added. “Theoretically, abdominal CT could be used for this.”

Along with validation of the AAC-24 score on lateral spine radiographs, he expressed a desire that future research would be “clearer regarding how this would potentially impact patient management. Prevalent fractures already are an indication to treat patients with osteoporosis-specific drugs. How would the results of this study impact management beyond that?”

The authors acknowledged their study’s other potential limitations, including limits in their ability to estimate absolute and relative hip fracture risk in men with low AAC scores but a prevalent vertebral fracture. In addition, they noted that their cohort was “mostly white, healthy, community-dwelling older men” and therefore may not be generalizable to other populations.

The study was supported by the National Institutes of Health, including grants from the National Institute on Aging, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Center for Advancing Translational Sciences, and the NIH Roadmap for Medical Research. One author reported being supported by a National Heart Foundation of Australia Future Leader Fellowship. The others disclosed no potential conflicts of interest.

A new study has found that older men with high levels of abdominal aortic calcification (AAC) and a prevalent vertebral fracture – both of which can be assessed via lateral spine radiographs – are at increased risk of hip, clinical vertebral, and major osteoporotic fractures.

“The results of this study and others suggest that it may be appropriate to expand lateral spine imaging to include those with a significant pre-test probability of higher AAC being present,” wrote John T. Schousboe, MD, of the Park Nicollet Clinic and HealthPartners Institute in Bloomington, Minn. The study was published in the Journal of Bone and Mineral Research.

To determine the impact of prevalent vertebral fractures and AAC on fracture risk, the researchers assessed the lateral spine radiographs of 5,365 men who were enrolled in the Osteoporotic Fractures in Men (MrOS) study. All participants were 65 years or older, community dwelling, able to walk without assistance, and without bilateral hip arthroplasties. They split patients’ 24-point AAC (ACC-24) scores at the baseline visit into four levels: 0-1, 2-4, 5-8, and greater than 9. Self-reports of fractures were solicited from the cohort every 4 months.

Of all participants, 7.6% (n = 407) had a prevalent vertebral fracture at baseline. They were, on average, 1.5 years older than participants without a fracture; they were also more likely to be white and to have a prior nonspine fracture, along with having a lower femoral neck BMD (0.718 g/cm², compared with 0.787 g/cm²; P < .001). In addition, significantly more men with a prevalent vertebral fracture had an AAC score greater than 9 (27% vs. 21.2%).

After an average follow-up period of 12.4 years (standard deviation, 5.2), 634 men had a major osteoporotic fracture, 283 had a hip fracture, 206 had a clinical vertebral fracture, and 2,626 died without having any of the three. After adjustment for risk factors such as age, prior nonspine fracture, and prevalent vertebral fracture, men with higher AAC-24 scores had a higher risk of major osteoporotic fracture, compared with men who had scores of 0-1: a hazard ratio of 1.38 (95% confidence interval, 1.10-1.73; P < .001) for scores 2-4, a HR of 1.45 (95% CI, 1.14-1.84; P < .001) for scores 5-8, and a HR of 1.65 (95% CI, 1.29-2.10; P < .001) for scores greater than 9.

Similar findings were reported regarding risk of hip fractures: a HR of 1.54 (95% CI, 1.07-2.20; P < .001) for men with AAC-24 scores 2-4, a HR of 1.40 (95% CI, 0.96-2.06; P < .001) for scores 5-8, and a HR of 2.17 (95% CI, 1.50-3.13; P < .001) for scores greater than 9. AAC-24 score severity was not associated with a higher risk of clinical vertebral fractures.

After adjustment for risk factors and AAC-24 score, men with prevalent vertebral fractures had an increased risk of all three fracture outcomes, compared with men without any fractures at baseline: a HR of 1.56 (95% CI, 1.12-2.16; P < .001) for hip fracture, a HR of 1.85 (95% CI, 1.48-2.31; P < .001) for major osteoporotic fracture, and a HR of 2.76 (95% CI, 1.94-3.91; P < .001) for clinical vertebral fracture.

Adjusting for competing mortality produced similar results: men with higher levels of AAC had increased risk of major osteoporotic fracture and hip fracture, although AAC-24 score was not associated with higher risk of clinical vertebral fractures. Prevalent vertebral fractures were also still associated with higher risk of hip (subdistribution HR, 1.42; 95% CI, 1.01-2.00; P = .004), major osteoporotic fracture (SHR, 1.71; 95% CI, 1.36-2.14; P < .001), and clinical vertebral fracture (SHR, 2.46; 95% CI, 1.72-3.52; P < .001).

Fracture risk assessment proves to be “a nice proof of concept”

“It’s well known that prevalent fractures predict future fractures,” said Thomas M. Link, MD, PhD, chief of the musculoskeletal imaging section in the department of radiology and biomedical imaging at the University of California, San Francisco, in an interview. “The new finding is that aortic calcifications combined with prevalent fractures perform better in predicting major osteoporotic fractures. Traditionally on radiographs, we note that patients who have more calcifications in vessels have less density or calcium in the bone, so this is a nice proof of concept.”

“While the study shows excellent reproducibility, it is not clear how the AAC-24 score was validated,” he added. “Theoretically, abdominal CT could be used for this.”

Along with validation of the AAC-24 score on lateral spine radiographs, he expressed a desire that future research would be “clearer regarding how this would potentially impact patient management. Prevalent fractures already are an indication to treat patients with osteoporosis-specific drugs. How would the results of this study impact management beyond that?”

The authors acknowledged their study’s other potential limitations, including limits in their ability to estimate absolute and relative hip fracture risk in men with low AAC scores but a prevalent vertebral fracture. In addition, they noted that their cohort was “mostly white, healthy, community-dwelling older men” and therefore may not be generalizable to other populations.

The study was supported by the National Institutes of Health, including grants from the National Institute on Aging, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Center for Advancing Translational Sciences, and the NIH Roadmap for Medical Research. One author reported being supported by a National Heart Foundation of Australia Future Leader Fellowship. The others disclosed no potential conflicts of interest.

Patients with advanced melanoma and preexisting autoimmune diseases (AIDs) who were treated with immune checkpoint inhibitors (ICIs) responded well and did not suffer more grade 3 or higher immune-related adverse events than patients without an AID, a new study finds, although some concerns were raised regarding patients with inflammatory bowel disease (IBD).

“To our knowledge, this is the first study to bridge this knowledge gap by presenting ‘real-world’ data on the safety and efficacy of ICI on a national scale,” wrote Monique K. van der Kooij, MD, of Leiden (the Netherlands) University Medical Center and coauthors. The study was published online in Annals of Internal Medicine.

To investigate ICI use and response among this specific subset of melanoma patients, the researchers launched a nationwide cohort study set in the Netherlands. Data were gathered via the Dutch Melanoma Treatment Registry (DMTR), in which 4,367 patients with advanced melanoma were enrolled between July 2013 and July 2018.

Within that cohort, 415 (9.5%) had preexisting AIDs. Nearly 55% had rheumatologic AIDs (n = 227) – which included RA, systemic lupus erythematosus, scleroderma, sarcoidosis, and vasculitis – with the next most frequent being endocrine AID (n = 143) and IBD (n = 55). Patients with AID were older than patients without (67 vs. 63 years) and were more likely to be female (53% vs. 41%).

The ICIs used in the study included anti-CTLA4 (ipilimumab), anti–programmed death 1 (PD-1) (nivolumab or pembrolizumab), or a combination of nivolumab and ipilimumab. Of the patients with AID, 55% (n = 228) were treated with ICI, compared with 58% of patients without AID. A total of 87 AID patients were treated with anti-CTLA4, 187 received anti-PD-1, and 34 received the combination. The combination was not readily available in the Netherlands until 2017, the authors stated, acknowledging that it may be wise to revisit its effects in the coming years.

Incidence of immune-related adverse events

The incidence of immune-related adverse events (irAEs) grade 3 and above for patients with and without AID who were given anti-CTLA4 was 30%. The incidence rate of irAEs was also similar for patients with (17%; 95% confidence interval, 12%-23%) and without (13%; 95% CI, 12%-15%) AID on anti-PD-1. Patients with AIDs who took anti-PD-1 therapy discontinued it more often because of toxicity than did the patients without AIDs.

The combination group had irAE incidence rates of 44% (95% CI, 27%-62%) for patients with AID, compared with 48% (95% CI, 43%-53%) for patients without AIDs. Overall, no patients with AIDs on ICIs died of toxicity, compared with three deaths among patients without AID on anti-CTLA4, five deaths among patients on anti-PD-1, and one patient on the combination.

Patients with IBD had a notably higher risk of anti-PD-1–induced colitis (19%; 95% CI, 7%-37%), compared with patients with other AIDs (3%; 95% CI, 0%-6%) and patients without AIDs (2%; 95% CI, 2%-3%). IBD patients were also more likely than all other groups on ICIs to stop treatment because of toxicity, leading the researchers to note that “close monitoring in patients with IBD is advised.”

Overall survival after diagnosis was similar in patients with AIDs (median, 13 months; 95% CI, 10-16 months) and without (median, 14 months; 95% CI, 13-15 months), as was the objective response rate to anti-CTLA4 treatment (10% vs. 16%), anti-PD-1 treatment (40% vs. 44%), and combination therapy (39% vs. 43%).

Study largely bypasses the effects of checkpoint inhibitors on RA patients

“For detail, you can’t look to this study,” Anne R. Bass, MD, of the division of rheumatology at the Hospital for Special Surgery in New York, said in an interview. “But for a big-picture look at ‘how safe are checkpoint inhibitors,’ I think it’s an important one.”

Dr. Bass noted that the investigators lumped certain elements together and bypassed others, including their focus on grade 3 or higher adverse events. That was a decision the authors themselves recognized as a potential limitation of their research.

“Understandably, they were worried about life-threatening adverse events, and that’s fine,” she said. But for patients with arthritis who flare, their events are usually grade 2 or even grade 1 and therefore not captured or analyzed in the study. “This does not really address the risk of flare in an RA patient.”

She also questioned their grouping of AIDs, with a bevy of rheumatic diseases categorized as one cluster and the “other” group being particularly broad in its inclusion of “all AIDs not listed” – though only eight patients were placed into that group.

That said, the researchers relied on an oncology database, not one aimed at AID or adverse events. “The numbers are so much bigger than any other study in this area that’s been done,” she said. “It’s both a strength and a weakness of this kind of database.”

Indeed, the authors considered their use of nationwide, population-based data from the DMTR a benefit, calling it “a strength of our approach.”

The DMTR was funded by a grant from the Netherlands Organization for Health Research and Development and sponsored by Bristol-Myers Squibb, Novartis, Roche Nederland, Merck Sharp & Dohme, and Pierre Fabre via the Dutch Institute for Clinical Auditing.

Patients with advanced melanoma and preexisting autoimmune diseases (AIDs) who were treated with immune checkpoint inhibitors (ICIs) responded well and did not suffer more grade 3 or higher immune-related adverse events than patients without an AID, a new study finds, although some concerns were raised regarding patients with inflammatory bowel disease (IBD).

“To our knowledge, this is the first study to bridge this knowledge gap by presenting ‘real-world’ data on the safety and efficacy of ICI on a national scale,” wrote Monique K. van der Kooij, MD, of Leiden (the Netherlands) University Medical Center and coauthors. The study was published online in Annals of Internal Medicine.

To investigate ICI use and response among this specific subset of melanoma patients, the researchers launched a nationwide cohort study set in the Netherlands. Data were gathered via the Dutch Melanoma Treatment Registry (DMTR), in which 4,367 patients with advanced melanoma were enrolled between July 2013 and July 2018.

Within that cohort, 415 (9.5%) had preexisting AIDs. Nearly 55% had rheumatologic AIDs (n = 227) – which included RA, systemic lupus erythematosus, scleroderma, sarcoidosis, and vasculitis – with the next most frequent being endocrine AID (n = 143) and IBD (n = 55). Patients with AID were older than patients without (67 vs. 63 years) and were more likely to be female (53% vs. 41%).

The ICIs used in the study included anti-CTLA4 (ipilimumab), anti–programmed death 1 (PD-1) (nivolumab or pembrolizumab), or a combination of nivolumab and ipilimumab. Of the patients with AID, 55% (n = 228) were treated with ICI, compared with 58% of patients without AID. A total of 87 AID patients were treated with anti-CTLA4, 187 received anti-PD-1, and 34 received the combination. The combination was not readily available in the Netherlands until 2017, the authors stated, acknowledging that it may be wise to revisit its effects in the coming years.

Incidence of immune-related adverse events

The incidence of immune-related adverse events (irAEs) grade 3 and above for patients with and without AID who were given anti-CTLA4 was 30%. The incidence rate of irAEs was also similar for patients with (17%; 95% confidence interval, 12%-23%) and without (13%; 95% CI, 12%-15%) AID on anti-PD-1. Patients with AIDs who took anti-PD-1 therapy discontinued it more often because of toxicity than did the patients without AIDs.

The combination group had irAE incidence rates of 44% (95% CI, 27%-62%) for patients with AID, compared with 48% (95% CI, 43%-53%) for patients without AIDs. Overall, no patients with AIDs on ICIs died of toxicity, compared with three deaths among patients without AID on anti-CTLA4, five deaths among patients on anti-PD-1, and one patient on the combination.

Patients with IBD had a notably higher risk of anti-PD-1–induced colitis (19%; 95% CI, 7%-37%), compared with patients with other AIDs (3%; 95% CI, 0%-6%) and patients without AIDs (2%; 95% CI, 2%-3%). IBD patients were also more likely than all other groups on ICIs to stop treatment because of toxicity, leading the researchers to note that “close monitoring in patients with IBD is advised.”

Overall survival after diagnosis was similar in patients with AIDs (median, 13 months; 95% CI, 10-16 months) and without (median, 14 months; 95% CI, 13-15 months), as was the objective response rate to anti-CTLA4 treatment (10% vs. 16%), anti-PD-1 treatment (40% vs. 44%), and combination therapy (39% vs. 43%).

Study largely bypasses the effects of checkpoint inhibitors on RA patients

“For detail, you can’t look to this study,” Anne R. Bass, MD, of the division of rheumatology at the Hospital for Special Surgery in New York, said in an interview. “But for a big-picture look at ‘how safe are checkpoint inhibitors,’ I think it’s an important one.”

Dr. Bass noted that the investigators lumped certain elements together and bypassed others, including their focus on grade 3 or higher adverse events. That was a decision the authors themselves recognized as a potential limitation of their research.

“Understandably, they were worried about life-threatening adverse events, and that’s fine,” she said. But for patients with arthritis who flare, their events are usually grade 2 or even grade 1 and therefore not captured or analyzed in the study. “This does not really address the risk of flare in an RA patient.”

She also questioned their grouping of AIDs, with a bevy of rheumatic diseases categorized as one cluster and the “other” group being particularly broad in its inclusion of “all AIDs not listed” – though only eight patients were placed into that group.

That said, the researchers relied on an oncology database, not one aimed at AID or adverse events. “The numbers are so much bigger than any other study in this area that’s been done,” she said. “It’s both a strength and a weakness of this kind of database.”

Indeed, the authors considered their use of nationwide, population-based data from the DMTR a benefit, calling it “a strength of our approach.”

The DMTR was funded by a grant from the Netherlands Organization for Health Research and Development and sponsored by Bristol-Myers Squibb, Novartis, Roche Nederland, Merck Sharp & Dohme, and Pierre Fabre via the Dutch Institute for Clinical Auditing.

Patients with advanced melanoma and preexisting autoimmune diseases (AIDs) who were treated with immune checkpoint inhibitors (ICIs) responded well and did not suffer more grade 3 or higher immune-related adverse events than patients without an AID, a new study finds, although some concerns were raised regarding patients with inflammatory bowel disease (IBD).

“To our knowledge, this is the first study to bridge this knowledge gap by presenting ‘real-world’ data on the safety and efficacy of ICI on a national scale,” wrote Monique K. van der Kooij, MD, of Leiden (the Netherlands) University Medical Center and coauthors. The study was published online in Annals of Internal Medicine.

To investigate ICI use and response among this specific subset of melanoma patients, the researchers launched a nationwide cohort study set in the Netherlands. Data were gathered via the Dutch Melanoma Treatment Registry (DMTR), in which 4,367 patients with advanced melanoma were enrolled between July 2013 and July 2018.

Within that cohort, 415 (9.5%) had preexisting AIDs. Nearly 55% had rheumatologic AIDs (n = 227) – which included RA, systemic lupus erythematosus, scleroderma, sarcoidosis, and vasculitis – with the next most frequent being endocrine AID (n = 143) and IBD (n = 55). Patients with AID were older than patients without (67 vs. 63 years) and were more likely to be female (53% vs. 41%).

The ICIs used in the study included anti-CTLA4 (ipilimumab), anti–programmed death 1 (PD-1) (nivolumab or pembrolizumab), or a combination of nivolumab and ipilimumab. Of the patients with AID, 55% (n = 228) were treated with ICI, compared with 58% of patients without AID. A total of 87 AID patients were treated with anti-CTLA4, 187 received anti-PD-1, and 34 received the combination. The combination was not readily available in the Netherlands until 2017, the authors stated, acknowledging that it may be wise to revisit its effects in the coming years.

Incidence of immune-related adverse events

The incidence of immune-related adverse events (irAEs) grade 3 and above for patients with and without AID who were given anti-CTLA4 was 30%. The incidence rate of irAEs was also similar for patients with (17%; 95% confidence interval, 12%-23%) and without (13%; 95% CI, 12%-15%) AID on anti-PD-1. Patients with AIDs who took anti-PD-1 therapy discontinued it more often because of toxicity than did the patients without AIDs.

The combination group had irAE incidence rates of 44% (95% CI, 27%-62%) for patients with AID, compared with 48% (95% CI, 43%-53%) for patients without AIDs. Overall, no patients with AIDs on ICIs died of toxicity, compared with three deaths among patients without AID on anti-CTLA4, five deaths among patients on anti-PD-1, and one patient on the combination.

Patients with IBD had a notably higher risk of anti-PD-1–induced colitis (19%; 95% CI, 7%-37%), compared with patients with other AIDs (3%; 95% CI, 0%-6%) and patients without AIDs (2%; 95% CI, 2%-3%). IBD patients were also more likely than all other groups on ICIs to stop treatment because of toxicity, leading the researchers to note that “close monitoring in patients with IBD is advised.”

Overall survival after diagnosis was similar in patients with AIDs (median, 13 months; 95% CI, 10-16 months) and without (median, 14 months; 95% CI, 13-15 months), as was the objective response rate to anti-CTLA4 treatment (10% vs. 16%), anti-PD-1 treatment (40% vs. 44%), and combination therapy (39% vs. 43%).

Study largely bypasses the effects of checkpoint inhibitors on RA patients

“For detail, you can’t look to this study,” Anne R. Bass, MD, of the division of rheumatology at the Hospital for Special Surgery in New York, said in an interview. “But for a big-picture look at ‘how safe are checkpoint inhibitors,’ I think it’s an important one.”

Dr. Bass noted that the investigators lumped certain elements together and bypassed others, including their focus on grade 3 or higher adverse events. That was a decision the authors themselves recognized as a potential limitation of their research.

“Understandably, they were worried about life-threatening adverse events, and that’s fine,” she said. But for patients with arthritis who flare, their events are usually grade 2 or even grade 1 and therefore not captured or analyzed in the study. “This does not really address the risk of flare in an RA patient.”

She also questioned their grouping of AIDs, with a bevy of rheumatic diseases categorized as one cluster and the “other” group being particularly broad in its inclusion of “all AIDs not listed” – though only eight patients were placed into that group.

That said, the researchers relied on an oncology database, not one aimed at AID or adverse events. “The numbers are so much bigger than any other study in this area that’s been done,” she said. “It’s both a strength and a weakness of this kind of database.”

Indeed, the authors considered their use of nationwide, population-based data from the DMTR a benefit, calling it “a strength of our approach.”

The DMTR was funded by a grant from the Netherlands Organization for Health Research and Development and sponsored by Bristol-Myers Squibb, Novartis, Roche Nederland, Merck Sharp & Dohme, and Pierre Fabre via the Dutch Institute for Clinical Auditing.

Daily treatment with tofacitinib (Xeljanz) led to more malignancies and adverse cardiovascular events in older rheumatoid arthritis patients compared with treatment with a tumor necrosis factor (TNF) inhibitor, according to the partial results of a safety study announced last week by Pfizer.

The postmarketing study known as ORAL Surveillance began in 2014 to evaluate the safety of the Janus kinase (JAK) inhibitor tofacitinib compared to a TNF inhibitor in RA patients 50 years of age or older with at least one additional cardiovascular risk factor. Its 4,362 participants were randomized to either daily doses of 5 mg (n = 1,455) or 10 mg (n = 1,456) of tofacitinib or the TNFi (n = 1,451), which was adalimumab for patients in the United States, Canada, and Puerto Rico, and etanercept elsewhere. During analysis, adverse events were pooled for all patients on tofacitinib.

Overall, 135 patients developed major adverse cardiovascular events (MACE) and 164 developed malignancies – excluding nonmelanoma skin cancer. The incidence of adjudicated malignancies was significantly higher in the tofacitinib group, compared with the TNFi group (1.13 vs. 0.77 per 100 person-years; hazard ratio, 1.48; 95% confidence interval, 1.04-2.09). The rate of MACE was also higher in the combined tofacitinib group (0.98 vs. 0.73 per 100 person-years; HR, 1.33; 95% CI, 0.91-1.94). Both rates for tofacitinib did not meet the trial’s noninferiority criteria.

Among the patients on tofacitinib, the most reported MACE was myocardial infarction and the most reported malignancy was lung cancer. Study participants with noted risk factors – including older age and smoking – were more likely to experience adverse events.

In February 2019, patients in the 10-mg tofacitinib group were switched to the 5-mg because of a safety signal indicating increased risk of pulmonary embolism and death.

Tofacitinib was approved for RA in November 2012, though concerns about serious side effects had been noted during clinical trials and a boxed warning was ultimately added to the drug’s label. Tofacitinib is also approved for adults with active psoriatic arthritis, adults with moderately to severely active ulcerative colitis, and patients aged 2 years or older with active polyarticular course juvenile idiopathic arthritis. Other JAK inhibitors such as baricitinib and upadacitinib have been approved for RA in the interim as well, though the higher dose of baricitinib was rejected in committee because of safety concerns and both their boxes also warn against infections, thrombosis, and cancer.

A postmarketing safety study on baricitinib is expected to be completed in 2025.

The full results of the ORAL Surveillance study – which should address safety regarding pulmonary embolism and mortality, as well as efficacy data – have not yet been released. “Pfizer is working with the [FDA] and other regulatory agencies to review the full results and analyses as they become available,” the press release said.

Daily treatment with tofacitinib (Xeljanz) led to more malignancies and adverse cardiovascular events in older rheumatoid arthritis patients compared with treatment with a tumor necrosis factor (TNF) inhibitor, according to the partial results of a safety study announced last week by Pfizer.

The postmarketing study known as ORAL Surveillance began in 2014 to evaluate the safety of the Janus kinase (JAK) inhibitor tofacitinib compared to a TNF inhibitor in RA patients 50 years of age or older with at least one additional cardiovascular risk factor. Its 4,362 participants were randomized to either daily doses of 5 mg (n = 1,455) or 10 mg (n = 1,456) of tofacitinib or the TNFi (n = 1,451), which was adalimumab for patients in the United States, Canada, and Puerto Rico, and etanercept elsewhere. During analysis, adverse events were pooled for all patients on tofacitinib.

Overall, 135 patients developed major adverse cardiovascular events (MACE) and 164 developed malignancies – excluding nonmelanoma skin cancer. The incidence of adjudicated malignancies was significantly higher in the tofacitinib group, compared with the TNFi group (1.13 vs. 0.77 per 100 person-years; hazard ratio, 1.48; 95% confidence interval, 1.04-2.09). The rate of MACE was also higher in the combined tofacitinib group (0.98 vs. 0.73 per 100 person-years; HR, 1.33; 95% CI, 0.91-1.94). Both rates for tofacitinib did not meet the trial’s noninferiority criteria.

Among the patients on tofacitinib, the most reported MACE was myocardial infarction and the most reported malignancy was lung cancer. Study participants with noted risk factors – including older age and smoking – were more likely to experience adverse events.

In February 2019, patients in the 10-mg tofacitinib group were switched to the 5-mg because of a safety signal indicating increased risk of pulmonary embolism and death.

Tofacitinib was approved for RA in November 2012, though concerns about serious side effects had been noted during clinical trials and a boxed warning was ultimately added to the drug’s label. Tofacitinib is also approved for adults with active psoriatic arthritis, adults with moderately to severely active ulcerative colitis, and patients aged 2 years or older with active polyarticular course juvenile idiopathic arthritis. Other JAK inhibitors such as baricitinib and upadacitinib have been approved for RA in the interim as well, though the higher dose of baricitinib was rejected in committee because of safety concerns and both their boxes also warn against infections, thrombosis, and cancer.

A postmarketing safety study on baricitinib is expected to be completed in 2025.

The full results of the ORAL Surveillance study – which should address safety regarding pulmonary embolism and mortality, as well as efficacy data – have not yet been released. “Pfizer is working with the [FDA] and other regulatory agencies to review the full results and analyses as they become available,” the press release said.

Daily treatment with tofacitinib (Xeljanz) led to more malignancies and adverse cardiovascular events in older rheumatoid arthritis patients compared with treatment with a tumor necrosis factor (TNF) inhibitor, according to the partial results of a safety study announced last week by Pfizer.

The postmarketing study known as ORAL Surveillance began in 2014 to evaluate the safety of the Janus kinase (JAK) inhibitor tofacitinib compared to a TNF inhibitor in RA patients 50 years of age or older with at least one additional cardiovascular risk factor. Its 4,362 participants were randomized to either daily doses of 5 mg (n = 1,455) or 10 mg (n = 1,456) of tofacitinib or the TNFi (n = 1,451), which was adalimumab for patients in the United States, Canada, and Puerto Rico, and etanercept elsewhere. During analysis, adverse events were pooled for all patients on tofacitinib.

Overall, 135 patients developed major adverse cardiovascular events (MACE) and 164 developed malignancies – excluding nonmelanoma skin cancer. The incidence of adjudicated malignancies was significantly higher in the tofacitinib group, compared with the TNFi group (1.13 vs. 0.77 per 100 person-years; hazard ratio, 1.48; 95% confidence interval, 1.04-2.09). The rate of MACE was also higher in the combined tofacitinib group (0.98 vs. 0.73 per 100 person-years; HR, 1.33; 95% CI, 0.91-1.94). Both rates for tofacitinib did not meet the trial’s noninferiority criteria.

Among the patients on tofacitinib, the most reported MACE was myocardial infarction and the most reported malignancy was lung cancer. Study participants with noted risk factors – including older age and smoking – were more likely to experience adverse events.

In February 2019, patients in the 10-mg tofacitinib group were switched to the 5-mg because of a safety signal indicating increased risk of pulmonary embolism and death.

Tofacitinib was approved for RA in November 2012, though concerns about serious side effects had been noted during clinical trials and a boxed warning was ultimately added to the drug’s label. Tofacitinib is also approved for adults with active psoriatic arthritis, adults with moderately to severely active ulcerative colitis, and patients aged 2 years or older with active polyarticular course juvenile idiopathic arthritis. Other JAK inhibitors such as baricitinib and upadacitinib have been approved for RA in the interim as well, though the higher dose of baricitinib was rejected in committee because of safety concerns and both their boxes also warn against infections, thrombosis, and cancer.

A postmarketing safety study on baricitinib is expected to be completed in 2025.

The full results of the ORAL Surveillance study – which should address safety regarding pulmonary embolism and mortality, as well as efficacy data – have not yet been released. “Pfizer is working with the [FDA] and other regulatory agencies to review the full results and analyses as they become available,” the press release said.

Inhaled treprostinil improved the exercise capacity of patients with pulmonary hypertension attributable to interstitial lung disease and was associated with some additional clinical benefits, according to a new study published in the New England Journal of Medicine.

To investigate treprostinil therapy for pulmonary hypertension in this subset of patients with lung disease, Aaron Waxman, MD, PhD, of Brigham and Women’s Hospital in Boston, and his fellow researchers launched the multicenter, randomized, double-blind, placebo-controlled INCREASE trial. They assigned 163 patients to the inhaled treprostinil group – administered via an ultrasonic, pulsed-delivery nebulizer over 16 weeks – and 163 patients to the placebo group. Their average age was 66.5 years, 73% were white, and 47% were female

At baseline, the mean 6-minute walk distance (6MWD) for all patients was 259.6 m. After 16 weeks, the treprostinil group gained a mean of 21.08 m in 6MWD, and the placebo group lost 10.04 m. The least-squares mean difference between the groups from baseline in the 6MWD was 31.12 m (95% confidence interval, 16.85-45.39; P < .001). After sensitivity analysis with multiple imputation, the difference remained significant at 30.97 m (95% CI, 16.53-45.41; P < .001).

In a comparison of N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels from baseline to 16 weeks, the treprostinil group saw a decrease of 15% while the placebo group’s levels increased by 46% (treatment ratio 0.58; 95% CI, 0.47-0.72; P < .001). Clinical worsening occurred in 37 patients (23%) in the treprostinil group and 54 patients (33%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40-0.92; P = .04), while serious adverse events occurred in 23.3% of the patients on treprostinil and 25.8% of the patients on placebo. There was no significant difference between groups in patient-reported quality of life, as assessed via the St. George’s Respiratory Questionnaire.

“There was no guarantee that this was going to work in this condition,” said Adriano Tonelli, MD, of the department of pulmonary medicine at the Cleveland Clinic, in an interview. “Several small studies have tried different medications, for pulmonary hypertension or otherwise, in patients with interstitial lung disease with minimal effect, if any. Given that all the prior studies were not categorically positive, the expectation, at least on my end, was that we needed to wait and see.” Dr. Tonelli and coauthors published a post hoc analysis of inhaled treprostinil studied in the TRIUMPH and BEAT trials.

Next steps: Assess clinical outcomes after inhaled treprostinil

Although the results of this study by Waxman et al, are encouraging, and the need for a treatment in this type of pulmonary hypertension is very real, more narrowing down will be needed to confirm the benefits of inhaled treprostinil, wrote Darren B. Taichman, MD, PhD, of the University of Pennsylvania in an accompanying editorial. He wrote, “After all, patients and physicians may reason, ‘It can’t hurt.’ Unfortunately, however, it could. Therapies approved for pulmonary arterial hypertension have been studied in patients with [ILD]-associated pulmonary hypertension and have shown inconsistent results, with some studies showing no benefit or suggesting harm.”

While the 6MWD has been used as an end point in previous drug trials for pulmonary arterial hypertension, Dr. Taichman wrote that improvements in such a variable were “probably too modest to be unequivocally consequential for many patients.” To confirm the benefits – and detriments – of treatments like inhaled treprostinil, it’s time for studies to focus on clinical end points, he stated, including hospitalizations, disease progression, and death.

He also highlighted the disparity between a treatment that led to increased walk distance and decreased clinical worsening yet did not register an improvement in health-related quality of life. He noted that the oft-cited minimal clinically important difference for 6MWD is approximately 30 m – similar to the difference recorded here. That said, he wrote, “prevention of deterioration is not to be ignored, even if it does not make a patient feel better.”

Regarding quality of life, Dr. Tonelli observed that this questionnaire, standard fare in respiratory research, may not have been perfectly suited for this particular study.

“You have to put it in the context of, ‘How good is the questionnaire to capture a difference in this particular disease over a 16-week period?’ ” he said. “It might not be sensitive enough to capture a significant change. The questionnaire was not developed for pulmonary hypertension in interstitial lung disease, of course. It was developed more generically. It may not capture all that you need to show significance.”

The investigators acknowledged the study’s other potential limitations, including a short duration, a notable percentage of patients who discontinued the trial early, and the fact that clinical worsening and exacerbation of disease were investigator reported and not confirmed by an independent committee.

As for next steps in assessing pulmonary hypertension treatments, Dr. Tonelli pointed to the direction of future research. “The other big study that needs to come out in our field, and I believe it’s being worked on, is inhaled treprostinil in pulmonary hypertension due to chronic obstructive pulmonary disease [COPD],” he said. “That’s a major unmet need; the COPD population is larger than the population for interstitial lung disease, and one would wonder whether inhaled treprostinil would benefit those patients as well. At the moment, we have no treatments for that condition. In the future, a COPD study will be needed.”

The study was supported by United Therapeutics. Author disclosures are listed on the New England Journal of Medicine website.

Inhaled treprostinil improved the exercise capacity of patients with pulmonary hypertension attributable to interstitial lung disease and was associated with some additional clinical benefits, according to a new study published in the New England Journal of Medicine.

To investigate treprostinil therapy for pulmonary hypertension in this subset of patients with lung disease, Aaron Waxman, MD, PhD, of Brigham and Women’s Hospital in Boston, and his fellow researchers launched the multicenter, randomized, double-blind, placebo-controlled INCREASE trial. They assigned 163 patients to the inhaled treprostinil group – administered via an ultrasonic, pulsed-delivery nebulizer over 16 weeks – and 163 patients to the placebo group. Their average age was 66.5 years, 73% were white, and 47% were female

At baseline, the mean 6-minute walk distance (6MWD) for all patients was 259.6 m. After 16 weeks, the treprostinil group gained a mean of 21.08 m in 6MWD, and the placebo group lost 10.04 m. The least-squares mean difference between the groups from baseline in the 6MWD was 31.12 m (95% confidence interval, 16.85-45.39; P < .001). After sensitivity analysis with multiple imputation, the difference remained significant at 30.97 m (95% CI, 16.53-45.41; P < .001).

In a comparison of N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels from baseline to 16 weeks, the treprostinil group saw a decrease of 15% while the placebo group’s levels increased by 46% (treatment ratio 0.58; 95% CI, 0.47-0.72; P < .001). Clinical worsening occurred in 37 patients (23%) in the treprostinil group and 54 patients (33%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40-0.92; P = .04), while serious adverse events occurred in 23.3% of the patients on treprostinil and 25.8% of the patients on placebo. There was no significant difference between groups in patient-reported quality of life, as assessed via the St. George’s Respiratory Questionnaire.

“There was no guarantee that this was going to work in this condition,” said Adriano Tonelli, MD, of the department of pulmonary medicine at the Cleveland Clinic, in an interview. “Several small studies have tried different medications, for pulmonary hypertension or otherwise, in patients with interstitial lung disease with minimal effect, if any. Given that all the prior studies were not categorically positive, the expectation, at least on my end, was that we needed to wait and see.” Dr. Tonelli and coauthors published a post hoc analysis of inhaled treprostinil studied in the TRIUMPH and BEAT trials.

Next steps: Assess clinical outcomes after inhaled treprostinil

Although the results of this study by Waxman et al, are encouraging, and the need for a treatment in this type of pulmonary hypertension is very real, more narrowing down will be needed to confirm the benefits of inhaled treprostinil, wrote Darren B. Taichman, MD, PhD, of the University of Pennsylvania in an accompanying editorial. He wrote, “After all, patients and physicians may reason, ‘It can’t hurt.’ Unfortunately, however, it could. Therapies approved for pulmonary arterial hypertension have been studied in patients with [ILD]-associated pulmonary hypertension and have shown inconsistent results, with some studies showing no benefit or suggesting harm.”

While the 6MWD has been used as an end point in previous drug trials for pulmonary arterial hypertension, Dr. Taichman wrote that improvements in such a variable were “probably too modest to be unequivocally consequential for many patients.” To confirm the benefits – and detriments – of treatments like inhaled treprostinil, it’s time for studies to focus on clinical end points, he stated, including hospitalizations, disease progression, and death.

He also highlighted the disparity between a treatment that led to increased walk distance and decreased clinical worsening yet did not register an improvement in health-related quality of life. He noted that the oft-cited minimal clinically important difference for 6MWD is approximately 30 m – similar to the difference recorded here. That said, he wrote, “prevention of deterioration is not to be ignored, even if it does not make a patient feel better.”

Regarding quality of life, Dr. Tonelli observed that this questionnaire, standard fare in respiratory research, may not have been perfectly suited for this particular study.

“You have to put it in the context of, ‘How good is the questionnaire to capture a difference in this particular disease over a 16-week period?’ ” he said. “It might not be sensitive enough to capture a significant change. The questionnaire was not developed for pulmonary hypertension in interstitial lung disease, of course. It was developed more generically. It may not capture all that you need to show significance.”

The investigators acknowledged the study’s other potential limitations, including a short duration, a notable percentage of patients who discontinued the trial early, and the fact that clinical worsening and exacerbation of disease were investigator reported and not confirmed by an independent committee.

As for next steps in assessing pulmonary hypertension treatments, Dr. Tonelli pointed to the direction of future research. “The other big study that needs to come out in our field, and I believe it’s being worked on, is inhaled treprostinil in pulmonary hypertension due to chronic obstructive pulmonary disease [COPD],” he said. “That’s a major unmet need; the COPD population is larger than the population for interstitial lung disease, and one would wonder whether inhaled treprostinil would benefit those patients as well. At the moment, we have no treatments for that condition. In the future, a COPD study will be needed.”

The study was supported by United Therapeutics. Author disclosures are listed on the New England Journal of Medicine website.

Inhaled treprostinil improved the exercise capacity of patients with pulmonary hypertension attributable to interstitial lung disease and was associated with some additional clinical benefits, according to a new study published in the New England Journal of Medicine.

To investigate treprostinil therapy for pulmonary hypertension in this subset of patients with lung disease, Aaron Waxman, MD, PhD, of Brigham and Women’s Hospital in Boston, and his fellow researchers launched the multicenter, randomized, double-blind, placebo-controlled INCREASE trial. They assigned 163 patients to the inhaled treprostinil group – administered via an ultrasonic, pulsed-delivery nebulizer over 16 weeks – and 163 patients to the placebo group. Their average age was 66.5 years, 73% were white, and 47% were female

At baseline, the mean 6-minute walk distance (6MWD) for all patients was 259.6 m. After 16 weeks, the treprostinil group gained a mean of 21.08 m in 6MWD, and the placebo group lost 10.04 m. The least-squares mean difference between the groups from baseline in the 6MWD was 31.12 m (95% confidence interval, 16.85-45.39; P < .001). After sensitivity analysis with multiple imputation, the difference remained significant at 30.97 m (95% CI, 16.53-45.41; P < .001).

In a comparison of N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels from baseline to 16 weeks, the treprostinil group saw a decrease of 15% while the placebo group’s levels increased by 46% (treatment ratio 0.58; 95% CI, 0.47-0.72; P < .001). Clinical worsening occurred in 37 patients (23%) in the treprostinil group and 54 patients (33%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40-0.92; P = .04), while serious adverse events occurred in 23.3% of the patients on treprostinil and 25.8% of the patients on placebo. There was no significant difference between groups in patient-reported quality of life, as assessed via the St. George’s Respiratory Questionnaire.

“There was no guarantee that this was going to work in this condition,” said Adriano Tonelli, MD, of the department of pulmonary medicine at the Cleveland Clinic, in an interview. “Several small studies have tried different medications, for pulmonary hypertension or otherwise, in patients with interstitial lung disease with minimal effect, if any. Given that all the prior studies were not categorically positive, the expectation, at least on my end, was that we needed to wait and see.” Dr. Tonelli and coauthors published a post hoc analysis of inhaled treprostinil studied in the TRIUMPH and BEAT trials.

Next steps: Assess clinical outcomes after inhaled treprostinil

Although the results of this study by Waxman et al, are encouraging, and the need for a treatment in this type of pulmonary hypertension is very real, more narrowing down will be needed to confirm the benefits of inhaled treprostinil, wrote Darren B. Taichman, MD, PhD, of the University of Pennsylvania in an accompanying editorial. He wrote, “After all, patients and physicians may reason, ‘It can’t hurt.’ Unfortunately, however, it could. Therapies approved for pulmonary arterial hypertension have been studied in patients with [ILD]-associated pulmonary hypertension and have shown inconsistent results, with some studies showing no benefit or suggesting harm.”

While the 6MWD has been used as an end point in previous drug trials for pulmonary arterial hypertension, Dr. Taichman wrote that improvements in such a variable were “probably too modest to be unequivocally consequential for many patients.” To confirm the benefits – and detriments – of treatments like inhaled treprostinil, it’s time for studies to focus on clinical end points, he stated, including hospitalizations, disease progression, and death.

He also highlighted the disparity between a treatment that led to increased walk distance and decreased clinical worsening yet did not register an improvement in health-related quality of life. He noted that the oft-cited minimal clinically important difference for 6MWD is approximately 30 m – similar to the difference recorded here. That said, he wrote, “prevention of deterioration is not to be ignored, even if it does not make a patient feel better.”

Regarding quality of life, Dr. Tonelli observed that this questionnaire, standard fare in respiratory research, may not have been perfectly suited for this particular study.

“You have to put it in the context of, ‘How good is the questionnaire to capture a difference in this particular disease over a 16-week period?’ ” he said. “It might not be sensitive enough to capture a significant change. The questionnaire was not developed for pulmonary hypertension in interstitial lung disease, of course. It was developed more generically. It may not capture all that you need to show significance.”

The investigators acknowledged the study’s other potential limitations, including a short duration, a notable percentage of patients who discontinued the trial early, and the fact that clinical worsening and exacerbation of disease were investigator reported and not confirmed by an independent committee.

As for next steps in assessing pulmonary hypertension treatments, Dr. Tonelli pointed to the direction of future research. “The other big study that needs to come out in our field, and I believe it’s being worked on, is inhaled treprostinil in pulmonary hypertension due to chronic obstructive pulmonary disease [COPD],” he said. “That’s a major unmet need; the COPD population is larger than the population for interstitial lung disease, and one would wonder whether inhaled treprostinil would benefit those patients as well. At the moment, we have no treatments for that condition. In the future, a COPD study will be needed.”

The study was supported by United Therapeutics. Author disclosures are listed on the New England Journal of Medicine website.

Hospitalized patients with Ehlers-Danlos syndrome (EDS) are more likely to have gastrointestinal, cardiovascular, autonomic, and allergic disorders than are hospitalized patients who do not have EDS, according to a new study of hospital outcomes in these four areas.

“Further research is necessary to explore the prevalence of these manifestations in the different subtypes of EDS and in outpatient population,” wrote Rachel S. Brooks of the University of Connecticut, Farmington, and her coauthors. The study was published in Rheumatology.

To investigate previously observed connections between EDS and these four types of complications, the researchers launched a case-control study using hospital records from the 2016 National Inpatient Sample. A total of 2,007 patients with EDS were identified via ICD-10 code and matched with 4,014 non-EDS patients according to 5-year age intervals, sex, and month of admission. EDS patients had an average age of nearly 37, and 84% were female. The average hospitalization was lengthier for EDS patients (4.77 days) than for controls (4.07 days).

GI conditions were found in 44% of EDS patients, compared with 18% of controls (odds ratio, 3.57; 95% confidence interval, 3.17-4.02; P < .0001). Among the more likely conditions were functional disorders of the stomach (OR, 5.18; 95% CI, 2.16-12.42; P < .0001), unspecified abdominal pain (OR, 3.97; 95% CI, 2.34-6.73; P < .0001), irritable bowel syndrome (OR, 7.44; 95% CI, 5.07-10.94; P < .0001), and nausea (OR, 3.20; 95% CI, 1.95-5.24; P < .0001).

Autonomic dysfunction was found in 20% of EDS patients, compared with 6% of controls (OR, 4.45; 95% CI, 3.71-5.32; P < .0001). They were significantly more likely to have postural orthostatic tachycardia syndrome (OR, 223.77; 95% CI, 31.21-1604.46; P < .0001), orthostatic hypotension (OR, 8.98; 95% CI, 5.36-15.03; P < .0001), syncope (OR, 3.62; 95% CI, 2.23-5.82; P < .0001), and other autonomic nervous system disorders (OR, 54.72; 95% CI, 7.43-403.00; P < .0001).

Food allergies were also considerably more likely to occur in EDS patients (OR, 3.88; 95% CI, 2.65-5.66; P < .0001), as were cardiovascular complications like mitral valve disorders, aortic aneurysm, and cardiac dysrhythmias (OR, 6.16; 95% CI, 4.60-8.23; P < .0001). Although EDS patients were more likely to have hospital stays that lasted longer than 4 days, there was no notable difference in mortality (OR, 0.79; 95% CI, 0.41-1.50; P = .47).

After multivariate regression analysis that adjusted for age, sex, race, and smoking status, EDS patients were more likely to have GI (OR, 3.53; 95% CI, 3.08-4.03; P < .0001), autonomic (OR, 4.13; 95% CI, 3.40-5.01; P < .0001), allergic (OR, 3.92; 95% CI, 2.57-5.98; P < .0001), and cardiovascular complications (OR, 5.82; 95% CI, 4.21-8.03; P < .0001).
 

Shining a much-needed light on the conditions associated with EDS

“Anyone who takes care of patients with EDS has likely seen some of these complications before and knows they can occur,” Jordan T. Jones, DO, a pediatric rheumatologist at Children’s Mercy Hospital in Kansas City, Mo., said in an interview. “I think this study legitimizes what many who take care of patients with EDS know to be true, and for those who don’t, it brings a lot of attention to many of the symptoms and associated conditions.”

He did, however, draw a conclusion that differed from one of the researchers’ chief observations.

“They note that these patients have a longer-than-average hospital stay, suggesting that EDS may be linked to adverse complications during hospitalization,” he said. “I think the reason for longer-than-average hospital stays is due to the number of symptoms and complexity of these patients, which can lead to delays in diagnosis. The complexity can lead to more involved evaluation that keeps them in the hospital longer than usual. Another reason for longer-than-average hospital stays that I’ve seen is the presentation of severe and chronic pain, which can be difficult to treat in the hospital and then transition to outpatient therapy. An inpatient hospitalization is not always the best place to treat chronic pain symptoms, which can drag out a hospital stay.”

He also highlighted the lack of discussion regarding musculoskeletal complications, which he sees as one of the most common symptoms related to EDS.

“As a rheumatologist, I see many patients with EDS present with chronic pain, chronic muscle weakness, and chronic fatigue. If you think about the joint laxity with EDS, these patients are a perfect setup to develop tight, weak muscles, which leads to a lot of musculoskeletal pain and fatigue.”

That said, he ultimately emphasized the clear benefits of such a large study on such an under-researched subject.

“We think EDS is more common than is reported,” he said. “But despite that, there are still a lot of people who don’t know about EDS, understand it, or appreciate how to evaluate for it. One of the best things this study does is bring more visibility to this disease and the associated conditions related to it.”

The authors declared no potential conflicts of interest.

SOURCE: Brooks RS et al. Rheumatology. 2021 Jan 7. doi: 10.1093/rheumatology/keaa926.

Hospitalized patients with Ehlers-Danlos syndrome (EDS) are more likely to have gastrointestinal, cardiovascular, autonomic, and allergic disorders than are hospitalized patients who do not have EDS, according to a new study of hospital outcomes in these four areas.

“Further research is necessary to explore the prevalence of these manifestations in the different subtypes of EDS and in outpatient population,” wrote Rachel S. Brooks of the University of Connecticut, Farmington, and her coauthors. The study was published in Rheumatology.

To investigate previously observed connections between EDS and these four types of complications, the researchers launched a case-control study using hospital records from the 2016 National Inpatient Sample. A total of 2,007 patients with EDS were identified via ICD-10 code and matched with 4,014 non-EDS patients according to 5-year age intervals, sex, and month of admission. EDS patients had an average age of nearly 37, and 84% were female. The average hospitalization was lengthier for EDS patients (4.77 days) than for controls (4.07 days).

GI conditions were found in 44% of EDS patients, compared with 18% of controls (odds ratio, 3.57; 95% confidence interval, 3.17-4.02; P < .0001). Among the more likely conditions were functional disorders of the stomach (OR, 5.18; 95% CI, 2.16-12.42; P < .0001), unspecified abdominal pain (OR, 3.97; 95% CI, 2.34-6.73; P < .0001), irritable bowel syndrome (OR, 7.44; 95% CI, 5.07-10.94; P < .0001), and nausea (OR, 3.20; 95% CI, 1.95-5.24; P < .0001).

Autonomic dysfunction was found in 20% of EDS patients, compared with 6% of controls (OR, 4.45; 95% CI, 3.71-5.32; P < .0001). They were significantly more likely to have postural orthostatic tachycardia syndrome (OR, 223.77; 95% CI, 31.21-1604.46; P < .0001), orthostatic hypotension (OR, 8.98; 95% CI, 5.36-15.03; P < .0001), syncope (OR, 3.62; 95% CI, 2.23-5.82; P < .0001), and other autonomic nervous system disorders (OR, 54.72; 95% CI, 7.43-403.00; P < .0001).

Food allergies were also considerably more likely to occur in EDS patients (OR, 3.88; 95% CI, 2.65-5.66; P < .0001), as were cardiovascular complications like mitral valve disorders, aortic aneurysm, and cardiac dysrhythmias (OR, 6.16; 95% CI, 4.60-8.23; P < .0001). Although EDS patients were more likely to have hospital stays that lasted longer than 4 days, there was no notable difference in mortality (OR, 0.79; 95% CI, 0.41-1.50; P = .47).

After multivariate regression analysis that adjusted for age, sex, race, and smoking status, EDS patients were more likely to have GI (OR, 3.53; 95% CI, 3.08-4.03; P < .0001), autonomic (OR, 4.13; 95% CI, 3.40-5.01; P < .0001), allergic (OR, 3.92; 95% CI, 2.57-5.98; P < .0001), and cardiovascular complications (OR, 5.82; 95% CI, 4.21-8.03; P < .0001).
 

Shining a much-needed light on the conditions associated with EDS

“Anyone who takes care of patients with EDS has likely seen some of these complications before and knows they can occur,” Jordan T. Jones, DO, a pediatric rheumatologist at Children’s Mercy Hospital in Kansas City, Mo., said in an interview. “I think this study legitimizes what many who take care of patients with EDS know to be true, and for those who don’t, it brings a lot of attention to many of the symptoms and associated conditions.”

He did, however, draw a conclusion that differed from one of the researchers’ chief observations.

“They note that these patients have a longer-than-average hospital stay, suggesting that EDS may be linked to adverse complications during hospitalization,” he said. “I think the reason for longer-than-average hospital stays is due to the number of symptoms and complexity of these patients, which can lead to delays in diagnosis. The complexity can lead to more involved evaluation that keeps them in the hospital longer than usual. Another reason for longer-than-average hospital stays that I’ve seen is the presentation of severe and chronic pain, which can be difficult to treat in the hospital and then transition to outpatient therapy. An inpatient hospitalization is not always the best place to treat chronic pain symptoms, which can drag out a hospital stay.”

He also highlighted the lack of discussion regarding musculoskeletal complications, which he sees as one of the most common symptoms related to EDS.

“As a rheumatologist, I see many patients with EDS present with chronic pain, chronic muscle weakness, and chronic fatigue. If you think about the joint laxity with EDS, these patients are a perfect setup to develop tight, weak muscles, which leads to a lot of musculoskeletal pain and fatigue.”

That said, he ultimately emphasized the clear benefits of such a large study on such an under-researched subject.

“We think EDS is more common than is reported,” he said. “But despite that, there are still a lot of people who don’t know about EDS, understand it, or appreciate how to evaluate for it. One of the best things this study does is bring more visibility to this disease and the associated conditions related to it.”

The authors declared no potential conflicts of interest.

SOURCE: Brooks RS et al. Rheumatology. 2021 Jan 7. doi: 10.1093/rheumatology/keaa926.

Hospitalized patients with Ehlers-Danlos syndrome (EDS) are more likely to have gastrointestinal, cardiovascular, autonomic, and allergic disorders than are hospitalized patients who do not have EDS, according to a new study of hospital outcomes in these four areas.

“Further research is necessary to explore the prevalence of these manifestations in the different subtypes of EDS and in outpatient population,” wrote Rachel S. Brooks of the University of Connecticut, Farmington, and her coauthors. The study was published in Rheumatology.

To investigate previously observed connections between EDS and these four types of complications, the researchers launched a case-control study using hospital records from the 2016 National Inpatient Sample. A total of 2,007 patients with EDS were identified via ICD-10 code and matched with 4,014 non-EDS patients according to 5-year age intervals, sex, and month of admission. EDS patients had an average age of nearly 37, and 84% were female. The average hospitalization was lengthier for EDS patients (4.77 days) than for controls (4.07 days).

GI conditions were found in 44% of EDS patients, compared with 18% of controls (odds ratio, 3.57; 95% confidence interval, 3.17-4.02; P < .0001). Among the more likely conditions were functional disorders of the stomach (OR, 5.18; 95% CI, 2.16-12.42; P < .0001), unspecified abdominal pain (OR, 3.97; 95% CI, 2.34-6.73; P < .0001), irritable bowel syndrome (OR, 7.44; 95% CI, 5.07-10.94; P < .0001), and nausea (OR, 3.20; 95% CI, 1.95-5.24; P < .0001).

Autonomic dysfunction was found in 20% of EDS patients, compared with 6% of controls (OR, 4.45; 95% CI, 3.71-5.32; P < .0001). They were significantly more likely to have postural orthostatic tachycardia syndrome (OR, 223.77; 95% CI, 31.21-1604.46; P < .0001), orthostatic hypotension (OR, 8.98; 95% CI, 5.36-15.03; P < .0001), syncope (OR, 3.62; 95% CI, 2.23-5.82; P < .0001), and other autonomic nervous system disorders (OR, 54.72; 95% CI, 7.43-403.00; P < .0001).

Food allergies were also considerably more likely to occur in EDS patients (OR, 3.88; 95% CI, 2.65-5.66; P < .0001), as were cardiovascular complications like mitral valve disorders, aortic aneurysm, and cardiac dysrhythmias (OR, 6.16; 95% CI, 4.60-8.23; P < .0001). Although EDS patients were more likely to have hospital stays that lasted longer than 4 days, there was no notable difference in mortality (OR, 0.79; 95% CI, 0.41-1.50; P = .47).

After multivariate regression analysis that adjusted for age, sex, race, and smoking status, EDS patients were more likely to have GI (OR, 3.53; 95% CI, 3.08-4.03; P < .0001), autonomic (OR, 4.13; 95% CI, 3.40-5.01; P < .0001), allergic (OR, 3.92; 95% CI, 2.57-5.98; P < .0001), and cardiovascular complications (OR, 5.82; 95% CI, 4.21-8.03; P < .0001).
 

Shining a much-needed light on the conditions associated with EDS

“Anyone who takes care of patients with EDS has likely seen some of these complications before and knows they can occur,” Jordan T. Jones, DO, a pediatric rheumatologist at Children’s Mercy Hospital in Kansas City, Mo., said in an interview. “I think this study legitimizes what many who take care of patients with EDS know to be true, and for those who don’t, it brings a lot of attention to many of the symptoms and associated conditions.”

He did, however, draw a conclusion that differed from one of the researchers’ chief observations.

“They note that these patients have a longer-than-average hospital stay, suggesting that EDS may be linked to adverse complications during hospitalization,” he said. “I think the reason for longer-than-average hospital stays is due to the number of symptoms and complexity of these patients, which can lead to delays in diagnosis. The complexity can lead to more involved evaluation that keeps them in the hospital longer than usual. Another reason for longer-than-average hospital stays that I’ve seen is the presentation of severe and chronic pain, which can be difficult to treat in the hospital and then transition to outpatient therapy. An inpatient hospitalization is not always the best place to treat chronic pain symptoms, which can drag out a hospital stay.”

He also highlighted the lack of discussion regarding musculoskeletal complications, which he sees as one of the most common symptoms related to EDS.

“As a rheumatologist, I see many patients with EDS present with chronic pain, chronic muscle weakness, and chronic fatigue. If you think about the joint laxity with EDS, these patients are a perfect setup to develop tight, weak muscles, which leads to a lot of musculoskeletal pain and fatigue.”

That said, he ultimately emphasized the clear benefits of such a large study on such an under-researched subject.

“We think EDS is more common than is reported,” he said. “But despite that, there are still a lot of people who don’t know about EDS, understand it, or appreciate how to evaluate for it. One of the best things this study does is bring more visibility to this disease and the associated conditions related to it.”

The authors declared no potential conflicts of interest.

SOURCE: Brooks RS et al. Rheumatology. 2021 Jan 7. doi: 10.1093/rheumatology/keaa926.

Rheumatoid arthritis patients who are on both oral glucocorticoids (CGs) and proton pump inhibitors (PPIs) have an increased risk of osteoporotic fractures, according to a retrospective study of RA patients in the United Kingdom.

“Considering the increasing life expectancies and high consumption of PPIs among elderly patients, fracture risk assessment could be considered when a patient with RA is co-prescribed oral GCs and PPIs,” wrote Shahab Abtahi, MD, of Maastricht (Netherlands) University Medical Centre and colleagues. The study was published in Annals of the Rheumatic Diseases.

To determine if concomitant use of the two medications – both already associated with osteoporotic fractures – would lead to a notable increase in fracture risk, the researchers conducted a population-based cohort study of RA patients aged 50 years or older who were diagnosed during 1997-2017. Patient data was gathered via the Clinical Practice Research Datalink, a primary care database of millions of U.K. medical records.

Patients with a recent history of GC/PPI use or those with a previous osteoporotic fracture were excluded from the study. Osteoporotic fractures were defined as fractures of the hip, vertebrae, humerus, forearm, pelvis, or rib. The study population included 12,351 patients, roughly two-thirds of whom were women, with a mean age of 68 years. Of the population, 4,254 patients were concomitant users of oral GCs and PPIs, compared with 3,138 patients who were not on either medication.

Among all patients, 1,411 osteoporotic fractures occurred, 264 of which occurred in the concomitant users group. After adjustments for age and sex, patients on both medications had a higher risk of fracture (adjusted hazard ratio, 1.93; 95% confidence interval, 1.65-2.27), compared to patients on oral GCs alone (aHR, 1.34; 95% CI, 1.12-1.59) or PPIs alone (aHR, 1.32; 95% CI, 1.14-1.54). After full adjustment, concomitant users again had a higher risk of fracture (aHR, 1.60; 95% CI, 1.35-1.89).

Regarding specific types of breaks, the concomitant users had a notably higher risk of hip (aHR, 1.45; 95% CI, 1.11-1.91), vertebrae (aHR, 2.84; 95% CI, 1.87-4.32), pelvis (aHR, 2.47; 95% CI, 1.41-4.34), and rib fractures (aHR, 4.03; 95% CI, 2.13-7.63). No increased risk was found for either humerus or forearm fractures. The risk of fracture did not rise for concomitant users who had either increasing daily doses of PPI or a longer duration of use.

The authors noted their study’s potential limitations, including having access to data on prescriptions only, not the actual use of medication, and a lack of information in the medical records regarding biologic therapies or certain indicators of RA disease activity. In addition, there was a likelihood that some patients who were improving might have stopped taking the drugs and lessened their risk of fracture, though the researchers attempted to account for this by “adjusting our analyses for six indicators of RA severity, including analgesics and csDMARDs.”

Two of the authors reported receiving research grants and speakers’ fees from various pharmaceutical companies. The others reported no conflicts of interest.

SOURCE: Abtahi S et al. Ann Rheum Dis. 2020 Dec 11. doi: 10.1136/annrheumdis-2020-218758.

Rheumatoid arthritis patients who are on both oral glucocorticoids (CGs) and proton pump inhibitors (PPIs) have an increased risk of osteoporotic fractures, according to a retrospective study of RA patients in the United Kingdom.

“Considering the increasing life expectancies and high consumption of PPIs among elderly patients, fracture risk assessment could be considered when a patient with RA is co-prescribed oral GCs and PPIs,” wrote Shahab Abtahi, MD, of Maastricht (Netherlands) University Medical Centre and colleagues. The study was published in Annals of the Rheumatic Diseases.

To determine if concomitant use of the two medications – both already associated with osteoporotic fractures – would lead to a notable increase in fracture risk, the researchers conducted a population-based cohort study of RA patients aged 50 years or older who were diagnosed during 1997-2017. Patient data was gathered via the Clinical Practice Research Datalink, a primary care database of millions of U.K. medical records.

Patients with a recent history of GC/PPI use or those with a previous osteoporotic fracture were excluded from the study. Osteoporotic fractures were defined as fractures of the hip, vertebrae, humerus, forearm, pelvis, or rib. The study population included 12,351 patients, roughly two-thirds of whom were women, with a mean age of 68 years. Of the population, 4,254 patients were concomitant users of oral GCs and PPIs, compared with 3,138 patients who were not on either medication.

Among all patients, 1,411 osteoporotic fractures occurred, 264 of which occurred in the concomitant users group. After adjustments for age and sex, patients on both medications had a higher risk of fracture (adjusted hazard ratio, 1.93; 95% confidence interval, 1.65-2.27), compared to patients on oral GCs alone (aHR, 1.34; 95% CI, 1.12-1.59) or PPIs alone (aHR, 1.32; 95% CI, 1.14-1.54). After full adjustment, concomitant users again had a higher risk of fracture (aHR, 1.60; 95% CI, 1.35-1.89).

Regarding specific types of breaks, the concomitant users had a notably higher risk of hip (aHR, 1.45; 95% CI, 1.11-1.91), vertebrae (aHR, 2.84; 95% CI, 1.87-4.32), pelvis (aHR, 2.47; 95% CI, 1.41-4.34), and rib fractures (aHR, 4.03; 95% CI, 2.13-7.63). No increased risk was found for either humerus or forearm fractures. The risk of fracture did not rise for concomitant users who had either increasing daily doses of PPI or a longer duration of use.

The authors noted their study’s potential limitations, including having access to data on prescriptions only, not the actual use of medication, and a lack of information in the medical records regarding biologic therapies or certain indicators of RA disease activity. In addition, there was a likelihood that some patients who were improving might have stopped taking the drugs and lessened their risk of fracture, though the researchers attempted to account for this by “adjusting our analyses for six indicators of RA severity, including analgesics and csDMARDs.”

Two of the authors reported receiving research grants and speakers’ fees from various pharmaceutical companies. The others reported no conflicts of interest.

SOURCE: Abtahi S et al. Ann Rheum Dis. 2020 Dec 11. doi: 10.1136/annrheumdis-2020-218758.

Rheumatoid arthritis patients who are on both oral glucocorticoids (CGs) and proton pump inhibitors (PPIs) have an increased risk of osteoporotic fractures, according to a retrospective study of RA patients in the United Kingdom.

“Considering the increasing life expectancies and high consumption of PPIs among elderly patients, fracture risk assessment could be considered when a patient with RA is co-prescribed oral GCs and PPIs,” wrote Shahab Abtahi, MD, of Maastricht (Netherlands) University Medical Centre and colleagues. The study was published in Annals of the Rheumatic Diseases.

To determine if concomitant use of the two medications – both already associated with osteoporotic fractures – would lead to a notable increase in fracture risk, the researchers conducted a population-based cohort study of RA patients aged 50 years or older who were diagnosed during 1997-2017. Patient data was gathered via the Clinical Practice Research Datalink, a primary care database of millions of U.K. medical records.

Patients with a recent history of GC/PPI use or those with a previous osteoporotic fracture were excluded from the study. Osteoporotic fractures were defined as fractures of the hip, vertebrae, humerus, forearm, pelvis, or rib. The study population included 12,351 patients, roughly two-thirds of whom were women, with a mean age of 68 years. Of the population, 4,254 patients were concomitant users of oral GCs and PPIs, compared with 3,138 patients who were not on either medication.

Among all patients, 1,411 osteoporotic fractures occurred, 264 of which occurred in the concomitant users group. After adjustments for age and sex, patients on both medications had a higher risk of fracture (adjusted hazard ratio, 1.93; 95% confidence interval, 1.65-2.27), compared to patients on oral GCs alone (aHR, 1.34; 95% CI, 1.12-1.59) or PPIs alone (aHR, 1.32; 95% CI, 1.14-1.54). After full adjustment, concomitant users again had a higher risk of fracture (aHR, 1.60; 95% CI, 1.35-1.89).

Regarding specific types of breaks, the concomitant users had a notably higher risk of hip (aHR, 1.45; 95% CI, 1.11-1.91), vertebrae (aHR, 2.84; 95% CI, 1.87-4.32), pelvis (aHR, 2.47; 95% CI, 1.41-4.34), and rib fractures (aHR, 4.03; 95% CI, 2.13-7.63). No increased risk was found for either humerus or forearm fractures. The risk of fracture did not rise for concomitant users who had either increasing daily doses of PPI or a longer duration of use.

The authors noted their study’s potential limitations, including having access to data on prescriptions only, not the actual use of medication, and a lack of information in the medical records regarding biologic therapies or certain indicators of RA disease activity. In addition, there was a likelihood that some patients who were improving might have stopped taking the drugs and lessened their risk of fracture, though the researchers attempted to account for this by “adjusting our analyses for six indicators of RA severity, including analgesics and csDMARDs.”

Two of the authors reported receiving research grants and speakers’ fees from various pharmaceutical companies. The others reported no conflicts of interest.

SOURCE: Abtahi S et al. Ann Rheum Dis. 2020 Dec 11. doi: 10.1136/annrheumdis-2020-218758.

Slowly tapering off – or remaining on – antimalarial medications can help prevent disease flare in patients with systemic lupus erythematosus (SLE) who’ve achieved clinical remission for at least a year, according to a new study that was presented at the virtual annual meeting of the American College of Rheumatology.

“Except in the setting of toxicity, cessation of antimalarial medication in patients with disease quiescence is feasible using a slow taper,” lead author Danaë Papachristos, MBBS, said during an oral abstract presentation at the online meeting. Dr. Papachristos conducted the research while a clinical and research fellow at the University of Toronto’s lupus clinic, but is now a consultant rheumatologist at the Wesley Hospital in Brisbane, Queensland, Australia.

To investigate flare in patients with SLE who were on or recently off antimalarial medications (AMs), the researchers identified 1,573 potential participants from a long-term observational cohort study at the university’s lupus clinic. From that larger group, 88 cases – patients who achieved clinical remission for at least a year and stopped taking AMs – were matched to at least one control – patients who also achieved remission and continued on medication. Most cases were also matched to a second control, bringing the total number to 173. All patients had at least 2 years of follow-up.

Flare was defined as any increase in the SLEDAI-2K score, with major flare defined as an increase of 4 or more. Patients in the case group were roughly 44 years old, compared with an average age of 46 in the control group. Both groups were almost entirely female and largely white. Reasons for withdrawal in the case group included self-cessation, disease quiescence, and retinal, mucocutaneous, or cardiac toxicities. Twenty participants in the case group reported AM toxicity, compared with four controls.

Dr. Papachristos noted in her presentation that the toxicity disparity was expected, “because controls are those who continue their medication, and most patients who have toxicity will stop their medication.”

Disease flare occurred in 61.4% of cases, compared with 45.1% of controls (P = .002), with the most common types being cutaneous and musculoskeletal flares. After multivariate analysis, the risk of flare more than doubled for those who ceased AMs (odds ratio, 2.26; 95% confidence interval, 1.24-4.11; P = .008). More than half of the cases (n = 46) restarted AMs after withdrawal, which was largely due to disease flare. Of the patients who restarted due to flare, 88% either recaptured control or improved, and the remaining 12% had further flares.

Of the 88 patients in the case group, 51 abruptly withdrew AMs while 37 tapered off. Patients who tapered had fewer flares (45.9%), compared with patients who withdrew abruptly (72.6%). After multivariate analysis, the risk of flare more than tripled for the abrupt withdrawal group (OR, 3.42; 95% CI, 1.26-9.26; P = .016). Fewer patients who tapered later restarted AMs, compared with the abrupt withdrawal group (37.8% vs. 62.7%; P = .02).

When asked about other differences in medications between the two groups, Dr. Papachristos answered: “We didn’t look into that specifically. We did look at those patients who were on prednisone and on any immunosuppression, although we didn’t look at specific therapies. Those variables were adjusted for in the analysis, and it didn’t make any difference if patients were on immunosuppression or prednisone at the point of index date.

“But we would like to look into the different forms of immunosuppression,” she added, “just to see if that made any difference.”

Withdrawing hydroxychloroquine in older patients

Older patients with SLE who discontinue their use of hydroxychloroquine (HCQ) are also not at increased risk of disease flare, according to a retrospective chart review from rheumatologists Ruth Fernandez-Ruiz, MD, and Peter M. Izmirly, MD, of New York University (Arthritis Res Ther. 2020;22:191. doi: 10.1186/s13075-020-02282-0).

“We wanted to focus on older patients who may have a lower risk of flaring and a higher risk of side effects from the drug,” Dr. Fernandez-Ruiz said in an interview.

The doctors embarked on the study after noticing eye and heart toxicities in certain older patients. They matched 26 lupus patients who had been on HCQ for at least 5 years before discontinuing the drug with 32 control patients who remained on HCQ, ultimately finding that withdrawal had no effect on their risk of lupus flares within a year.

“After starting a drug, the second question most people ask, after ‘What are the side effects?’ is ‘How long do I have to be on this?’ ” Dr. Izmirly said in an interview. “These patients are having side effects associated with long-term HCQ use. And we were noticing that, after you stop the drug, despite what you’re taught, they weren’t flaring.”

Only five patients from each group – 19.2% of the withdrawal group and 15.6% of the continuation group – experienced a flare (OR, 1.28; 95% CI, 0.31-5.30; P = .73). Most of the flares were cutaneous and musculoskeletal in nature, and no severe flares occurred in either group.

“On each side, the overall flare rate was not that high, and they were all relatively mild,” Dr. Izmirly said.

The two doctors acknowledged their study’s smaller sample size, compared with the study by Papachristos and colleagues, along with the advanced age of their patient population, which limits the generalizability of their findings. “We selected patients who had a very low disease activity to begin with, and who were older,” Dr. Fernandez-Ruiz noted.

That said, they reinforced the scarcity of existing research on this subset of lupus patients, one that will only continue to grow.

“Older [patients with] lupus,” Dr. Izmirly said, are “an understudied demographic.”

One of the authors of the study presented at ACR 2020 acknowledged receiving research support and consulting fees from various pharmaceutical companies. The HCQ study was supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases; its authors declared no conflicts of interest.

SOURCE: Papachristos D et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 0983.

Slowly tapering off – or remaining on – antimalarial medications can help prevent disease flare in patients with systemic lupus erythematosus (SLE) who’ve achieved clinical remission for at least a year, according to a new study that was presented at the virtual annual meeting of the American College of Rheumatology.

“Except in the setting of toxicity, cessation of antimalarial medication in patients with disease quiescence is feasible using a slow taper,” lead author Danaë Papachristos, MBBS, said during an oral abstract presentation at the online meeting. Dr. Papachristos conducted the research while a clinical and research fellow at the University of Toronto’s lupus clinic, but is now a consultant rheumatologist at the Wesley Hospital in Brisbane, Queensland, Australia.

To investigate flare in patients with SLE who were on or recently off antimalarial medications (AMs), the researchers identified 1,573 potential participants from a long-term observational cohort study at the university’s lupus clinic. From that larger group, 88 cases – patients who achieved clinical remission for at least a year and stopped taking AMs – were matched to at least one control – patients who also achieved remission and continued on medication. Most cases were also matched to a second control, bringing the total number to 173. All patients had at least 2 years of follow-up.

Flare was defined as any increase in the SLEDAI-2K score, with major flare defined as an increase of 4 or more. Patients in the case group were roughly 44 years old, compared with an average age of 46 in the control group. Both groups were almost entirely female and largely white. Reasons for withdrawal in the case group included self-cessation, disease quiescence, and retinal, mucocutaneous, or cardiac toxicities. Twenty participants in the case group reported AM toxicity, compared with four controls.

Dr. Papachristos noted in her presentation that the toxicity disparity was expected, “because controls are those who continue their medication, and most patients who have toxicity will stop their medication.”

Disease flare occurred in 61.4% of cases, compared with 45.1% of controls (P = .002), with the most common types being cutaneous and musculoskeletal flares. After multivariate analysis, the risk of flare more than doubled for those who ceased AMs (odds ratio, 2.26; 95% confidence interval, 1.24-4.11; P = .008). More than half of the cases (n = 46) restarted AMs after withdrawal, which was largely due to disease flare. Of the patients who restarted due to flare, 88% either recaptured control or improved, and the remaining 12% had further flares.

Of the 88 patients in the case group, 51 abruptly withdrew AMs while 37 tapered off. Patients who tapered had fewer flares (45.9%), compared with patients who withdrew abruptly (72.6%). After multivariate analysis, the risk of flare more than tripled for the abrupt withdrawal group (OR, 3.42; 95% CI, 1.26-9.26; P = .016). Fewer patients who tapered later restarted AMs, compared with the abrupt withdrawal group (37.8% vs. 62.7%; P = .02).

When asked about other differences in medications between the two groups, Dr. Papachristos answered: “We didn’t look into that specifically. We did look at those patients who were on prednisone and on any immunosuppression, although we didn’t look at specific therapies. Those variables were adjusted for in the analysis, and it didn’t make any difference if patients were on immunosuppression or prednisone at the point of index date.

“But we would like to look into the different forms of immunosuppression,” she added, “just to see if that made any difference.”

Withdrawing hydroxychloroquine in older patients

Older patients with SLE who discontinue their use of hydroxychloroquine (HCQ) are also not at increased risk of disease flare, according to a retrospective chart review from rheumatologists Ruth Fernandez-Ruiz, MD, and Peter M. Izmirly, MD, of New York University (Arthritis Res Ther. 2020;22:191. doi: 10.1186/s13075-020-02282-0).

“We wanted to focus on older patients who may have a lower risk of flaring and a higher risk of side effects from the drug,” Dr. Fernandez-Ruiz said in an interview.

The doctors embarked on the study after noticing eye and heart toxicities in certain older patients. They matched 26 lupus patients who had been on HCQ for at least 5 years before discontinuing the drug with 32 control patients who remained on HCQ, ultimately finding that withdrawal had no effect on their risk of lupus flares within a year.

“After starting a drug, the second question most people ask, after ‘What are the side effects?’ is ‘How long do I have to be on this?’ ” Dr. Izmirly said in an interview. “These patients are having side effects associated with long-term HCQ use. And we were noticing that, after you stop the drug, despite what you’re taught, they weren’t flaring.”

Only five patients from each group – 19.2% of the withdrawal group and 15.6% of the continuation group – experienced a flare (OR, 1.28; 95% CI, 0.31-5.30; P = .73). Most of the flares were cutaneous and musculoskeletal in nature, and no severe flares occurred in either group.

“On each side, the overall flare rate was not that high, and they were all relatively mild,” Dr. Izmirly said.

The two doctors acknowledged their study’s smaller sample size, compared with the study by Papachristos and colleagues, along with the advanced age of their patient population, which limits the generalizability of their findings. “We selected patients who had a very low disease activity to begin with, and who were older,” Dr. Fernandez-Ruiz noted.

That said, they reinforced the scarcity of existing research on this subset of lupus patients, one that will only continue to grow.

“Older [patients with] lupus,” Dr. Izmirly said, are “an understudied demographic.”

One of the authors of the study presented at ACR 2020 acknowledged receiving research support and consulting fees from various pharmaceutical companies. The HCQ study was supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases; its authors declared no conflicts of interest.

SOURCE: Papachristos D et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 0983.

Slowly tapering off – or remaining on – antimalarial medications can help prevent disease flare in patients with systemic lupus erythematosus (SLE) who’ve achieved clinical remission for at least a year, according to a new study that was presented at the virtual annual meeting of the American College of Rheumatology.

“Except in the setting of toxicity, cessation of antimalarial medication in patients with disease quiescence is feasible using a slow taper,” lead author Danaë Papachristos, MBBS, said during an oral abstract presentation at the online meeting. Dr. Papachristos conducted the research while a clinical and research fellow at the University of Toronto’s lupus clinic, but is now a consultant rheumatologist at the Wesley Hospital in Brisbane, Queensland, Australia.

To investigate flare in patients with SLE who were on or recently off antimalarial medications (AMs), the researchers identified 1,573 potential participants from a long-term observational cohort study at the university’s lupus clinic. From that larger group, 88 cases – patients who achieved clinical remission for at least a year and stopped taking AMs – were matched to at least one control – patients who also achieved remission and continued on medication. Most cases were also matched to a second control, bringing the total number to 173. All patients had at least 2 years of follow-up.

Flare was defined as any increase in the SLEDAI-2K score, with major flare defined as an increase of 4 or more. Patients in the case group were roughly 44 years old, compared with an average age of 46 in the control group. Both groups were almost entirely female and largely white. Reasons for withdrawal in the case group included self-cessation, disease quiescence, and retinal, mucocutaneous, or cardiac toxicities. Twenty participants in the case group reported AM toxicity, compared with four controls.

Dr. Papachristos noted in her presentation that the toxicity disparity was expected, “because controls are those who continue their medication, and most patients who have toxicity will stop their medication.”

Disease flare occurred in 61.4% of cases, compared with 45.1% of controls (P = .002), with the most common types being cutaneous and musculoskeletal flares. After multivariate analysis, the risk of flare more than doubled for those who ceased AMs (odds ratio, 2.26; 95% confidence interval, 1.24-4.11; P = .008). More than half of the cases (n = 46) restarted AMs after withdrawal, which was largely due to disease flare. Of the patients who restarted due to flare, 88% either recaptured control or improved, and the remaining 12% had further flares.

Of the 88 patients in the case group, 51 abruptly withdrew AMs while 37 tapered off. Patients who tapered had fewer flares (45.9%), compared with patients who withdrew abruptly (72.6%). After multivariate analysis, the risk of flare more than tripled for the abrupt withdrawal group (OR, 3.42; 95% CI, 1.26-9.26; P = .016). Fewer patients who tapered later restarted AMs, compared with the abrupt withdrawal group (37.8% vs. 62.7%; P = .02).

When asked about other differences in medications between the two groups, Dr. Papachristos answered: “We didn’t look into that specifically. We did look at those patients who were on prednisone and on any immunosuppression, although we didn’t look at specific therapies. Those variables were adjusted for in the analysis, and it didn’t make any difference if patients were on immunosuppression or prednisone at the point of index date.

“But we would like to look into the different forms of immunosuppression,” she added, “just to see if that made any difference.”

Withdrawing hydroxychloroquine in older patients

Older patients with SLE who discontinue their use of hydroxychloroquine (HCQ) are also not at increased risk of disease flare, according to a retrospective chart review from rheumatologists Ruth Fernandez-Ruiz, MD, and Peter M. Izmirly, MD, of New York University (Arthritis Res Ther. 2020;22:191. doi: 10.1186/s13075-020-02282-0).

“We wanted to focus on older patients who may have a lower risk of flaring and a higher risk of side effects from the drug,” Dr. Fernandez-Ruiz said in an interview.

The doctors embarked on the study after noticing eye and heart toxicities in certain older patients. They matched 26 lupus patients who had been on HCQ for at least 5 years before discontinuing the drug with 32 control patients who remained on HCQ, ultimately finding that withdrawal had no effect on their risk of lupus flares within a year.

“After starting a drug, the second question most people ask, after ‘What are the side effects?’ is ‘How long do I have to be on this?’ ” Dr. Izmirly said in an interview. “These patients are having side effects associated with long-term HCQ use. And we were noticing that, after you stop the drug, despite what you’re taught, they weren’t flaring.”

Only five patients from each group – 19.2% of the withdrawal group and 15.6% of the continuation group – experienced a flare (OR, 1.28; 95% CI, 0.31-5.30; P = .73). Most of the flares were cutaneous and musculoskeletal in nature, and no severe flares occurred in either group.

“On each side, the overall flare rate was not that high, and they were all relatively mild,” Dr. Izmirly said.

The two doctors acknowledged their study’s smaller sample size, compared with the study by Papachristos and colleagues, along with the advanced age of their patient population, which limits the generalizability of their findings. “We selected patients who had a very low disease activity to begin with, and who were older,” Dr. Fernandez-Ruiz noted.

That said, they reinforced the scarcity of existing research on this subset of lupus patients, one that will only continue to grow.

“Older [patients with] lupus,” Dr. Izmirly said, are “an understudied demographic.”

One of the authors of the study presented at ACR 2020 acknowledged receiving research support and consulting fees from various pharmaceutical companies. The HCQ study was supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases; its authors declared no conflicts of interest.

SOURCE: Papachristos D et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 0983.

Abatacept’s safety as well as indicators of its potential efficacy in the treatment of patients with early diffuse cutaneous systemic sclerosis (dcSSc) were reinforced by newly reported results from the 6-month, open-label extension of the phase 2 ASSET trial.

“Exploratory outcome measures during the open-label extension, including the composite ACR CRISS [American College of Rheumatology Combined Response Index in diffuse cutaneous Systemic Sclerosis] score, indicate that abatacept [Orencia] might promote overall global improvement in these participants,” Lorinda Chung, MD, of Stanford (Calif.) University, and colleagues wrote in the Lancet Rheumatology.

To continue to determine the safety and efficacy of abatacept as a treatment for dcSSc, the researchers launched the open-label extension of the randomized, double-blind ASSET trial. After patients in ASSET completed 12 months of treatment with either 125 mg weekly of subcutaneous abatacept or placebo, they were invited to join the extension period. ASSET’s primary endpoint was the change in modified Rodnan Skin Score (mRSS) from baseline to 12 months.

Of the 88 patients who began the ASSET trial – half of which were assigned to the abatacept group and the other half to the placebo group – 33 and 34 transitioned to weekly open-label treatment with 125 mg of abatacept, respectively. In the trial’s primary endpoint at 12 months, mean improvement in mRSS with abatacept was –6.6 (standard deviation, 6.4), compared to –3.7 (SD, 7.6) with placebo.

All told, 32 patients in each group completed 18 months of treatment. Patients who received abatacept in both periods had even more improvement in mRSS score (–9.8 [SD, 8.1]), as did patients who received placebo and then abatacept (–6.3 [SD, 9.3]). After 12 months, 68% of patients (23 of 34) in the abatacept group had a 5-unit or greater improvement in mRSS, compared with 50% of patients (19 of 38) in the placebo group. After 18 months, that percentage went up to 72% (23 of 32) among patients who took abatacept in both periods and 65% (20 of 31) for those who received it only in the extension.

Although the median ACR CRISS score was significantly greater at 12 months with abatacept, compared with placebo, both groups improved during the open-label period. After 12 months, an ACR CRISS score of 0.60 or higher was achieved by 55% (18 of 33) of the abatacept group and 36% (13 of 36) of the placebo group. In the extension, those percentages leapt to 66% (19 of 29) and 50% (13 of 26), respectively.

Throughout the double-blind phase, adverse events – including infectious events, serious events, and those that led to study withdrawal – were more frequent with placebo than with abatacept. During the extension period, although adverse events occurred slightly more among 18-month abatacept users, they ultimately occurred in fewer participants than in the double-blind phase.

Time to push forward with additional studies on abatacept

The results fortified by this open-label extension from Dr. Chung and colleagues should lay the groundwork for a phase 3 study on treatment with abatacept, wrote Francesco Del Galdo, MD, PhD, of the University of Leeds (England), in an accompanying editorial.

Along with clinically important improvements in several key measures, Dr. Del Galdo restated the value of abatacept’s “very benign” safety profile over the 18-month study period. However, he also acknowledged the “absence of concurrent immunosuppression” in the ASSET trial, noting that there is not yet a record of combination therapy safety across the board.

Beyond safety, he wondered if perhaps the time has passed for a placebo arm in dcSSc patients. He noted that participants in the initial placebo group were more likely to have “clinically relevant worsening of disease that required escape treatment,” which could make it ethically and analytically difficult to justify placebo.

The authors acknowledged the extension’s limitations, including the possibility that the survivors of the 12-month trial who joined the extension were more responsive to treatment or suffered from less severe disease. In addition, they noted that the study “was not powered for formal statistical comparison of the two treatment arms,” meaning all open-label results are considered exploratory. Finally, the number of participants in the extension period was small and likely contributed to low rates of adverse events, such as infection.

The trial was funded by Bristol-Myers Squibb, which markets abatacept, and the National Institutes of Health. The authors reported numerous potential conflicts of interest, including receiving grants, clinical trial support, and personal fees from various organizations and pharmaceutical companies, as well as serving on the advisory boards for such companies. Dr. Del Galdo reported receiving consultancy fees and research grants from several pharmaceutical companies.

SOURCE: Chung L et al. Lancet Rheumatol. 2020 Oct 19. doi: 10.1016/S2665-9913(20)30237-X.

Abatacept’s safety as well as indicators of its potential efficacy in the treatment of patients with early diffuse cutaneous systemic sclerosis (dcSSc) were reinforced by newly reported results from the 6-month, open-label extension of the phase 2 ASSET trial.

“Exploratory outcome measures during the open-label extension, including the composite ACR CRISS [American College of Rheumatology Combined Response Index in diffuse cutaneous Systemic Sclerosis] score, indicate that abatacept [Orencia] might promote overall global improvement in these participants,” Lorinda Chung, MD, of Stanford (Calif.) University, and colleagues wrote in the Lancet Rheumatology.

To continue to determine the safety and efficacy of abatacept as a treatment for dcSSc, the researchers launched the open-label extension of the randomized, double-blind ASSET trial. After patients in ASSET completed 12 months of treatment with either 125 mg weekly of subcutaneous abatacept or placebo, they were invited to join the extension period. ASSET’s primary endpoint was the change in modified Rodnan Skin Score (mRSS) from baseline to 12 months.

Of the 88 patients who began the ASSET trial – half of which were assigned to the abatacept group and the other half to the placebo group – 33 and 34 transitioned to weekly open-label treatment with 125 mg of abatacept, respectively. In the trial’s primary endpoint at 12 months, mean improvement in mRSS with abatacept was –6.6 (standard deviation, 6.4), compared to –3.7 (SD, 7.6) with placebo.

All told, 32 patients in each group completed 18 months of treatment. Patients who received abatacept in both periods had even more improvement in mRSS score (–9.8 [SD, 8.1]), as did patients who received placebo and then abatacept (–6.3 [SD, 9.3]). After 12 months, 68% of patients (23 of 34) in the abatacept group had a 5-unit or greater improvement in mRSS, compared with 50% of patients (19 of 38) in the placebo group. After 18 months, that percentage went up to 72% (23 of 32) among patients who took abatacept in both periods and 65% (20 of 31) for those who received it only in the extension.

Although the median ACR CRISS score was significantly greater at 12 months with abatacept, compared with placebo, both groups improved during the open-label period. After 12 months, an ACR CRISS score of 0.60 or higher was achieved by 55% (18 of 33) of the abatacept group and 36% (13 of 36) of the placebo group. In the extension, those percentages leapt to 66% (19 of 29) and 50% (13 of 26), respectively.

Throughout the double-blind phase, adverse events – including infectious events, serious events, and those that led to study withdrawal – were more frequent with placebo than with abatacept. During the extension period, although adverse events occurred slightly more among 18-month abatacept users, they ultimately occurred in fewer participants than in the double-blind phase.

Time to push forward with additional studies on abatacept

The results fortified by this open-label extension from Dr. Chung and colleagues should lay the groundwork for a phase 3 study on treatment with abatacept, wrote Francesco Del Galdo, MD, PhD, of the University of Leeds (England), in an accompanying editorial.

Along with clinically important improvements in several key measures, Dr. Del Galdo restated the value of abatacept’s “very benign” safety profile over the 18-month study period. However, he also acknowledged the “absence of concurrent immunosuppression” in the ASSET trial, noting that there is not yet a record of combination therapy safety across the board.

Beyond safety, he wondered if perhaps the time has passed for a placebo arm in dcSSc patients. He noted that participants in the initial placebo group were more likely to have “clinically relevant worsening of disease that required escape treatment,” which could make it ethically and analytically difficult to justify placebo.

The authors acknowledged the extension’s limitations, including the possibility that the survivors of the 12-month trial who joined the extension were more responsive to treatment or suffered from less severe disease. In addition, they noted that the study “was not powered for formal statistical comparison of the two treatment arms,” meaning all open-label results are considered exploratory. Finally, the number of participants in the extension period was small and likely contributed to low rates of adverse events, such as infection.

The trial was funded by Bristol-Myers Squibb, which markets abatacept, and the National Institutes of Health. The authors reported numerous potential conflicts of interest, including receiving grants, clinical trial support, and personal fees from various organizations and pharmaceutical companies, as well as serving on the advisory boards for such companies. Dr. Del Galdo reported receiving consultancy fees and research grants from several pharmaceutical companies.

SOURCE: Chung L et al. Lancet Rheumatol. 2020 Oct 19. doi: 10.1016/S2665-9913(20)30237-X.

Abatacept’s safety as well as indicators of its potential efficacy in the treatment of patients with early diffuse cutaneous systemic sclerosis (dcSSc) were reinforced by newly reported results from the 6-month, open-label extension of the phase 2 ASSET trial.

“Exploratory outcome measures during the open-label extension, including the composite ACR CRISS [American College of Rheumatology Combined Response Index in diffuse cutaneous Systemic Sclerosis] score, indicate that abatacept [Orencia] might promote overall global improvement in these participants,” Lorinda Chung, MD, of Stanford (Calif.) University, and colleagues wrote in the Lancet Rheumatology.

To continue to determine the safety and efficacy of abatacept as a treatment for dcSSc, the researchers launched the open-label extension of the randomized, double-blind ASSET trial. After patients in ASSET completed 12 months of treatment with either 125 mg weekly of subcutaneous abatacept or placebo, they were invited to join the extension period. ASSET’s primary endpoint was the change in modified Rodnan Skin Score (mRSS) from baseline to 12 months.

Of the 88 patients who began the ASSET trial – half of which were assigned to the abatacept group and the other half to the placebo group – 33 and 34 transitioned to weekly open-label treatment with 125 mg of abatacept, respectively. In the trial’s primary endpoint at 12 months, mean improvement in mRSS with abatacept was –6.6 (standard deviation, 6.4), compared to –3.7 (SD, 7.6) with placebo.

All told, 32 patients in each group completed 18 months of treatment. Patients who received abatacept in both periods had even more improvement in mRSS score (–9.8 [SD, 8.1]), as did patients who received placebo and then abatacept (–6.3 [SD, 9.3]). After 12 months, 68% of patients (23 of 34) in the abatacept group had a 5-unit or greater improvement in mRSS, compared with 50% of patients (19 of 38) in the placebo group. After 18 months, that percentage went up to 72% (23 of 32) among patients who took abatacept in both periods and 65% (20 of 31) for those who received it only in the extension.

Although the median ACR CRISS score was significantly greater at 12 months with abatacept, compared with placebo, both groups improved during the open-label period. After 12 months, an ACR CRISS score of 0.60 or higher was achieved by 55% (18 of 33) of the abatacept group and 36% (13 of 36) of the placebo group. In the extension, those percentages leapt to 66% (19 of 29) and 50% (13 of 26), respectively.

Throughout the double-blind phase, adverse events – including infectious events, serious events, and those that led to study withdrawal – were more frequent with placebo than with abatacept. During the extension period, although adverse events occurred slightly more among 18-month abatacept users, they ultimately occurred in fewer participants than in the double-blind phase.

Time to push forward with additional studies on abatacept

The results fortified by this open-label extension from Dr. Chung and colleagues should lay the groundwork for a phase 3 study on treatment with abatacept, wrote Francesco Del Galdo, MD, PhD, of the University of Leeds (England), in an accompanying editorial.

Along with clinically important improvements in several key measures, Dr. Del Galdo restated the value of abatacept’s “very benign” safety profile over the 18-month study period. However, he also acknowledged the “absence of concurrent immunosuppression” in the ASSET trial, noting that there is not yet a record of combination therapy safety across the board.

Beyond safety, he wondered if perhaps the time has passed for a placebo arm in dcSSc patients. He noted that participants in the initial placebo group were more likely to have “clinically relevant worsening of disease that required escape treatment,” which could make it ethically and analytically difficult to justify placebo.

The authors acknowledged the extension’s limitations, including the possibility that the survivors of the 12-month trial who joined the extension were more responsive to treatment or suffered from less severe disease. In addition, they noted that the study “was not powered for formal statistical comparison of the two treatment arms,” meaning all open-label results are considered exploratory. Finally, the number of participants in the extension period was small and likely contributed to low rates of adverse events, such as infection.

The trial was funded by Bristol-Myers Squibb, which markets abatacept, and the National Institutes of Health. The authors reported numerous potential conflicts of interest, including receiving grants, clinical trial support, and personal fees from various organizations and pharmaceutical companies, as well as serving on the advisory boards for such companies. Dr. Del Galdo reported receiving consultancy fees and research grants from several pharmaceutical companies.

SOURCE: Chung L et al. Lancet Rheumatol. 2020 Oct 19. doi: 10.1016/S2665-9913(20)30237-X.

A new study of immunoglobulin levels in adult patients with systemic lupus erythematosus (SLE) has found that acquired low levels of IgA are associated with a higher risk of infection.

To the knowledge of first author Ibrahim Almaghlouth, MD, of the division of rheumatology at the University of Toronto, and colleagues, “this is the first dedicated study to examine the relationship between acquired low immunoglobulins and infection risk in adult patients with SLE.” But as to whether there may be a “protective role for immunoglobulins and the potential effect of immunoglobulin replacement in a setting of recurrent or severe infection among SLE patients requires further study.”

To determine if the risk of infection was tied to acquired low immunoglobulin levels, the researchers launched a retrospective analysis of data from a prospective cohort study of adult SLE patients from a Toronto lupus cohort that was established in 1970. The study was published in Rheumatology.

A total of 448 patients with at least two low immunoglobulin tests were matched with 656 SLE patients with no low immunoglobulins according to enrollment decade. The average age of the low-immunoglobulin group was 41.8 years, compared with 39.3 years in the control group. Average disease duration was 11.2 years in the low-immunoglobulin group and 7.6 years in the control group.

Of the patients in the low-immunoglobulin group, 221 had consecutive low tests and 227 had nonconsecutive low tests. Overall, 98 of those patients had low IgG, 251 patients had low IgM, and 51 patients had low IgA. Only 48 patients had overlapping low levels, including 5 with all three.

Average levels among the low-immunoglobulin group at baseline were 11.5 (standard deviation, 6.1) g/L of IgG, 0.8 (1.1) g/L of IgM, and 2.4 (1.6) g/L of IgA, while average levels among the control group were 16.3 (6.4) g/L of IgG, 1.8 (1.2) g/L of IgM, and 3.2 (1.5) g/L of IgA. In the primary analysis, after adjustment using propensity scoring, there were 97 infections: 47 in the low-immunoglobulin group and 50 in the control group. The most common types were respiratory and urinary tract infections, and the rate of infection was higher in patients with low IgA. The IgA level associated with risk of infection was less than 0.75 g/L.

After Cox regression analysis, the only variable that significantly increased infection risk was a low IgA level (hazard ratio, 3.19; 95% confidence interval, 1.17-8.71), not a low IgG level (HR, 1.87; 95% CI, 0.77-4.54) or low IgM level (HR, 0.63; 95% CI, 0.34-1.17). In regard to recovery among the low-immunoglobulin group, 11 patients (2.5%) recovered from low immunoglobulins within in the first year, followed by 36 (8.2%) in the second year, 44 (10.1%) in the third year, and 80 (18.4%) in the fourth year. All told, 60% (263) of patients with acquired hypogammaglobulinemia recovered over a 4-year period.

Is there clinical relevance to low IgA?

“I don’t see us using this clinically immediately,” Karen Costenbader, MD, a rheumatologist at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston, said in an interview. “We do test immunoglobulins often, especially in patients who’ve had biologic therapy. Will we start thinking about their IgA levels? It’s not clear, and the researchers leave it up in the air as to what this means, beyond them being at high risk.”

That said, she added, “IgA levels are interesting, especially in a time of COVID, because they’re associated with mucosal immunity. Is this subset of patients going to be at particularly high risk for the coronavirus?”

She also noted that, though immunoglobulin replacement has been helpful in her patients, it’s an expensive therapy to recommend for low IgA levels without knowing exactly what is causing these deficiencies. “My question is, would it be useful to follow these levels in lupus patients, even we don’t know what to do about them?” she asked. “We know there are a lot of risk factors for infections, so is the IgA going to be useful above and beyond that, and then what can we do about it?”

The authors acknowledged their study’s potential limitations, including low infection rates and yearly measurements of immunoglobulin levels, which could’ve led to misclassifying a lab error as true low immunoglobulin. They also highlighted its strengths, including using various methods to reduce selection and confounding bias while also reporting consistent results after examining multiple definitions of low immunoglobulins and outcomes.

The study received no specific funding, and the authors reported no potential conflicts of interest.

SOURCE: Almaghlouth I et al. Rheumatology. 2020 Oct 2. doi: 10.1093/rheumatology/keaa641.

A new study of immunoglobulin levels in adult patients with systemic lupus erythematosus (SLE) has found that acquired low levels of IgA are associated with a higher risk of infection.

To the knowledge of first author Ibrahim Almaghlouth, MD, of the division of rheumatology at the University of Toronto, and colleagues, “this is the first dedicated study to examine the relationship between acquired low immunoglobulins and infection risk in adult patients with SLE.” But as to whether there may be a “protective role for immunoglobulins and the potential effect of immunoglobulin replacement in a setting of recurrent or severe infection among SLE patients requires further study.”

To determine if the risk of infection was tied to acquired low immunoglobulin levels, the researchers launched a retrospective analysis of data from a prospective cohort study of adult SLE patients from a Toronto lupus cohort that was established in 1970. The study was published in Rheumatology.

A total of 448 patients with at least two low immunoglobulin tests were matched with 656 SLE patients with no low immunoglobulins according to enrollment decade. The average age of the low-immunoglobulin group was 41.8 years, compared with 39.3 years in the control group. Average disease duration was 11.2 years in the low-immunoglobulin group and 7.6 years in the control group.

Of the patients in the low-immunoglobulin group, 221 had consecutive low tests and 227 had nonconsecutive low tests. Overall, 98 of those patients had low IgG, 251 patients had low IgM, and 51 patients had low IgA. Only 48 patients had overlapping low levels, including 5 with all three.

Average levels among the low-immunoglobulin group at baseline were 11.5 (standard deviation, 6.1) g/L of IgG, 0.8 (1.1) g/L of IgM, and 2.4 (1.6) g/L of IgA, while average levels among the control group were 16.3 (6.4) g/L of IgG, 1.8 (1.2) g/L of IgM, and 3.2 (1.5) g/L of IgA. In the primary analysis, after adjustment using propensity scoring, there were 97 infections: 47 in the low-immunoglobulin group and 50 in the control group. The most common types were respiratory and urinary tract infections, and the rate of infection was higher in patients with low IgA. The IgA level associated with risk of infection was less than 0.75 g/L.

After Cox regression analysis, the only variable that significantly increased infection risk was a low IgA level (hazard ratio, 3.19; 95% confidence interval, 1.17-8.71), not a low IgG level (HR, 1.87; 95% CI, 0.77-4.54) or low IgM level (HR, 0.63; 95% CI, 0.34-1.17). In regard to recovery among the low-immunoglobulin group, 11 patients (2.5%) recovered from low immunoglobulins within in the first year, followed by 36 (8.2%) in the second year, 44 (10.1%) in the third year, and 80 (18.4%) in the fourth year. All told, 60% (263) of patients with acquired hypogammaglobulinemia recovered over a 4-year period.

Is there clinical relevance to low IgA?

“I don’t see us using this clinically immediately,” Karen Costenbader, MD, a rheumatologist at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston, said in an interview. “We do test immunoglobulins often, especially in patients who’ve had biologic therapy. Will we start thinking about their IgA levels? It’s not clear, and the researchers leave it up in the air as to what this means, beyond them being at high risk.”

That said, she added, “IgA levels are interesting, especially in a time of COVID, because they’re associated with mucosal immunity. Is this subset of patients going to be at particularly high risk for the coronavirus?”

She also noted that, though immunoglobulin replacement has been helpful in her patients, it’s an expensive therapy to recommend for low IgA levels without knowing exactly what is causing these deficiencies. “My question is, would it be useful to follow these levels in lupus patients, even we don’t know what to do about them?” she asked. “We know there are a lot of risk factors for infections, so is the IgA going to be useful above and beyond that, and then what can we do about it?”

The authors acknowledged their study’s potential limitations, including low infection rates and yearly measurements of immunoglobulin levels, which could’ve led to misclassifying a lab error as true low immunoglobulin. They also highlighted its strengths, including using various methods to reduce selection and confounding bias while also reporting consistent results after examining multiple definitions of low immunoglobulins and outcomes.

The study received no specific funding, and the authors reported no potential conflicts of interest.

SOURCE: Almaghlouth I et al. Rheumatology. 2020 Oct 2. doi: 10.1093/rheumatology/keaa641.

A new study of immunoglobulin levels in adult patients with systemic lupus erythematosus (SLE) has found that acquired low levels of IgA are associated with a higher risk of infection.

To the knowledge of first author Ibrahim Almaghlouth, MD, of the division of rheumatology at the University of Toronto, and colleagues, “this is the first dedicated study to examine the relationship between acquired low immunoglobulins and infection risk in adult patients with SLE.” But as to whether there may be a “protective role for immunoglobulins and the potential effect of immunoglobulin replacement in a setting of recurrent or severe infection among SLE patients requires further study.”

To determine if the risk of infection was tied to acquired low immunoglobulin levels, the researchers launched a retrospective analysis of data from a prospective cohort study of adult SLE patients from a Toronto lupus cohort that was established in 1970. The study was published in Rheumatology.

A total of 448 patients with at least two low immunoglobulin tests were matched with 656 SLE patients with no low immunoglobulins according to enrollment decade. The average age of the low-immunoglobulin group was 41.8 years, compared with 39.3 years in the control group. Average disease duration was 11.2 years in the low-immunoglobulin group and 7.6 years in the control group.

Of the patients in the low-immunoglobulin group, 221 had consecutive low tests and 227 had nonconsecutive low tests. Overall, 98 of those patients had low IgG, 251 patients had low IgM, and 51 patients had low IgA. Only 48 patients had overlapping low levels, including 5 with all three.

Average levels among the low-immunoglobulin group at baseline were 11.5 (standard deviation, 6.1) g/L of IgG, 0.8 (1.1) g/L of IgM, and 2.4 (1.6) g/L of IgA, while average levels among the control group were 16.3 (6.4) g/L of IgG, 1.8 (1.2) g/L of IgM, and 3.2 (1.5) g/L of IgA. In the primary analysis, after adjustment using propensity scoring, there were 97 infections: 47 in the low-immunoglobulin group and 50 in the control group. The most common types were respiratory and urinary tract infections, and the rate of infection was higher in patients with low IgA. The IgA level associated with risk of infection was less than 0.75 g/L.

After Cox regression analysis, the only variable that significantly increased infection risk was a low IgA level (hazard ratio, 3.19; 95% confidence interval, 1.17-8.71), not a low IgG level (HR, 1.87; 95% CI, 0.77-4.54) or low IgM level (HR, 0.63; 95% CI, 0.34-1.17). In regard to recovery among the low-immunoglobulin group, 11 patients (2.5%) recovered from low immunoglobulins within in the first year, followed by 36 (8.2%) in the second year, 44 (10.1%) in the third year, and 80 (18.4%) in the fourth year. All told, 60% (263) of patients with acquired hypogammaglobulinemia recovered over a 4-year period.

Is there clinical relevance to low IgA?

“I don’t see us using this clinically immediately,” Karen Costenbader, MD, a rheumatologist at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston, said in an interview. “We do test immunoglobulins often, especially in patients who’ve had biologic therapy. Will we start thinking about their IgA levels? It’s not clear, and the researchers leave it up in the air as to what this means, beyond them being at high risk.”

That said, she added, “IgA levels are interesting, especially in a time of COVID, because they’re associated with mucosal immunity. Is this subset of patients going to be at particularly high risk for the coronavirus?”

She also noted that, though immunoglobulin replacement has been helpful in her patients, it’s an expensive therapy to recommend for low IgA levels without knowing exactly what is causing these deficiencies. “My question is, would it be useful to follow these levels in lupus patients, even we don’t know what to do about them?” she asked. “We know there are a lot of risk factors for infections, so is the IgA going to be useful above and beyond that, and then what can we do about it?”

The authors acknowledged their study’s potential limitations, including low infection rates and yearly measurements of immunoglobulin levels, which could’ve led to misclassifying a lab error as true low immunoglobulin. They also highlighted its strengths, including using various methods to reduce selection and confounding bias while also reporting consistent results after examining multiple definitions of low immunoglobulins and outcomes.

The study received no specific funding, and the authors reported no potential conflicts of interest.

SOURCE: Almaghlouth I et al. Rheumatology. 2020 Oct 2. doi: 10.1093/rheumatology/keaa641.

Upadacitinib (Rinvoq) proved superior to abatacept in both disease activity and remission in rheumatoid arthritis patients yet led to more adverse events, according to a new study that compared the two drugs.

“Additional data from longer and larger trials are needed to better understand long-term outcomes and safety of upadacitinib as compared with other drugs for the treatment of rheumatoid arthritis,” wrote Andrea Rubbert-Roth, MD, of the Cantonal Clinic St. Gallen in St. Gallen, Switzerland, and her colleagues. The study was published in the New England Journal of Medicine.

The Food and Drug Administration approved upadacitinib for the treatment of rheumatoid arthritis in August 2019.

To compare the Janus kinase (JAK) inhibitor upadacitinib and the biologic disease-modifying antirheumatic drug (DMARD) abatacept as safe and effective treatments for RA, the researchers launched a randomized, double-blind, phase 3 clinical trial dubbed SELECT-CHOICE at 120 sites in 28 countries. All patients had moderate to severe active disease after previously having inadequate responses to at least one biologic DMARD. Slightly more than 82% of the participants were female, with a mean age of 55 years and mean RA duration of 12 years.

Patients were assigned either 15 mg of oral upadacitinib daily (n = 303) or intravenous abatacept at day 1 and weeks 2, 4, 8, 12, 16 and 20 (n = 309) with dosage tied to body weight, each in combination with stable synthetic DMARDs. Disease activity was measured after 12 weeks via the Disease Activity Score for 28 joints using C-reactive protein (DAS28-CRP). A DAS28-CRP of more than 5.1 was categorized as high disease activity, while 3.2-5.1 meant moderate disease activity, 2.6-3.2 meant low disease activity, and less than 2.6 indicated remission.

The mean DAS28-CRP at baseline was 5.70 in the upadacitinib group and 5.88 in the abatacept group. After 12 weeks, the mean change from baseline was –2.52 points and –2.00 points, respectively (difference, –0.52 points; 95% confidence interval, –0.69 to –0.35; P < .001 for noninferiority; P < .001 for superiority). In patients with a DAS28-CRP of less than 2.6, the percentage of those having remission was 30% with upadacitinib and 13.3% with abatacept (difference, 16.8 percentage points; 95% CI, 10.4 to 23.2; P < .001 for superiority).

Over the 24-week trial period, the incidence of all adverse events (209 vs. 189) and serious adverse events (10 vs. 5) was higher in the upadacitinib group than in the abatacept group. There were 23 cases of hepatic disorder with upadacitinib, compared with 5 with abatacept; 2 thromboembolic events with upadacitinib, compared with 0 with abatacept; and 2 deaths with upadacitinib, compared with 1 with abatacept.

“The thing that bothers me, actually, is the adverse events,” Daniel E. Furst, MD, professor of medicine (emeritus) and rheumatology at the University of California, Los Angeles, said in an interview. “There were a fair number of them, all of which were a little higher in upadacitinib. They certainly made very little of those.”

He noted several other concerns about the study, including a potential geographic effect stemming from 60% of the study’s centers being in South and Central America and Eastern Europe. “Those patients don’t always have very good medical care,” he said. “They have an inherent, underlying placebo response that can be much different than Western Europe and North America.”

He also questioned their choice of primary endpoint metric.

“I think a much more legitimate way at looking at remission is the CDAI [Clinical Disease Activity Index] rather than the DAS28,” he said. “The DAS28, even at its best, is low disease activity, not true remission.”

“Bottom line,” he added, “this is a legitimate study that supports previous findings. One more important thing that is overlooked, though, is an economic analysis. A true economic analysis would be very important to place this in the armamentarium.”
 

Study affirms upadacitinib’s place in the RA treatment pecking order

By showing that upadacitinib was not only noninferior but superior to abatacept in decreasing disease activity, Rubbert-Roth and colleagues have positioned the JAK inhibitor at “the forefront of treatment for rheumatoid arthritis,” wrote Guro L. Goll, MD, PhD, and Tore K. Kvien, MD, PhD, of Diakonhjemmet Hospital in Oslo, in an accompanying editorial.

Though the authors noted that the 24-week trial was likely too short to make meaningful assumptions about long-term outcomes, they recognized the notably improved treatment outcomes over the study period and stated the importance of “head-to-head trials ... to inform evidence-based clinical decisions.” Similar to Dr. Furst, however, they stated an interest in “detailed data on changes in the CDAI score as a continuous measure.”

They also acknowledged the significant increase in adverse events among patients in the upadacitinib group, underlining the need to learn more in forthcoming, lengthier trials. “Rheumatologists will be looking hard at future data,” they wrote, “to assess whether improved treatment outcomes justify an increased risk of adverse events.”

The study was supported by AbbVie. The authors acknowledged numerous potential conflicts of interest, including receiving research grants and fees from various pharmaceutical companies for consulting, lectures, and being on advisory boards.

SOURCE: Rubbert-Roth A et al. N Engl J Med. 2020 Oct 14. doi: 10.1056/NEJMoa2008250.

Upadacitinib (Rinvoq) proved superior to abatacept in both disease activity and remission in rheumatoid arthritis patients yet led to more adverse events, according to a new study that compared the two drugs.

“Additional data from longer and larger trials are needed to better understand long-term outcomes and safety of upadacitinib as compared with other drugs for the treatment of rheumatoid arthritis,” wrote Andrea Rubbert-Roth, MD, of the Cantonal Clinic St. Gallen in St. Gallen, Switzerland, and her colleagues. The study was published in the New England Journal of Medicine.

The Food and Drug Administration approved upadacitinib for the treatment of rheumatoid arthritis in August 2019.

To compare the Janus kinase (JAK) inhibitor upadacitinib and the biologic disease-modifying antirheumatic drug (DMARD) abatacept as safe and effective treatments for RA, the researchers launched a randomized, double-blind, phase 3 clinical trial dubbed SELECT-CHOICE at 120 sites in 28 countries. All patients had moderate to severe active disease after previously having inadequate responses to at least one biologic DMARD. Slightly more than 82% of the participants were female, with a mean age of 55 years and mean RA duration of 12 years.

Patients were assigned either 15 mg of oral upadacitinib daily (n = 303) or intravenous abatacept at day 1 and weeks 2, 4, 8, 12, 16 and 20 (n = 309) with dosage tied to body weight, each in combination with stable synthetic DMARDs. Disease activity was measured after 12 weeks via the Disease Activity Score for 28 joints using C-reactive protein (DAS28-CRP). A DAS28-CRP of more than 5.1 was categorized as high disease activity, while 3.2-5.1 meant moderate disease activity, 2.6-3.2 meant low disease activity, and less than 2.6 indicated remission.

The mean DAS28-CRP at baseline was 5.70 in the upadacitinib group and 5.88 in the abatacept group. After 12 weeks, the mean change from baseline was –2.52 points and –2.00 points, respectively (difference, –0.52 points; 95% confidence interval, –0.69 to –0.35; P < .001 for noninferiority; P < .001 for superiority). In patients with a DAS28-CRP of less than 2.6, the percentage of those having remission was 30% with upadacitinib and 13.3% with abatacept (difference, 16.8 percentage points; 95% CI, 10.4 to 23.2; P < .001 for superiority).

Over the 24-week trial period, the incidence of all adverse events (209 vs. 189) and serious adverse events (10 vs. 5) was higher in the upadacitinib group than in the abatacept group. There were 23 cases of hepatic disorder with upadacitinib, compared with 5 with abatacept; 2 thromboembolic events with upadacitinib, compared with 0 with abatacept; and 2 deaths with upadacitinib, compared with 1 with abatacept.

“The thing that bothers me, actually, is the adverse events,” Daniel E. Furst, MD, professor of medicine (emeritus) and rheumatology at the University of California, Los Angeles, said in an interview. “There were a fair number of them, all of which were a little higher in upadacitinib. They certainly made very little of those.”

He noted several other concerns about the study, including a potential geographic effect stemming from 60% of the study’s centers being in South and Central America and Eastern Europe. “Those patients don’t always have very good medical care,” he said. “They have an inherent, underlying placebo response that can be much different than Western Europe and North America.”

He also questioned their choice of primary endpoint metric.

“I think a much more legitimate way at looking at remission is the CDAI [Clinical Disease Activity Index] rather than the DAS28,” he said. “The DAS28, even at its best, is low disease activity, not true remission.”

“Bottom line,” he added, “this is a legitimate study that supports previous findings. One more important thing that is overlooked, though, is an economic analysis. A true economic analysis would be very important to place this in the armamentarium.”
 

Study affirms upadacitinib’s place in the RA treatment pecking order

By showing that upadacitinib was not only noninferior but superior to abatacept in decreasing disease activity, Rubbert-Roth and colleagues have positioned the JAK inhibitor at “the forefront of treatment for rheumatoid arthritis,” wrote Guro L. Goll, MD, PhD, and Tore K. Kvien, MD, PhD, of Diakonhjemmet Hospital in Oslo, in an accompanying editorial.

Though the authors noted that the 24-week trial was likely too short to make meaningful assumptions about long-term outcomes, they recognized the notably improved treatment outcomes over the study period and stated the importance of “head-to-head trials ... to inform evidence-based clinical decisions.” Similar to Dr. Furst, however, they stated an interest in “detailed data on changes in the CDAI score as a continuous measure.”

They also acknowledged the significant increase in adverse events among patients in the upadacitinib group, underlining the need to learn more in forthcoming, lengthier trials. “Rheumatologists will be looking hard at future data,” they wrote, “to assess whether improved treatment outcomes justify an increased risk of adverse events.”

The study was supported by AbbVie. The authors acknowledged numerous potential conflicts of interest, including receiving research grants and fees from various pharmaceutical companies for consulting, lectures, and being on advisory boards.

SOURCE: Rubbert-Roth A et al. N Engl J Med. 2020 Oct 14. doi: 10.1056/NEJMoa2008250.

Upadacitinib (Rinvoq) proved superior to abatacept in both disease activity and remission in rheumatoid arthritis patients yet led to more adverse events, according to a new study that compared the two drugs.

“Additional data from longer and larger trials are needed to better understand long-term outcomes and safety of upadacitinib as compared with other drugs for the treatment of rheumatoid arthritis,” wrote Andrea Rubbert-Roth, MD, of the Cantonal Clinic St. Gallen in St. Gallen, Switzerland, and her colleagues. The study was published in the New England Journal of Medicine.

The Food and Drug Administration approved upadacitinib for the treatment of rheumatoid arthritis in August 2019.

To compare the Janus kinase (JAK) inhibitor upadacitinib and the biologic disease-modifying antirheumatic drug (DMARD) abatacept as safe and effective treatments for RA, the researchers launched a randomized, double-blind, phase 3 clinical trial dubbed SELECT-CHOICE at 120 sites in 28 countries. All patients had moderate to severe active disease after previously having inadequate responses to at least one biologic DMARD. Slightly more than 82% of the participants were female, with a mean age of 55 years and mean RA duration of 12 years.

Patients were assigned either 15 mg of oral upadacitinib daily (n = 303) or intravenous abatacept at day 1 and weeks 2, 4, 8, 12, 16 and 20 (n = 309) with dosage tied to body weight, each in combination with stable synthetic DMARDs. Disease activity was measured after 12 weeks via the Disease Activity Score for 28 joints using C-reactive protein (DAS28-CRP). A DAS28-CRP of more than 5.1 was categorized as high disease activity, while 3.2-5.1 meant moderate disease activity, 2.6-3.2 meant low disease activity, and less than 2.6 indicated remission.

The mean DAS28-CRP at baseline was 5.70 in the upadacitinib group and 5.88 in the abatacept group. After 12 weeks, the mean change from baseline was –2.52 points and –2.00 points, respectively (difference, –0.52 points; 95% confidence interval, –0.69 to –0.35; P < .001 for noninferiority; P < .001 for superiority). In patients with a DAS28-CRP of less than 2.6, the percentage of those having remission was 30% with upadacitinib and 13.3% with abatacept (difference, 16.8 percentage points; 95% CI, 10.4 to 23.2; P < .001 for superiority).

Over the 24-week trial period, the incidence of all adverse events (209 vs. 189) and serious adverse events (10 vs. 5) was higher in the upadacitinib group than in the abatacept group. There were 23 cases of hepatic disorder with upadacitinib, compared with 5 with abatacept; 2 thromboembolic events with upadacitinib, compared with 0 with abatacept; and 2 deaths with upadacitinib, compared with 1 with abatacept.

“The thing that bothers me, actually, is the adverse events,” Daniel E. Furst, MD, professor of medicine (emeritus) and rheumatology at the University of California, Los Angeles, said in an interview. “There were a fair number of them, all of which were a little higher in upadacitinib. They certainly made very little of those.”

He noted several other concerns about the study, including a potential geographic effect stemming from 60% of the study’s centers being in South and Central America and Eastern Europe. “Those patients don’t always have very good medical care,” he said. “They have an inherent, underlying placebo response that can be much different than Western Europe and North America.”

He also questioned their choice of primary endpoint metric.

“I think a much more legitimate way at looking at remission is the CDAI [Clinical Disease Activity Index] rather than the DAS28,” he said. “The DAS28, even at its best, is low disease activity, not true remission.”

“Bottom line,” he added, “this is a legitimate study that supports previous findings. One more important thing that is overlooked, though, is an economic analysis. A true economic analysis would be very important to place this in the armamentarium.”
 

Study affirms upadacitinib’s place in the RA treatment pecking order

By showing that upadacitinib was not only noninferior but superior to abatacept in decreasing disease activity, Rubbert-Roth and colleagues have positioned the JAK inhibitor at “the forefront of treatment for rheumatoid arthritis,” wrote Guro L. Goll, MD, PhD, and Tore K. Kvien, MD, PhD, of Diakonhjemmet Hospital in Oslo, in an accompanying editorial.

Though the authors noted that the 24-week trial was likely too short to make meaningful assumptions about long-term outcomes, they recognized the notably improved treatment outcomes over the study period and stated the importance of “head-to-head trials ... to inform evidence-based clinical decisions.” Similar to Dr. Furst, however, they stated an interest in “detailed data on changes in the CDAI score as a continuous measure.”

They also acknowledged the significant increase in adverse events among patients in the upadacitinib group, underlining the need to learn more in forthcoming, lengthier trials. “Rheumatologists will be looking hard at future data,” they wrote, “to assess whether improved treatment outcomes justify an increased risk of adverse events.”

The study was supported by AbbVie. The authors acknowledged numerous potential conflicts of interest, including receiving research grants and fees from various pharmaceutical companies for consulting, lectures, and being on advisory boards.

SOURCE: Rubbert-Roth A et al. N Engl J Med. 2020 Oct 14. doi: 10.1056/NEJMoa2008250.