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IMAGINE-RA: No need for MRI with treat-to-target strategy
AMSTERDAM – Results of the
“Despite patients achieving a target of clinical remission, we still see erosive progression in about 20%-30%,” study investigator Signe Møller-Bisgaard, MD, PhD, said at the European Congress of Rheumatology. That’s regardless of the definition of remission that you use, she added.
Dr. Møller-Bisgaard, a resident in rheumatology and postdoctoral researcher who works at Rigshospitalet and Frederiksberg Hospital in Copenhagen, observed that both synovial inflammation and bone marrow edema seen on MRI had been shown to predict progression in patients with rheumatoid arthritis.
What was not known, however, was whether there was any value in specifically targeting MRI remission in patients who had already achieved clinical remission. This is what the IMAGINE-RA study set out to address. It was a 2-year trial of 200 patients with rheumatoid arthritis in clinical remission who were recruited and randomized to either an MRI or conventional treat-to-target strategy. The study involved nine rheumatology and eight radiological departments, Dr. Møller-Bisgaard said.
The protocol for the study (Trials. 2015;16:178) defined clinical remission as a DAS28-CRP of 3.2 or lower and no swollen joints. Patients had to have erosions on x-ray, be anti–cyclic citrullinated peptide positive, and be treated only with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) at the time of entry.
During the study patients were assessed every 4 months via the DAS28 or DAS28 plus MRI of the dominant hand and wrist, with radiographs of the hands and feet performed annually in both groups and MRI also performed yearly in the conventional treat-to-target group.
“Treatment was intensified in both arms if the DAS28-CRP was above 3.2, and there was at least one clinical swollen joint,” Dr. Møller-Bisgaard explained. Treatment was also intensified in the MRI group if bone marrow edema was observed. Treatment intensification involved maximal doses of csDMARDs alone or in combinations, and then addition of biologic treatments, such as a tumor necrosis factor inhibitor.
“Targeting absence of MRI bone marrow edema in addition to a conventional treat-to-target strategy in RA patients in clinical remission had no effect on the probability of achieving DAS28-CRP remission or halting radiographic progression,” she said.
However, there were some positive effects on several predefined secondary endpoints. For instance, more patients in the MRI group than in the conventional treat-to-target group achieved American College of Rheumatology/EULAR remission (49% vs. 32%; P = .017). There was a significant improvement in the number of swollen joints and a patient and physician global assessment. “There was also more improvement in HAQ [Health Assessment Questionnaire], with a difference between the groups of .14 [P less than .001], Dr. Møller-Bisgaard reported.
The IMAGINE-RA study is funded by grants from the Danish Rheumatism Association and the Research Fund of Region Zealand. Funding is also provided by AbbVie via a nonrestricted grant, and adalimumab is provided free of charge. Dr. Møller-Bisgaard and coauthors had no personal conflicts of interest to declare.
SOURCE: Møller-Bisgaard S et al. EULAR 2018 Congress. Abstract OP0018.
AMSTERDAM – Results of the
“Despite patients achieving a target of clinical remission, we still see erosive progression in about 20%-30%,” study investigator Signe Møller-Bisgaard, MD, PhD, said at the European Congress of Rheumatology. That’s regardless of the definition of remission that you use, she added.
Dr. Møller-Bisgaard, a resident in rheumatology and postdoctoral researcher who works at Rigshospitalet and Frederiksberg Hospital in Copenhagen, observed that both synovial inflammation and bone marrow edema seen on MRI had been shown to predict progression in patients with rheumatoid arthritis.
What was not known, however, was whether there was any value in specifically targeting MRI remission in patients who had already achieved clinical remission. This is what the IMAGINE-RA study set out to address. It was a 2-year trial of 200 patients with rheumatoid arthritis in clinical remission who were recruited and randomized to either an MRI or conventional treat-to-target strategy. The study involved nine rheumatology and eight radiological departments, Dr. Møller-Bisgaard said.
The protocol for the study (Trials. 2015;16:178) defined clinical remission as a DAS28-CRP of 3.2 or lower and no swollen joints. Patients had to have erosions on x-ray, be anti–cyclic citrullinated peptide positive, and be treated only with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) at the time of entry.
During the study patients were assessed every 4 months via the DAS28 or DAS28 plus MRI of the dominant hand and wrist, with radiographs of the hands and feet performed annually in both groups and MRI also performed yearly in the conventional treat-to-target group.
“Treatment was intensified in both arms if the DAS28-CRP was above 3.2, and there was at least one clinical swollen joint,” Dr. Møller-Bisgaard explained. Treatment was also intensified in the MRI group if bone marrow edema was observed. Treatment intensification involved maximal doses of csDMARDs alone or in combinations, and then addition of biologic treatments, such as a tumor necrosis factor inhibitor.
“Targeting absence of MRI bone marrow edema in addition to a conventional treat-to-target strategy in RA patients in clinical remission had no effect on the probability of achieving DAS28-CRP remission or halting radiographic progression,” she said.
However, there were some positive effects on several predefined secondary endpoints. For instance, more patients in the MRI group than in the conventional treat-to-target group achieved American College of Rheumatology/EULAR remission (49% vs. 32%; P = .017). There was a significant improvement in the number of swollen joints and a patient and physician global assessment. “There was also more improvement in HAQ [Health Assessment Questionnaire], with a difference between the groups of .14 [P less than .001], Dr. Møller-Bisgaard reported.
The IMAGINE-RA study is funded by grants from the Danish Rheumatism Association and the Research Fund of Region Zealand. Funding is also provided by AbbVie via a nonrestricted grant, and adalimumab is provided free of charge. Dr. Møller-Bisgaard and coauthors had no personal conflicts of interest to declare.
SOURCE: Møller-Bisgaard S et al. EULAR 2018 Congress. Abstract OP0018.
AMSTERDAM – Results of the
“Despite patients achieving a target of clinical remission, we still see erosive progression in about 20%-30%,” study investigator Signe Møller-Bisgaard, MD, PhD, said at the European Congress of Rheumatology. That’s regardless of the definition of remission that you use, she added.
Dr. Møller-Bisgaard, a resident in rheumatology and postdoctoral researcher who works at Rigshospitalet and Frederiksberg Hospital in Copenhagen, observed that both synovial inflammation and bone marrow edema seen on MRI had been shown to predict progression in patients with rheumatoid arthritis.
What was not known, however, was whether there was any value in specifically targeting MRI remission in patients who had already achieved clinical remission. This is what the IMAGINE-RA study set out to address. It was a 2-year trial of 200 patients with rheumatoid arthritis in clinical remission who were recruited and randomized to either an MRI or conventional treat-to-target strategy. The study involved nine rheumatology and eight radiological departments, Dr. Møller-Bisgaard said.
The protocol for the study (Trials. 2015;16:178) defined clinical remission as a DAS28-CRP of 3.2 or lower and no swollen joints. Patients had to have erosions on x-ray, be anti–cyclic citrullinated peptide positive, and be treated only with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) at the time of entry.
During the study patients were assessed every 4 months via the DAS28 or DAS28 plus MRI of the dominant hand and wrist, with radiographs of the hands and feet performed annually in both groups and MRI also performed yearly in the conventional treat-to-target group.
“Treatment was intensified in both arms if the DAS28-CRP was above 3.2, and there was at least one clinical swollen joint,” Dr. Møller-Bisgaard explained. Treatment was also intensified in the MRI group if bone marrow edema was observed. Treatment intensification involved maximal doses of csDMARDs alone or in combinations, and then addition of biologic treatments, such as a tumor necrosis factor inhibitor.
“Targeting absence of MRI bone marrow edema in addition to a conventional treat-to-target strategy in RA patients in clinical remission had no effect on the probability of achieving DAS28-CRP remission or halting radiographic progression,” she said.
However, there were some positive effects on several predefined secondary endpoints. For instance, more patients in the MRI group than in the conventional treat-to-target group achieved American College of Rheumatology/EULAR remission (49% vs. 32%; P = .017). There was a significant improvement in the number of swollen joints and a patient and physician global assessment. “There was also more improvement in HAQ [Health Assessment Questionnaire], with a difference between the groups of .14 [P less than .001], Dr. Møller-Bisgaard reported.
The IMAGINE-RA study is funded by grants from the Danish Rheumatism Association and the Research Fund of Region Zealand. Funding is also provided by AbbVie via a nonrestricted grant, and adalimumab is provided free of charge. Dr. Møller-Bisgaard and coauthors had no personal conflicts of interest to declare.
SOURCE: Møller-Bisgaard S et al. EULAR 2018 Congress. Abstract OP0018.
REPORTING FROM THE EULAR 2018 CONGRESS
Key clinical point: When a treat-to-target approach is used there is no added benefit of using magnetic resonance imaging.
Major finding: At 2 years, a similar percentage of patients achieved a DAS28-CRP of less than 2.6 and had no radiographic progression with an MRI-guided and conventional treat-to-target strategy.
Study details: The IMAGINE-RA study, a 2-year, prospective, randomized, multicenter trial of 200 patients with rheumatoid arthritis in clinical remission treated at 10 Danish hospitals.
Disclosures: The IMAGINE-RA study is funded by grants from the Danish Rheumatism Association and the Research Fund of Region Zealand. Funding is also provided by AbbVie via a nonrestricted grant and adalimumab is provided free of charge. Dr. Møller-Bisgaard and her coauthors had no personal conflicts of interest to declare.
Source: Møller-Bisgaard S et al. EULAR 2018 Congress. Abstract OP0018.
Heart failure confers poor prognosis in rheumatoid arthritis
AMSTERDAM – The combination of heart failure and rheumatoid arthritis carries a poor prognosis, according to data from the German biologics register.
Of 393 patients enrolled in RABBIT (Rheumatoide Arthritis: Beobachtung der Biologika-Therapie) who had heart failure in addition to their rheumatoid arthritis, 131 (33%) needed hospital treatment or died over a 10-year period. The mean time to hospitalization or death was 2.5-3.0 years.
“We include patients at the start of their DMARD [disease modifying antirheumatic drug] treatment and follow them up for at least 5 years,” said Dr. Meissner, explaining how the German biologics register works. “For this analysis, we selected all the patients with prevalent heart failure and followed them up until either the database was closed, they dropped out, or had an event.” In this case, an event was defined as a composite of deterioration in heart failure that required hospitalization or death from any cause.
Dr. Meissner, of the German Rheumatism Research Center in Berlin, noted that 19 (14.5%) patients experienced a deterioration in their heart failure and 123 deaths were recorded during the study period that started in May 2001 and ended in October 2017. Around one-third of deaths were attributable to infections (34%), and one-third were attributable to cardiovascular causes (31%). Of the CV deaths, more than half (58%) were attributed to patients’ heart failure.
“What impressed us the most is the number of comorbidities at baseline,” Dr. Meissner said. Not including heart failure or rheumatoid arthritis, patients who experienced an event had an average of 6.5 comorbidities versus 5.6 for those who did not have an event. These additional comorbidities included hypertension, coronary artery disease, diabetes mellitus, chronic renal disease, and osteoporosis.
Crude incidence rates (IRs) for heart failure deterioration or death were calculated according to the rheumatoid arthritis treatment being used and found to be highest in those treated with conventional DMARDs, at 18.1/100 patient-years. IRs with biologic treatments were lower, at 10.2/100 patient-years for abatacept, 9.3 for TNF inhibitors, 8.8 for tocilizumab, and 6.0 for rituximab. What this suggests it that better control of inflammation results in a lower risk for hospitalization and death, Dr. Meissner and her associates reported in their poster presentation.
“If patients are not effectively treated for rheumatoid arthritis, there might be other consequences like the deterioration of heart failure or death,” Dr. Meissner said.
She noted that investigators also looked at identifying risk factors for hospitalization or death and found that there was a greater adjusted relative risk if patients were male (RR = 2.4), older (RR = 1.3 per 5-year increase in age), or if they smoked (RR = 1.7). Using higher doses of glucocorticoids also was a risk factor, with a RR of 1.4 for every 5 mg/day increase in dose.
Better physical function was associated with a lower risk of an event (RR = 0.9) and, along with smoking and adjustment of the steroid dose, is a risk factor that could potentially be influenced, Dr. Meissner proposed.
No data on how the heart failure was being managed are available for this cohort and more research is needed.
“There is still not enough known about this topic, and we need the research to determine how to best manage these patients,” Dr. Meissner said. “The time to an event was only 3 years from the time of inclusion in the register, so we need better management of those patients with heart failure as a comorbidity.”
RABBIT is supported by a joint, unconditional grant from AbbVie, Bristol-Myers Squibb, Celltrion, Hexal AG, Lilly, MSD Sharp & Dohme, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, and UCB. Dr. Meissner disclosed being on a speakers bureau for Pfizer.
SOURCE: Meissner Y et al. EULAR 2018 Congress. Abstract THU0142 .
AMSTERDAM – The combination of heart failure and rheumatoid arthritis carries a poor prognosis, according to data from the German biologics register.
Of 393 patients enrolled in RABBIT (Rheumatoide Arthritis: Beobachtung der Biologika-Therapie) who had heart failure in addition to their rheumatoid arthritis, 131 (33%) needed hospital treatment or died over a 10-year period. The mean time to hospitalization or death was 2.5-3.0 years.
“We include patients at the start of their DMARD [disease modifying antirheumatic drug] treatment and follow them up for at least 5 years,” said Dr. Meissner, explaining how the German biologics register works. “For this analysis, we selected all the patients with prevalent heart failure and followed them up until either the database was closed, they dropped out, or had an event.” In this case, an event was defined as a composite of deterioration in heart failure that required hospitalization or death from any cause.
Dr. Meissner, of the German Rheumatism Research Center in Berlin, noted that 19 (14.5%) patients experienced a deterioration in their heart failure and 123 deaths were recorded during the study period that started in May 2001 and ended in October 2017. Around one-third of deaths were attributable to infections (34%), and one-third were attributable to cardiovascular causes (31%). Of the CV deaths, more than half (58%) were attributed to patients’ heart failure.
“What impressed us the most is the number of comorbidities at baseline,” Dr. Meissner said. Not including heart failure or rheumatoid arthritis, patients who experienced an event had an average of 6.5 comorbidities versus 5.6 for those who did not have an event. These additional comorbidities included hypertension, coronary artery disease, diabetes mellitus, chronic renal disease, and osteoporosis.
Crude incidence rates (IRs) for heart failure deterioration or death were calculated according to the rheumatoid arthritis treatment being used and found to be highest in those treated with conventional DMARDs, at 18.1/100 patient-years. IRs with biologic treatments were lower, at 10.2/100 patient-years for abatacept, 9.3 for TNF inhibitors, 8.8 for tocilizumab, and 6.0 for rituximab. What this suggests it that better control of inflammation results in a lower risk for hospitalization and death, Dr. Meissner and her associates reported in their poster presentation.
“If patients are not effectively treated for rheumatoid arthritis, there might be other consequences like the deterioration of heart failure or death,” Dr. Meissner said.
She noted that investigators also looked at identifying risk factors for hospitalization or death and found that there was a greater adjusted relative risk if patients were male (RR = 2.4), older (RR = 1.3 per 5-year increase in age), or if they smoked (RR = 1.7). Using higher doses of glucocorticoids also was a risk factor, with a RR of 1.4 for every 5 mg/day increase in dose.
Better physical function was associated with a lower risk of an event (RR = 0.9) and, along with smoking and adjustment of the steroid dose, is a risk factor that could potentially be influenced, Dr. Meissner proposed.
No data on how the heart failure was being managed are available for this cohort and more research is needed.
“There is still not enough known about this topic, and we need the research to determine how to best manage these patients,” Dr. Meissner said. “The time to an event was only 3 years from the time of inclusion in the register, so we need better management of those patients with heart failure as a comorbidity.”
RABBIT is supported by a joint, unconditional grant from AbbVie, Bristol-Myers Squibb, Celltrion, Hexal AG, Lilly, MSD Sharp & Dohme, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, and UCB. Dr. Meissner disclosed being on a speakers bureau for Pfizer.
SOURCE: Meissner Y et al. EULAR 2018 Congress. Abstract THU0142 .
AMSTERDAM – The combination of heart failure and rheumatoid arthritis carries a poor prognosis, according to data from the German biologics register.
Of 393 patients enrolled in RABBIT (Rheumatoide Arthritis: Beobachtung der Biologika-Therapie) who had heart failure in addition to their rheumatoid arthritis, 131 (33%) needed hospital treatment or died over a 10-year period. The mean time to hospitalization or death was 2.5-3.0 years.
“We include patients at the start of their DMARD [disease modifying antirheumatic drug] treatment and follow them up for at least 5 years,” said Dr. Meissner, explaining how the German biologics register works. “For this analysis, we selected all the patients with prevalent heart failure and followed them up until either the database was closed, they dropped out, or had an event.” In this case, an event was defined as a composite of deterioration in heart failure that required hospitalization or death from any cause.
Dr. Meissner, of the German Rheumatism Research Center in Berlin, noted that 19 (14.5%) patients experienced a deterioration in their heart failure and 123 deaths were recorded during the study period that started in May 2001 and ended in October 2017. Around one-third of deaths were attributable to infections (34%), and one-third were attributable to cardiovascular causes (31%). Of the CV deaths, more than half (58%) were attributed to patients’ heart failure.
“What impressed us the most is the number of comorbidities at baseline,” Dr. Meissner said. Not including heart failure or rheumatoid arthritis, patients who experienced an event had an average of 6.5 comorbidities versus 5.6 for those who did not have an event. These additional comorbidities included hypertension, coronary artery disease, diabetes mellitus, chronic renal disease, and osteoporosis.
Crude incidence rates (IRs) for heart failure deterioration or death were calculated according to the rheumatoid arthritis treatment being used and found to be highest in those treated with conventional DMARDs, at 18.1/100 patient-years. IRs with biologic treatments were lower, at 10.2/100 patient-years for abatacept, 9.3 for TNF inhibitors, 8.8 for tocilizumab, and 6.0 for rituximab. What this suggests it that better control of inflammation results in a lower risk for hospitalization and death, Dr. Meissner and her associates reported in their poster presentation.
“If patients are not effectively treated for rheumatoid arthritis, there might be other consequences like the deterioration of heart failure or death,” Dr. Meissner said.
She noted that investigators also looked at identifying risk factors for hospitalization or death and found that there was a greater adjusted relative risk if patients were male (RR = 2.4), older (RR = 1.3 per 5-year increase in age), or if they smoked (RR = 1.7). Using higher doses of glucocorticoids also was a risk factor, with a RR of 1.4 for every 5 mg/day increase in dose.
Better physical function was associated with a lower risk of an event (RR = 0.9) and, along with smoking and adjustment of the steroid dose, is a risk factor that could potentially be influenced, Dr. Meissner proposed.
No data on how the heart failure was being managed are available for this cohort and more research is needed.
“There is still not enough known about this topic, and we need the research to determine how to best manage these patients,” Dr. Meissner said. “The time to an event was only 3 years from the time of inclusion in the register, so we need better management of those patients with heart failure as a comorbidity.”
RABBIT is supported by a joint, unconditional grant from AbbVie, Bristol-Myers Squibb, Celltrion, Hexal AG, Lilly, MSD Sharp & Dohme, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, and UCB. Dr. Meissner disclosed being on a speakers bureau for Pfizer.
SOURCE: Meissner Y et al. EULAR 2018 Congress. Abstract THU0142 .
REPORTING FROM THE EULAR 2018 CONGRESS
Key clinical point: Comorbid heart failure and rheumatoid arthritis carry an unfavorable prognosis, but risk factors have been identified.
Major finding: One-third of patients were hospitalized or died, with a mean time to deterioration or death of 2.5-3 years.
Study details: 393 patients with both heart failure and rheumatoid arthritis enrolled in the German biologics register RABBIT.
Disclosures: RABBIT is supported by a joint, unconditional grant from AbbVie, Bristol-Myers Squibb, Celltrion, Hexal AG, Lilly, MSD Sharp & Dohme, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, and UCB. Dr. Meissner disclosed being part of a speakers bureau for Pfizer.
Source: Meissner Y et al. EULAR 2018 Congress, Abstract THU0142.
Severe OA sparks depression, surgery “ameliorates” depression in RA
AMSTERDAM – Structural severity in OA is related to the onset of depressive symptoms while surgery “ameliorates” depression in RA, according to the results of two separate studies presented at the European Congress of Rheumatology.
Using data on more than 1,600 individuals with knee OA from the Osteoarthritis Initiative, Alan Rathbun, PhD, and his associates looked at the components of disease severity and how they might individually contribute to the development of depression. They found that the odds of having depression more than doubled as joint space width increased (odds ratio, 2.25) and gait speed decreased (OR, 2.08), and rose 60% as pain became more severe (OR, 1.60).
Worsening knee OA could set off depression
“Studies have consistently shown that depressive symptoms are associated with worse osteoarthritis disease severity, however, there is a lack of research focused on identifying the specific components that contribute to the onset of depressive symptoms in nondepressed OA patients,” said Dr. Rathbun in an interview ahead of his presentation.
Dr. Rathbun, a research associate in the departments of epidemiology and of public health and medicine at the University of Maryland, Baltimore, also said that while OA guidelines do advise on treating depression, there is no standardized way to manage comorbid depression in routine clinical practice.
“If OA disease severity contributes to the development and worsening of depressive symptoms, it may be necessary to intervene on both conditions simultaneously in order to successfully manage them,” he suggested.
“Depression is a frequently occurring comorbidity in persons with OA,” Dr. Rathbun later observed during a press conference. Around one in five people with knee OA have depression, he said. This is an important fact if you consider how common symptomatic knee OA is – affecting 10% of men and 13% of women aged over 60 years – and the impact that it has on people’s quality of life, healthcare utilization, and mortality.
Dr. Rathbun and colleagues examined data on 1,652 men and women who were part of the Osteoarthritis Initiative, a multicenter, prospective, longitudinal study of knee health sponsored by the National Institutes of Health. For inclusion in the study, participants had to have radiographic knee OA, no depressive symptoms, and complete data on the disease severity components of interest: minimum joint space width, 20-meter gait speed, and the pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index. Depression was assessed using the Center for Epidemiological Studies Depression Scale, with no depression ascribed a score of 16 or under. Data from three additional annual follow-up visits was also required.
“All three components of OA disease progression were associated with an increased risk for the onset of depressive symptoms in those with radiographic knee OA,” Dr. Rathbun said in the interview. While pain severity has previously been linked to depressive symptoms in OA, the finding of worsening structural disease is new.
“The clinical implications of our findings are that the onset of depressive symptoms in OA patients is related to worsening pain, physical function, and structural disease severity,” he added. They also mean that these components and depression need to be targeted at the same time.
“Future studies need to ascertain whether depressive symptoms modify clinical response to analgesic medications in OA patients,” Dr. Rathbun suggested. “Considering that analgesics are often the first-line treatment for OA patients and the high prevalence of depressive symptoms in this population, comorbid depression may be an important contributor to ineffective medical management in the many OA patients who undergo total joint replacement.”
Depression “ameliorated” by orthopedic surgery for RA
While the effects of analgesic medications might be something to look at in relation to depression in OA, research presented elsewhere at the congress suggested that appropriate surgical intervention might also be key to dealing with depressive symptoms, at least in patients with RA.
After a 1-year follow-up in patients with RA who underwent orthopedic surgery, the mean BDI-II score improved from 13.0 to 11.5 (P less than .01), and the percentage of patients with a BDI-II score of 14 or more fell from 43% to 35%. Improvements in other health assessments – the Japanese version of the Health Assessment Questionnaire and the EuroQol 5 dimensions instrument – were also seen.
The prospective, observational cohort study included 276 patients with structural damage caused by RA. The most common site of joint damage requiring elective surgery was the wrist (n = 74), followed by the hand (n = 63), knee (n = 50), forefoot (n = 50), elbow (n = 26), hand and wrist (n = 18), hip (n = 13), ankle (n = 12), and shoulder (n = 6).
Looking at the improvement in depression scores by surgical site revealed a significant difference from baseline for the elbow (P less than .001), wrist (P less than .001), and forefoot (P less than .05). The magnitude of decrease in the BDI-II scores was independently related to Steinbrocker stage and pain measured on a visual analog scale.
“Depression was ameliorated by surgical intervention in patients with RA,” Hajime Ishikawa, MD, PhD, of the department of rheumatology at Niigata Rheumatic Center in Shibata, Japan, and associates concluded in their poster presentation. They added that the psychological changes observed were “related to the preoperative severity of joint damage and pain in the affected joint.”
Dr. Rathbun’s work was supported by a Rheumatology Research Foundation Scientist Development Award. Dr. Ishikawa and associates stated they had no disclosures of interest.
SOURCES: Rathbun AM et al. Ann Rheum Dis. 2018;77(Suppl 2):50-1. Abstract OP0003; Ishikawa H et al. Ann Rheum Dis. 2018;77(Suppl 2):297-8. Abstract THU0156.
AMSTERDAM – Structural severity in OA is related to the onset of depressive symptoms while surgery “ameliorates” depression in RA, according to the results of two separate studies presented at the European Congress of Rheumatology.
Using data on more than 1,600 individuals with knee OA from the Osteoarthritis Initiative, Alan Rathbun, PhD, and his associates looked at the components of disease severity and how they might individually contribute to the development of depression. They found that the odds of having depression more than doubled as joint space width increased (odds ratio, 2.25) and gait speed decreased (OR, 2.08), and rose 60% as pain became more severe (OR, 1.60).
Worsening knee OA could set off depression
“Studies have consistently shown that depressive symptoms are associated with worse osteoarthritis disease severity, however, there is a lack of research focused on identifying the specific components that contribute to the onset of depressive symptoms in nondepressed OA patients,” said Dr. Rathbun in an interview ahead of his presentation.
Dr. Rathbun, a research associate in the departments of epidemiology and of public health and medicine at the University of Maryland, Baltimore, also said that while OA guidelines do advise on treating depression, there is no standardized way to manage comorbid depression in routine clinical practice.
“If OA disease severity contributes to the development and worsening of depressive symptoms, it may be necessary to intervene on both conditions simultaneously in order to successfully manage them,” he suggested.
“Depression is a frequently occurring comorbidity in persons with OA,” Dr. Rathbun later observed during a press conference. Around one in five people with knee OA have depression, he said. This is an important fact if you consider how common symptomatic knee OA is – affecting 10% of men and 13% of women aged over 60 years – and the impact that it has on people’s quality of life, healthcare utilization, and mortality.
Dr. Rathbun and colleagues examined data on 1,652 men and women who were part of the Osteoarthritis Initiative, a multicenter, prospective, longitudinal study of knee health sponsored by the National Institutes of Health. For inclusion in the study, participants had to have radiographic knee OA, no depressive symptoms, and complete data on the disease severity components of interest: minimum joint space width, 20-meter gait speed, and the pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index. Depression was assessed using the Center for Epidemiological Studies Depression Scale, with no depression ascribed a score of 16 or under. Data from three additional annual follow-up visits was also required.
“All three components of OA disease progression were associated with an increased risk for the onset of depressive symptoms in those with radiographic knee OA,” Dr. Rathbun said in the interview. While pain severity has previously been linked to depressive symptoms in OA, the finding of worsening structural disease is new.
“The clinical implications of our findings are that the onset of depressive symptoms in OA patients is related to worsening pain, physical function, and structural disease severity,” he added. They also mean that these components and depression need to be targeted at the same time.
“Future studies need to ascertain whether depressive symptoms modify clinical response to analgesic medications in OA patients,” Dr. Rathbun suggested. “Considering that analgesics are often the first-line treatment for OA patients and the high prevalence of depressive symptoms in this population, comorbid depression may be an important contributor to ineffective medical management in the many OA patients who undergo total joint replacement.”
Depression “ameliorated” by orthopedic surgery for RA
While the effects of analgesic medications might be something to look at in relation to depression in OA, research presented elsewhere at the congress suggested that appropriate surgical intervention might also be key to dealing with depressive symptoms, at least in patients with RA.
After a 1-year follow-up in patients with RA who underwent orthopedic surgery, the mean BDI-II score improved from 13.0 to 11.5 (P less than .01), and the percentage of patients with a BDI-II score of 14 or more fell from 43% to 35%. Improvements in other health assessments – the Japanese version of the Health Assessment Questionnaire and the EuroQol 5 dimensions instrument – were also seen.
The prospective, observational cohort study included 276 patients with structural damage caused by RA. The most common site of joint damage requiring elective surgery was the wrist (n = 74), followed by the hand (n = 63), knee (n = 50), forefoot (n = 50), elbow (n = 26), hand and wrist (n = 18), hip (n = 13), ankle (n = 12), and shoulder (n = 6).
Looking at the improvement in depression scores by surgical site revealed a significant difference from baseline for the elbow (P less than .001), wrist (P less than .001), and forefoot (P less than .05). The magnitude of decrease in the BDI-II scores was independently related to Steinbrocker stage and pain measured on a visual analog scale.
“Depression was ameliorated by surgical intervention in patients with RA,” Hajime Ishikawa, MD, PhD, of the department of rheumatology at Niigata Rheumatic Center in Shibata, Japan, and associates concluded in their poster presentation. They added that the psychological changes observed were “related to the preoperative severity of joint damage and pain in the affected joint.”
Dr. Rathbun’s work was supported by a Rheumatology Research Foundation Scientist Development Award. Dr. Ishikawa and associates stated they had no disclosures of interest.
SOURCES: Rathbun AM et al. Ann Rheum Dis. 2018;77(Suppl 2):50-1. Abstract OP0003; Ishikawa H et al. Ann Rheum Dis. 2018;77(Suppl 2):297-8. Abstract THU0156.
AMSTERDAM – Structural severity in OA is related to the onset of depressive symptoms while surgery “ameliorates” depression in RA, according to the results of two separate studies presented at the European Congress of Rheumatology.
Using data on more than 1,600 individuals with knee OA from the Osteoarthritis Initiative, Alan Rathbun, PhD, and his associates looked at the components of disease severity and how they might individually contribute to the development of depression. They found that the odds of having depression more than doubled as joint space width increased (odds ratio, 2.25) and gait speed decreased (OR, 2.08), and rose 60% as pain became more severe (OR, 1.60).
Worsening knee OA could set off depression
“Studies have consistently shown that depressive symptoms are associated with worse osteoarthritis disease severity, however, there is a lack of research focused on identifying the specific components that contribute to the onset of depressive symptoms in nondepressed OA patients,” said Dr. Rathbun in an interview ahead of his presentation.
Dr. Rathbun, a research associate in the departments of epidemiology and of public health and medicine at the University of Maryland, Baltimore, also said that while OA guidelines do advise on treating depression, there is no standardized way to manage comorbid depression in routine clinical practice.
“If OA disease severity contributes to the development and worsening of depressive symptoms, it may be necessary to intervene on both conditions simultaneously in order to successfully manage them,” he suggested.
“Depression is a frequently occurring comorbidity in persons with OA,” Dr. Rathbun later observed during a press conference. Around one in five people with knee OA have depression, he said. This is an important fact if you consider how common symptomatic knee OA is – affecting 10% of men and 13% of women aged over 60 years – and the impact that it has on people’s quality of life, healthcare utilization, and mortality.
Dr. Rathbun and colleagues examined data on 1,652 men and women who were part of the Osteoarthritis Initiative, a multicenter, prospective, longitudinal study of knee health sponsored by the National Institutes of Health. For inclusion in the study, participants had to have radiographic knee OA, no depressive symptoms, and complete data on the disease severity components of interest: minimum joint space width, 20-meter gait speed, and the pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index. Depression was assessed using the Center for Epidemiological Studies Depression Scale, with no depression ascribed a score of 16 or under. Data from three additional annual follow-up visits was also required.
“All three components of OA disease progression were associated with an increased risk for the onset of depressive symptoms in those with radiographic knee OA,” Dr. Rathbun said in the interview. While pain severity has previously been linked to depressive symptoms in OA, the finding of worsening structural disease is new.
“The clinical implications of our findings are that the onset of depressive symptoms in OA patients is related to worsening pain, physical function, and structural disease severity,” he added. They also mean that these components and depression need to be targeted at the same time.
“Future studies need to ascertain whether depressive symptoms modify clinical response to analgesic medications in OA patients,” Dr. Rathbun suggested. “Considering that analgesics are often the first-line treatment for OA patients and the high prevalence of depressive symptoms in this population, comorbid depression may be an important contributor to ineffective medical management in the many OA patients who undergo total joint replacement.”
Depression “ameliorated” by orthopedic surgery for RA
While the effects of analgesic medications might be something to look at in relation to depression in OA, research presented elsewhere at the congress suggested that appropriate surgical intervention might also be key to dealing with depressive symptoms, at least in patients with RA.
After a 1-year follow-up in patients with RA who underwent orthopedic surgery, the mean BDI-II score improved from 13.0 to 11.5 (P less than .01), and the percentage of patients with a BDI-II score of 14 or more fell from 43% to 35%. Improvements in other health assessments – the Japanese version of the Health Assessment Questionnaire and the EuroQol 5 dimensions instrument – were also seen.
The prospective, observational cohort study included 276 patients with structural damage caused by RA. The most common site of joint damage requiring elective surgery was the wrist (n = 74), followed by the hand (n = 63), knee (n = 50), forefoot (n = 50), elbow (n = 26), hand and wrist (n = 18), hip (n = 13), ankle (n = 12), and shoulder (n = 6).
Looking at the improvement in depression scores by surgical site revealed a significant difference from baseline for the elbow (P less than .001), wrist (P less than .001), and forefoot (P less than .05). The magnitude of decrease in the BDI-II scores was independently related to Steinbrocker stage and pain measured on a visual analog scale.
“Depression was ameliorated by surgical intervention in patients with RA,” Hajime Ishikawa, MD, PhD, of the department of rheumatology at Niigata Rheumatic Center in Shibata, Japan, and associates concluded in their poster presentation. They added that the psychological changes observed were “related to the preoperative severity of joint damage and pain in the affected joint.”
Dr. Rathbun’s work was supported by a Rheumatology Research Foundation Scientist Development Award. Dr. Ishikawa and associates stated they had no disclosures of interest.
SOURCES: Rathbun AM et al. Ann Rheum Dis. 2018;77(Suppl 2):50-1. Abstract OP0003; Ishikawa H et al. Ann Rheum Dis. 2018;77(Suppl 2):297-8. Abstract THU0156.
REPORTING FROM THE EULAR 2018 CONGRESS
Key clinical point: Structural severity is related to the onset of depressive symptoms in OA while surgery “ameliorates” depression in RA.
Major findings: Depression increased the odds of having worse OA (2.25 for greater joint space width, 2.08 for slower gait, and 1.60 for pain severity). The mean Beck Depression Inventory–II score of RA patients who underwent orthopedic surgery was 11.5 postsurgery, an improvement of 1.5 points versus presurgery scores (P less than .01).
Study details: Data on more than 1,600 individuals with knee OA from the Osteoarthritis Initiative and a separate prospective, observational cohort study of 276 patients with structural joint damage caused by RA who underwent elective surgery.
Disclosures: Dr. Rathbun’s work was supported by a Rheumatology Research Foundation Scientist Development Award. Dr. Ishikawa and associates reported no disclosures of interest.
Sources: Rathbun AM et al. Ann Rheum Dis. 2018;77(Suppl 2):50-1. Abstract OP0003; Ishikawa H et al. Ann Rheum Dis. 2018;77(Suppl 2):297-8. Abstract THU0156.
Checkpoint inhibitors in autoimmune disease: More flares, better cancer outcomes
AMSTERDAM – In patients with autoimmune diseases, cancer treatment with checkpoint inhibitor immunotherapy increases the risk of flares, but these flares are associated with improved cancer outcomes, according to a multicenter, retrospective study presented at the European Congress of Rheumatology.
“Survival was longer in patients who experienced a flare of their preexisting autoimmune disease or any other immune-related adverse event, but this gain was lost if an immunosuppressive therapy was used,” reported Alice Tison, a resident in rheumatology at the Centre Hospitalier Universitaire, Brest, France.
These were some of the mixed messages from this evaluation, which involved 112 patients with preexisting autoimmune disease (PAD) whose data were collected from 11 tertiary care centers in France. Of the cases of PAD represented, the majority involved joint diseases, including psoriatic arthritis (28%), rheumatoid arthritis (18%), and spondyloarthritis (4.5%). However, other types of PAD, including inflammatory bowel disease (13%), were included in the series.
Only 33% of the patients had active disease at the time that checkpoint inhibitor therapy was initiated, and only 21% were taking an immunosuppressive therapy for their disease. Of those on therapy, the majority were taking steroids, but about a third of those on therapy were taking a disease-modifying antirheumatic drug, such as methotrexate.
With the initiation of checkpoint inhibitors, which were offered primarily for the treatment of melanoma (59%) and non–small cell lung cancer (36%), 42% of patients with PAD developed a disease flare. Of these, 30% were considered severe. Other immune-related events not considered related to the underlying disease, such as colitis, were also observed but at rates not clearly different than those observed in patients without PAD.
The activity of checkpoint inhibitors did not appear to be different than that observed in non-PAD patients. For example, the overall response rate was 48% in those with melanoma and 54% in those with non–small cell lung cancer. After a median of 8 months of follow-up, the median progression-free survival was 12.4 months and 9.7 months for the two diseases, respectively. Median overall survival had not been reached in either disease.
However, those with a flare or another immune-related adverse event had significantly better progression-free survival (P = .016) and overall survival (P = .004) when compared with those who did not flare or have an immune-related adverse event. According to Ms. Tison, this has been reported before, but a more surprising finding was that the gain in progression-free survival and overall survival was lost in those treated with an immunosuppressive drug.
Even though non-PAD patients commonly receive steroids for immune-related adverse events such as colitis, the loss of benefit in PAD patients who received immunosuppressive therapies may be caused by, at least in part, cross-reactivity between tumor antigens and autoantigens, Ms. Tison speculated.
Ms. Tison was cautious in drawing conclusions about specific strategies to optimize benefits from checkpoint inhibitors in PAD based on this limited series of patients. However, she did suggest that discontinuation of immunosuppressive therapies prior to initiating checkpoint inhibitors may be prudent in PAD patients, particularly those with inactive disease.
Overall, she emphasized that checkpoint inhibitors “have revolutionized the management of several cancers” and should not be denied to PAD patients who are otherwise appropriate candidates. Although flares are common, more than half of PAD patients in this series did not flare and flares were mild to moderate in most of those who did.
“The response to checkpoint inhibitors in PAD patients is good,” Ms. Tison advised. For those who do flare, “we need prospective studies to understand which strategies provide a good balance of benefit to risk” for cancer immunotherapy and for the options to manage immune-related adverse events.
The study was not industry funded. Ms. Tison reported no potential conflicts of interest.
SOURCE: Tison A et al. Ann Rheum Dis. 2018;77(Suppl 2):147. EULAR Congress 2018, Abstract OP0196.
AMSTERDAM – In patients with autoimmune diseases, cancer treatment with checkpoint inhibitor immunotherapy increases the risk of flares, but these flares are associated with improved cancer outcomes, according to a multicenter, retrospective study presented at the European Congress of Rheumatology.
“Survival was longer in patients who experienced a flare of their preexisting autoimmune disease or any other immune-related adverse event, but this gain was lost if an immunosuppressive therapy was used,” reported Alice Tison, a resident in rheumatology at the Centre Hospitalier Universitaire, Brest, France.
These were some of the mixed messages from this evaluation, which involved 112 patients with preexisting autoimmune disease (PAD) whose data were collected from 11 tertiary care centers in France. Of the cases of PAD represented, the majority involved joint diseases, including psoriatic arthritis (28%), rheumatoid arthritis (18%), and spondyloarthritis (4.5%). However, other types of PAD, including inflammatory bowel disease (13%), were included in the series.
Only 33% of the patients had active disease at the time that checkpoint inhibitor therapy was initiated, and only 21% were taking an immunosuppressive therapy for their disease. Of those on therapy, the majority were taking steroids, but about a third of those on therapy were taking a disease-modifying antirheumatic drug, such as methotrexate.
With the initiation of checkpoint inhibitors, which were offered primarily for the treatment of melanoma (59%) and non–small cell lung cancer (36%), 42% of patients with PAD developed a disease flare. Of these, 30% were considered severe. Other immune-related events not considered related to the underlying disease, such as colitis, were also observed but at rates not clearly different than those observed in patients without PAD.
The activity of checkpoint inhibitors did not appear to be different than that observed in non-PAD patients. For example, the overall response rate was 48% in those with melanoma and 54% in those with non–small cell lung cancer. After a median of 8 months of follow-up, the median progression-free survival was 12.4 months and 9.7 months for the two diseases, respectively. Median overall survival had not been reached in either disease.
However, those with a flare or another immune-related adverse event had significantly better progression-free survival (P = .016) and overall survival (P = .004) when compared with those who did not flare or have an immune-related adverse event. According to Ms. Tison, this has been reported before, but a more surprising finding was that the gain in progression-free survival and overall survival was lost in those treated with an immunosuppressive drug.
Even though non-PAD patients commonly receive steroids for immune-related adverse events such as colitis, the loss of benefit in PAD patients who received immunosuppressive therapies may be caused by, at least in part, cross-reactivity between tumor antigens and autoantigens, Ms. Tison speculated.
Ms. Tison was cautious in drawing conclusions about specific strategies to optimize benefits from checkpoint inhibitors in PAD based on this limited series of patients. However, she did suggest that discontinuation of immunosuppressive therapies prior to initiating checkpoint inhibitors may be prudent in PAD patients, particularly those with inactive disease.
Overall, she emphasized that checkpoint inhibitors “have revolutionized the management of several cancers” and should not be denied to PAD patients who are otherwise appropriate candidates. Although flares are common, more than half of PAD patients in this series did not flare and flares were mild to moderate in most of those who did.
“The response to checkpoint inhibitors in PAD patients is good,” Ms. Tison advised. For those who do flare, “we need prospective studies to understand which strategies provide a good balance of benefit to risk” for cancer immunotherapy and for the options to manage immune-related adverse events.
The study was not industry funded. Ms. Tison reported no potential conflicts of interest.
SOURCE: Tison A et al. Ann Rheum Dis. 2018;77(Suppl 2):147. EULAR Congress 2018, Abstract OP0196.
AMSTERDAM – In patients with autoimmune diseases, cancer treatment with checkpoint inhibitor immunotherapy increases the risk of flares, but these flares are associated with improved cancer outcomes, according to a multicenter, retrospective study presented at the European Congress of Rheumatology.
“Survival was longer in patients who experienced a flare of their preexisting autoimmune disease or any other immune-related adverse event, but this gain was lost if an immunosuppressive therapy was used,” reported Alice Tison, a resident in rheumatology at the Centre Hospitalier Universitaire, Brest, France.
These were some of the mixed messages from this evaluation, which involved 112 patients with preexisting autoimmune disease (PAD) whose data were collected from 11 tertiary care centers in France. Of the cases of PAD represented, the majority involved joint diseases, including psoriatic arthritis (28%), rheumatoid arthritis (18%), and spondyloarthritis (4.5%). However, other types of PAD, including inflammatory bowel disease (13%), were included in the series.
Only 33% of the patients had active disease at the time that checkpoint inhibitor therapy was initiated, and only 21% were taking an immunosuppressive therapy for their disease. Of those on therapy, the majority were taking steroids, but about a third of those on therapy were taking a disease-modifying antirheumatic drug, such as methotrexate.
With the initiation of checkpoint inhibitors, which were offered primarily for the treatment of melanoma (59%) and non–small cell lung cancer (36%), 42% of patients with PAD developed a disease flare. Of these, 30% were considered severe. Other immune-related events not considered related to the underlying disease, such as colitis, were also observed but at rates not clearly different than those observed in patients without PAD.
The activity of checkpoint inhibitors did not appear to be different than that observed in non-PAD patients. For example, the overall response rate was 48% in those with melanoma and 54% in those with non–small cell lung cancer. After a median of 8 months of follow-up, the median progression-free survival was 12.4 months and 9.7 months for the two diseases, respectively. Median overall survival had not been reached in either disease.
However, those with a flare or another immune-related adverse event had significantly better progression-free survival (P = .016) and overall survival (P = .004) when compared with those who did not flare or have an immune-related adverse event. According to Ms. Tison, this has been reported before, but a more surprising finding was that the gain in progression-free survival and overall survival was lost in those treated with an immunosuppressive drug.
Even though non-PAD patients commonly receive steroids for immune-related adverse events such as colitis, the loss of benefit in PAD patients who received immunosuppressive therapies may be caused by, at least in part, cross-reactivity between tumor antigens and autoantigens, Ms. Tison speculated.
Ms. Tison was cautious in drawing conclusions about specific strategies to optimize benefits from checkpoint inhibitors in PAD based on this limited series of patients. However, she did suggest that discontinuation of immunosuppressive therapies prior to initiating checkpoint inhibitors may be prudent in PAD patients, particularly those with inactive disease.
Overall, she emphasized that checkpoint inhibitors “have revolutionized the management of several cancers” and should not be denied to PAD patients who are otherwise appropriate candidates. Although flares are common, more than half of PAD patients in this series did not flare and flares were mild to moderate in most of those who did.
“The response to checkpoint inhibitors in PAD patients is good,” Ms. Tison advised. For those who do flare, “we need prospective studies to understand which strategies provide a good balance of benefit to risk” for cancer immunotherapy and for the options to manage immune-related adverse events.
The study was not industry funded. Ms. Tison reported no potential conflicts of interest.
SOURCE: Tison A et al. Ann Rheum Dis. 2018;77(Suppl 2):147. EULAR Congress 2018, Abstract OP0196.
REPORTING FROM THE EULAR 2018 CONGRESS
Key clinical point: Cancer patients who take a checkpoint inhibitor and have a preexisting autoimmune disease were significantly more likely to have a disease flare but also a better cancer outcome than were those without preexisting disease.
Major finding: In those with a disease flare, progression-free and overall survival were significantly improved (P = .016 and P = .004, respectively).
Study details: Retrospective multicenter study.
Disclosures: The study was not industry funded. Ms. Tison reported no potential conflicts of interest.
Source: Tison A et al. Ann Rheum Dis. 2018;77(Suppl 2):147. EULAR Congress 2018, Abstract OP0196.
Serum troponin predicts cardiovascular death in early arthritis
LIVERPOOL, ENGLAND – Serum levels of the cardiac biomarker troponin might prove useful for assessing the risk of death from cardiovascular causes in patients with inflammatory arthritis, according to study findings presented at the British Society for Rheumatology annual conference.
“In this analysis we have shown that baseline troponin levels predict cardiovascular death in inflammatory arthritis, and this association is independent of the traditional risk factors, inflammation, and disease characteristics at baseline,” said study author Sarah Skeoch, MBChB, who works at the Arthritis Research UK Centre for Epidemiology in the division of musculoskeletal and dermatological sciences at the University of Manchester (England).
Furthermore, the association remained in patients who had rheumatoid arthritis classified according to the 2010 American College of Rheumatology and European League Against Rheumatism criteria (overall adjusted HR, 2.25) and in those without prior cardiovascular disease at baseline (HR, 1.63).
Individuals with inflammatory arthritis are known to have an increased risk of developing cardiovascular problems versus the general population, but current prediction models using traditional risk factors do not fully account for the increased risk seen in patients with inflammatory arthritis, Dr. Skeoch explained.
“There has been some work looking at troponin in inflammatory arthritis already,” she said, with “higher levels observed versus age- and sex-matched controls, and associations have been shown with traditional risk factors.” There has also been a link to C-reactive protein levels and disease activity, and there has also been an association with coronary stenosis on CT scans. The aim of the current study was to see if there was any link to cardiovascular events and death.
A total of 1,023 patients who had been recruited into NOAR between 2000 and 2009 were studied. NOAR is an inception cohort study that includes patients with a history of two or more swollen joints for 4 weeks or more and has been running for almost 30 years. At baseline serum samples are taken and a variety of assessments made, including cardiovascular risk factors.
The study population was mostly female (66%), aged a median of 56 years, and had symptoms for a median of 10.6 months. Around half were seropositive for rheumatoid factor, anti–citrullinated protein antibodies, or both. The median baseline disease activity score in 28 joints (DAS28) was 3.73, and 61% met ACR/EULAR 2010 criteria for RA.
Baseline serum samples were analyzed using a chemiluminescent assay to determine hs-TnI levels, with the median being 6.3 pg/mL. All patients had detectable hs-TnI levels, and 2.6% had levels exceeding 26.1 pg/mL, which is the level associated with having had an acute myocardial infarction. Almost 4% had a previous cardiovascular event, and 7% had diabetes. One in five were current smokers, and roughly 18% had hypertension. The investigators adjusted for all of these factors in the multivariate analyses.
The median follow up was 11.2 years, totaling 11,237 person-years, and during that time 158 deaths occurred, of which 27 were due to ischemic events. The median time from inclusion in NOAR to death was 7.4 years.
When levels of hs-TnI were separated into tertiles, a 12.5-fold increased risk was observed when comparing patients in the highest (more than 7.7 pg/mL) to lowest tertiles (less than 5.2 pg/mL).
“The magnitude of risk between the highest and the lowest tertile was much greater than observed in the general population,” Dr. Skeoch said, and although not directly comparable, she said the hazard ratios were 12.5 and 1.67, “which again suggests that troponin may be an effective tool or addition to the risk prediction models in inflammatory arthritis.”
Unlike some biomarkers, assays to assess troponin are already available in the clinic, Dr. Skeoch commented, “so if further work by us and other groups do suggest a role for troponin, this could be translated fairly rapidly into clinical practice.”
Further research needs to look at why troponin is raised and what is its relationship to other risk factors. “There is a strong association with traditional risk factors such as lipids, so it would stand to reason that managing those risk factors, as well as lifestyle factors, would have a positive impact,” Dr. Skeoch suggested.
The NOAR register is funded by Arthritis Research UK and the U.K. National Institute for Health Research. Dr. Skeoch and her coauthors had no relevant financial conflicts of interest.
SOURCE: Skeoch S et al. BSR 2018. Rheumatology. 2018;57[Suppl. 3]:key075.192.
LIVERPOOL, ENGLAND – Serum levels of the cardiac biomarker troponin might prove useful for assessing the risk of death from cardiovascular causes in patients with inflammatory arthritis, according to study findings presented at the British Society for Rheumatology annual conference.
“In this analysis we have shown that baseline troponin levels predict cardiovascular death in inflammatory arthritis, and this association is independent of the traditional risk factors, inflammation, and disease characteristics at baseline,” said study author Sarah Skeoch, MBChB, who works at the Arthritis Research UK Centre for Epidemiology in the division of musculoskeletal and dermatological sciences at the University of Manchester (England).
Furthermore, the association remained in patients who had rheumatoid arthritis classified according to the 2010 American College of Rheumatology and European League Against Rheumatism criteria (overall adjusted HR, 2.25) and in those without prior cardiovascular disease at baseline (HR, 1.63).
Individuals with inflammatory arthritis are known to have an increased risk of developing cardiovascular problems versus the general population, but current prediction models using traditional risk factors do not fully account for the increased risk seen in patients with inflammatory arthritis, Dr. Skeoch explained.
“There has been some work looking at troponin in inflammatory arthritis already,” she said, with “higher levels observed versus age- and sex-matched controls, and associations have been shown with traditional risk factors.” There has also been a link to C-reactive protein levels and disease activity, and there has also been an association with coronary stenosis on CT scans. The aim of the current study was to see if there was any link to cardiovascular events and death.
A total of 1,023 patients who had been recruited into NOAR between 2000 and 2009 were studied. NOAR is an inception cohort study that includes patients with a history of two or more swollen joints for 4 weeks or more and has been running for almost 30 years. At baseline serum samples are taken and a variety of assessments made, including cardiovascular risk factors.
The study population was mostly female (66%), aged a median of 56 years, and had symptoms for a median of 10.6 months. Around half were seropositive for rheumatoid factor, anti–citrullinated protein antibodies, or both. The median baseline disease activity score in 28 joints (DAS28) was 3.73, and 61% met ACR/EULAR 2010 criteria for RA.
Baseline serum samples were analyzed using a chemiluminescent assay to determine hs-TnI levels, with the median being 6.3 pg/mL. All patients had detectable hs-TnI levels, and 2.6% had levels exceeding 26.1 pg/mL, which is the level associated with having had an acute myocardial infarction. Almost 4% had a previous cardiovascular event, and 7% had diabetes. One in five were current smokers, and roughly 18% had hypertension. The investigators adjusted for all of these factors in the multivariate analyses.
The median follow up was 11.2 years, totaling 11,237 person-years, and during that time 158 deaths occurred, of which 27 were due to ischemic events. The median time from inclusion in NOAR to death was 7.4 years.
When levels of hs-TnI were separated into tertiles, a 12.5-fold increased risk was observed when comparing patients in the highest (more than 7.7 pg/mL) to lowest tertiles (less than 5.2 pg/mL).
“The magnitude of risk between the highest and the lowest tertile was much greater than observed in the general population,” Dr. Skeoch said, and although not directly comparable, she said the hazard ratios were 12.5 and 1.67, “which again suggests that troponin may be an effective tool or addition to the risk prediction models in inflammatory arthritis.”
Unlike some biomarkers, assays to assess troponin are already available in the clinic, Dr. Skeoch commented, “so if further work by us and other groups do suggest a role for troponin, this could be translated fairly rapidly into clinical practice.”
Further research needs to look at why troponin is raised and what is its relationship to other risk factors. “There is a strong association with traditional risk factors such as lipids, so it would stand to reason that managing those risk factors, as well as lifestyle factors, would have a positive impact,” Dr. Skeoch suggested.
The NOAR register is funded by Arthritis Research UK and the U.K. National Institute for Health Research. Dr. Skeoch and her coauthors had no relevant financial conflicts of interest.
SOURCE: Skeoch S et al. BSR 2018. Rheumatology. 2018;57[Suppl. 3]:key075.192.
LIVERPOOL, ENGLAND – Serum levels of the cardiac biomarker troponin might prove useful for assessing the risk of death from cardiovascular causes in patients with inflammatory arthritis, according to study findings presented at the British Society for Rheumatology annual conference.
“In this analysis we have shown that baseline troponin levels predict cardiovascular death in inflammatory arthritis, and this association is independent of the traditional risk factors, inflammation, and disease characteristics at baseline,” said study author Sarah Skeoch, MBChB, who works at the Arthritis Research UK Centre for Epidemiology in the division of musculoskeletal and dermatological sciences at the University of Manchester (England).
Furthermore, the association remained in patients who had rheumatoid arthritis classified according to the 2010 American College of Rheumatology and European League Against Rheumatism criteria (overall adjusted HR, 2.25) and in those without prior cardiovascular disease at baseline (HR, 1.63).
Individuals with inflammatory arthritis are known to have an increased risk of developing cardiovascular problems versus the general population, but current prediction models using traditional risk factors do not fully account for the increased risk seen in patients with inflammatory arthritis, Dr. Skeoch explained.
“There has been some work looking at troponin in inflammatory arthritis already,” she said, with “higher levels observed versus age- and sex-matched controls, and associations have been shown with traditional risk factors.” There has also been a link to C-reactive protein levels and disease activity, and there has also been an association with coronary stenosis on CT scans. The aim of the current study was to see if there was any link to cardiovascular events and death.
A total of 1,023 patients who had been recruited into NOAR between 2000 and 2009 were studied. NOAR is an inception cohort study that includes patients with a history of two or more swollen joints for 4 weeks or more and has been running for almost 30 years. At baseline serum samples are taken and a variety of assessments made, including cardiovascular risk factors.
The study population was mostly female (66%), aged a median of 56 years, and had symptoms for a median of 10.6 months. Around half were seropositive for rheumatoid factor, anti–citrullinated protein antibodies, or both. The median baseline disease activity score in 28 joints (DAS28) was 3.73, and 61% met ACR/EULAR 2010 criteria for RA.
Baseline serum samples were analyzed using a chemiluminescent assay to determine hs-TnI levels, with the median being 6.3 pg/mL. All patients had detectable hs-TnI levels, and 2.6% had levels exceeding 26.1 pg/mL, which is the level associated with having had an acute myocardial infarction. Almost 4% had a previous cardiovascular event, and 7% had diabetes. One in five were current smokers, and roughly 18% had hypertension. The investigators adjusted for all of these factors in the multivariate analyses.
The median follow up was 11.2 years, totaling 11,237 person-years, and during that time 158 deaths occurred, of which 27 were due to ischemic events. The median time from inclusion in NOAR to death was 7.4 years.
When levels of hs-TnI were separated into tertiles, a 12.5-fold increased risk was observed when comparing patients in the highest (more than 7.7 pg/mL) to lowest tertiles (less than 5.2 pg/mL).
“The magnitude of risk between the highest and the lowest tertile was much greater than observed in the general population,” Dr. Skeoch said, and although not directly comparable, she said the hazard ratios were 12.5 and 1.67, “which again suggests that troponin may be an effective tool or addition to the risk prediction models in inflammatory arthritis.”
Unlike some biomarkers, assays to assess troponin are already available in the clinic, Dr. Skeoch commented, “so if further work by us and other groups do suggest a role for troponin, this could be translated fairly rapidly into clinical practice.”
Further research needs to look at why troponin is raised and what is its relationship to other risk factors. “There is a strong association with traditional risk factors such as lipids, so it would stand to reason that managing those risk factors, as well as lifestyle factors, would have a positive impact,” Dr. Skeoch suggested.
The NOAR register is funded by Arthritis Research UK and the U.K. National Institute for Health Research. Dr. Skeoch and her coauthors had no relevant financial conflicts of interest.
SOURCE: Skeoch S et al. BSR 2018. Rheumatology. 2018;57[Suppl. 3]:key075.192.
REPORTING FROM BSR 2018
Key clinical point: Cardiovascular mortality was predicted by baseline levels of high-sensitivity troponin I.
Major finding: For every log unit increase in hs-TnI at baseline, there was an increase in cardiovascular mortality (HR, 2.16).
Study details: Analysis of data on 1,023 patients with inflammatory arthritis listed in the Norfolk Arthritis Register.
Disclosures: Dr. Skeoch and coauthors had no relevant financial conflicts of interest.
Source: Skeoch S et al. BSR 2018. Rheumatology. 2018;57[Suppl. 3]:key075.192.
TNF inhibitor linked to one-third drop in total mortality
AMSTERDAM – Patients treated with a tumor necrosis factor inhibitor for any indication had their mortality rate cut by about one third, compared with the general population, in a combined analysis of safety findings from 78 trials that involved nearly 30,000 patients.
This first indication that treatment with a tumor necrosis factor inhibitor (TNFi) significantly cut overall mortality only became apparent because of the very large number of patients and patient-years of treatment analyzed, and is likely a real effect – not an artifact – that’s probably linked in part to the anti-inflammatory effect from treatment and its favorable impact on cardiovascular disease events, Gerd R. Burmester, MD, said at the European Congress of Rheumatology.
The cut in overall mortality might also partially result from a “healthy cohort effect,” in which patients enrolled in trials pay more attention to their diet and other aspects of a healthy lifestyle, compared with the general population. But Dr. Burmester cited the recent results from the CANTOS trial that showed treatment with the anti-inflammatory drug canakinumab (Ilaris) was linked with a significant 12% relative reduction in cardiovascular death, myocardial infarction, and stroke (New Engl J Med. 2017 Sept 21;377[12]:1119-31).
“It may be that the anticytokine effect of TNFi works the same way as canakinumab,” Dr. Burmester said in an interview.
The results also confirmed previous reports, based on trial data from fewer numbers of TNFi-treated patients, of low rates of serious infections and malignancies, said Dr. Burmester, professor and director of the department of rheumatology and clinical immunology at Charité Medical University in Berlin.
The data he presented came from both randomized trials and open-label studies of adalimumab (Humira) conducted in several countries worldwide through the end of 2016. The various studies enrolled a total of 29,987 patients treated with adalimumab for 56,951 patient-years who had any of 11 different diseases, including rheumatologic, gastrointestinal, and dermatologic diseases. The most common condition treated in the studies was rheumatoid arthritis (in 33 of the 78 studies), followed by psoriasis (13 studies), and Crohn’s disease (11 studies).
The studies included 9,363 patients treated for at least 2 years, and 4,003 patients treated for at least 5 years. The median duration of adalimumab exposure was 0.7 years and the maximum exposure was just over 12 years.
The overall rate of serious infections in treated patients was 3.7 per 100 patient-years. The most common serious infections were pneumonia, at a rate of 0.6 per 100 patient-years, followed by cellulitis, at a rate of 0.2 per 100 patient-years. Active tuberculosis infections also occurred at a rate of 0.2 per 100 patient-years. Malignancies occurred at a rate of 0.6 per 100 patient-years. These rates were similar to those reported by Dr. Burmester and his associates in 2013 using data from a small pool of patients – 23,458 – enrolled in 71 studies of adalimumab (Ann Rheum Dis. 2013 Apr;72[4]:517-24).
In the current study, Dr. Burmester and his coauthors analyzed the observed mortality rate of the adalimumab-treated patients against the mortality rates for the general populations in the various countries in which the studies were run, based on World Health Organization statistics for the period 1997-2006, and adjusted so that the age and sex of the comparison general populations matched the age and sex of the treated patients. This analysis showed an overall, statistically significant mortality reduction in patients receiving adalimumab of 35%, which was consistent in both the subgroups of men and women.
The observed mortality reduction linked with TNFi treatment is likely a class effect, Dr. Burmester said, although similar analyses have not been conducted using data from patients treated with other TNFis. So far, he has been unsuccessful in getting similar, large-scale trial data from manufacturers of other TNFis that he has approached, but Dr. Burmester said he hopes to eventually receive these data so that he can perform an even larger analysis.
The study was sponsored by AbbVie, the company that markets adalimumab (Humira). Dr. Burmester has been a consultant to and speaker on behalf of AbbVie, as well as for Bristol Myers Squibb, Merk, Pfizer, Roche, and UCB.
SOURCE: Burmester GR et al. Ann Rheum Dis. 2018;77(Suppl 2):165. Abstract OP0233.
AMSTERDAM – Patients treated with a tumor necrosis factor inhibitor for any indication had their mortality rate cut by about one third, compared with the general population, in a combined analysis of safety findings from 78 trials that involved nearly 30,000 patients.
This first indication that treatment with a tumor necrosis factor inhibitor (TNFi) significantly cut overall mortality only became apparent because of the very large number of patients and patient-years of treatment analyzed, and is likely a real effect – not an artifact – that’s probably linked in part to the anti-inflammatory effect from treatment and its favorable impact on cardiovascular disease events, Gerd R. Burmester, MD, said at the European Congress of Rheumatology.
The cut in overall mortality might also partially result from a “healthy cohort effect,” in which patients enrolled in trials pay more attention to their diet and other aspects of a healthy lifestyle, compared with the general population. But Dr. Burmester cited the recent results from the CANTOS trial that showed treatment with the anti-inflammatory drug canakinumab (Ilaris) was linked with a significant 12% relative reduction in cardiovascular death, myocardial infarction, and stroke (New Engl J Med. 2017 Sept 21;377[12]:1119-31).
“It may be that the anticytokine effect of TNFi works the same way as canakinumab,” Dr. Burmester said in an interview.
The results also confirmed previous reports, based on trial data from fewer numbers of TNFi-treated patients, of low rates of serious infections and malignancies, said Dr. Burmester, professor and director of the department of rheumatology and clinical immunology at Charité Medical University in Berlin.
The data he presented came from both randomized trials and open-label studies of adalimumab (Humira) conducted in several countries worldwide through the end of 2016. The various studies enrolled a total of 29,987 patients treated with adalimumab for 56,951 patient-years who had any of 11 different diseases, including rheumatologic, gastrointestinal, and dermatologic diseases. The most common condition treated in the studies was rheumatoid arthritis (in 33 of the 78 studies), followed by psoriasis (13 studies), and Crohn’s disease (11 studies).
The studies included 9,363 patients treated for at least 2 years, and 4,003 patients treated for at least 5 years. The median duration of adalimumab exposure was 0.7 years and the maximum exposure was just over 12 years.
The overall rate of serious infections in treated patients was 3.7 per 100 patient-years. The most common serious infections were pneumonia, at a rate of 0.6 per 100 patient-years, followed by cellulitis, at a rate of 0.2 per 100 patient-years. Active tuberculosis infections also occurred at a rate of 0.2 per 100 patient-years. Malignancies occurred at a rate of 0.6 per 100 patient-years. These rates were similar to those reported by Dr. Burmester and his associates in 2013 using data from a small pool of patients – 23,458 – enrolled in 71 studies of adalimumab (Ann Rheum Dis. 2013 Apr;72[4]:517-24).
In the current study, Dr. Burmester and his coauthors analyzed the observed mortality rate of the adalimumab-treated patients against the mortality rates for the general populations in the various countries in which the studies were run, based on World Health Organization statistics for the period 1997-2006, and adjusted so that the age and sex of the comparison general populations matched the age and sex of the treated patients. This analysis showed an overall, statistically significant mortality reduction in patients receiving adalimumab of 35%, which was consistent in both the subgroups of men and women.
The observed mortality reduction linked with TNFi treatment is likely a class effect, Dr. Burmester said, although similar analyses have not been conducted using data from patients treated with other TNFis. So far, he has been unsuccessful in getting similar, large-scale trial data from manufacturers of other TNFis that he has approached, but Dr. Burmester said he hopes to eventually receive these data so that he can perform an even larger analysis.
The study was sponsored by AbbVie, the company that markets adalimumab (Humira). Dr. Burmester has been a consultant to and speaker on behalf of AbbVie, as well as for Bristol Myers Squibb, Merk, Pfizer, Roche, and UCB.
SOURCE: Burmester GR et al. Ann Rheum Dis. 2018;77(Suppl 2):165. Abstract OP0233.
AMSTERDAM – Patients treated with a tumor necrosis factor inhibitor for any indication had their mortality rate cut by about one third, compared with the general population, in a combined analysis of safety findings from 78 trials that involved nearly 30,000 patients.
This first indication that treatment with a tumor necrosis factor inhibitor (TNFi) significantly cut overall mortality only became apparent because of the very large number of patients and patient-years of treatment analyzed, and is likely a real effect – not an artifact – that’s probably linked in part to the anti-inflammatory effect from treatment and its favorable impact on cardiovascular disease events, Gerd R. Burmester, MD, said at the European Congress of Rheumatology.
The cut in overall mortality might also partially result from a “healthy cohort effect,” in which patients enrolled in trials pay more attention to their diet and other aspects of a healthy lifestyle, compared with the general population. But Dr. Burmester cited the recent results from the CANTOS trial that showed treatment with the anti-inflammatory drug canakinumab (Ilaris) was linked with a significant 12% relative reduction in cardiovascular death, myocardial infarction, and stroke (New Engl J Med. 2017 Sept 21;377[12]:1119-31).
“It may be that the anticytokine effect of TNFi works the same way as canakinumab,” Dr. Burmester said in an interview.
The results also confirmed previous reports, based on trial data from fewer numbers of TNFi-treated patients, of low rates of serious infections and malignancies, said Dr. Burmester, professor and director of the department of rheumatology and clinical immunology at Charité Medical University in Berlin.
The data he presented came from both randomized trials and open-label studies of adalimumab (Humira) conducted in several countries worldwide through the end of 2016. The various studies enrolled a total of 29,987 patients treated with adalimumab for 56,951 patient-years who had any of 11 different diseases, including rheumatologic, gastrointestinal, and dermatologic diseases. The most common condition treated in the studies was rheumatoid arthritis (in 33 of the 78 studies), followed by psoriasis (13 studies), and Crohn’s disease (11 studies).
The studies included 9,363 patients treated for at least 2 years, and 4,003 patients treated for at least 5 years. The median duration of adalimumab exposure was 0.7 years and the maximum exposure was just over 12 years.
The overall rate of serious infections in treated patients was 3.7 per 100 patient-years. The most common serious infections were pneumonia, at a rate of 0.6 per 100 patient-years, followed by cellulitis, at a rate of 0.2 per 100 patient-years. Active tuberculosis infections also occurred at a rate of 0.2 per 100 patient-years. Malignancies occurred at a rate of 0.6 per 100 patient-years. These rates were similar to those reported by Dr. Burmester and his associates in 2013 using data from a small pool of patients – 23,458 – enrolled in 71 studies of adalimumab (Ann Rheum Dis. 2013 Apr;72[4]:517-24).
In the current study, Dr. Burmester and his coauthors analyzed the observed mortality rate of the adalimumab-treated patients against the mortality rates for the general populations in the various countries in which the studies were run, based on World Health Organization statistics for the period 1997-2006, and adjusted so that the age and sex of the comparison general populations matched the age and sex of the treated patients. This analysis showed an overall, statistically significant mortality reduction in patients receiving adalimumab of 35%, which was consistent in both the subgroups of men and women.
The observed mortality reduction linked with TNFi treatment is likely a class effect, Dr. Burmester said, although similar analyses have not been conducted using data from patients treated with other TNFis. So far, he has been unsuccessful in getting similar, large-scale trial data from manufacturers of other TNFis that he has approached, but Dr. Burmester said he hopes to eventually receive these data so that he can perform an even larger analysis.
The study was sponsored by AbbVie, the company that markets adalimumab (Humira). Dr. Burmester has been a consultant to and speaker on behalf of AbbVie, as well as for Bristol Myers Squibb, Merk, Pfizer, Roche, and UCB.
SOURCE: Burmester GR et al. Ann Rheum Dis. 2018;77(Suppl 2):165. Abstract OP0233.
REPORTING FROM THE EULAR 2018 CONGRESS
Key clinical point: Major finding: Patients on a TNF inhibitor had 35% fewer deaths, compared with the age- and sex-matched general population.
Study details: Post-hoc analysis of data from 29,987 patients treated with adalimumab in 78 studies.
Disclosures: The study was sponsored by AbbVie, the company that markets adalimumab (Humira). Dr. Burmester has been a consultant to and speaker on behalf of AbbVie, as well as for Bristol Myers Squibb, Merk, Pfizer, Roche, and UCB.
Source: Burmester GR et al. Ann Rheum Dis. 2018;77(Suppl 2):165. Abstract OP0233.
NIH cans study that relied on millions in funding from alcohol companies
NIH Francis Collins, MD, said the ethical violations resulted in a fundamentally flawed study that could not proceed.
“NIH has strong policies that detail the standards of conduct for NIH employees, including prohibiting the solicitation of gifts and promoting fairness in grant competitions. We take very seriously any violations of these standards,” Dr. Collins said in a statement, which added that the agency will take appropriate personnel actions.
While testifying before the Senate Appropriations Committee in mid-May on NIH’s budget request for 2019, Dr. Collins vowed not only to appropriately close the Moderate Alcohol and Cardiovascular Health (MACH) study, but to investigate whether other potential conflicts exist in other NIH-funded studies.
The story broke in mid-March, when The New York Times reported that scientists and officials from the National Institute on Alcohol Abuse and Alcoholism who were working on the MACH trial met at informational sessions with five liquor and beer companies in 2013 and 2014. The officials suggested that “the research might reflect favorably on moderate drinking, while institute officials pressed the groups for support,” according to documents obtained by the Times.
In all, the Times reported, the alcohol companies agreed to foot $67 million of the trial’s total $100 million bill. Such action violates NIH policy. An NIH report named those companies as Anheuser-Busch InBev, Carlsberg Breweries A/S, Diageo plc, Heineken, and Pernod Ricard USA LLC.
The MACH study was a multicenter, randomized clinical trial to determine the effects of one serving of alcohol (approximately 15 grams) daily, compared to no alcohol intake, on the rate of new cases of cardiovascular disease and the rate of new cases of diabetes among participants free of diabetes at baseline.
“The study was launched because some epidemiological studies have shown that moderate alcohol consumption has health benefits by reducing risk for coronary artery disease, type 2 diabetes, and rheumatoid arthritis,” according to the NIH statement. “The study aimed to enroll 7,800 participants. After a planning phase, it began enrollment on Feb. 5, 2018, and was suspended on May 10, 2018, at which time there were 105 participants enrolled.”
The trial was being led by researchers at Beth Israel Deaconess Medical Center, Boston.
In response to the public disclosure of the study’s funding, NIH convened a working group to ascertain:
- the circumstances that led to securing private funding for MACH trial
- the scientific premise of and planning for the MACH trial
- the process used to decide to support the MACH trial
- program development and oversight once funding was secured by the secured by the Foundation for NIH (FNIH)
- a review of the NIAAA portfolio prior to and during the leadership of the current NIAAA Director to assess what programmatic shifts, if any, could be discerned.
While noting that public-private partnerships are key to advancing science, the committee found that soliciting funds from alcoholic beverage companies for a study that could prove such beverages are beneficial, crossed the “firewall” between public funds and private resources. The committee recommended terminating the study.
The committee also recommended an expanded investigation into measures that would prevent NIH staff from soliciting external funds to support research programs.
The committee uncovered an email trail strongly suggesting that the solicitation of funds was planned and intended to be secretive.
According to the working group report, there was “frequent email correspondence among members of NIAAA senior staff, select extramural investigators (including the eventual PI of the MACH trial), and industry representatives occurred prior to involvement of the FNIH and the development of the NIH funding opportunity announcement for a multi-site clinical trial on moderate drinking and cardiovascular health. These communications appear to be an attempt to persuade industry to provide funding for the MACH trial. Moreover, these senior members of NIAAA staff appear to have purposefully kept other key members of NIAAA staff and the FNIH ignorant of these efforts. For example, correspondence between NIAAA staff draws attention to a February 2014 wine industry blog that reports that FNIH is initiating a search for industry funding to support a major clinical study on the health effects of moderate alcohol consumption. One senior staff member at NIAAA is unaware of any such potential planning, asking another senior staff member about the article. ‘... Anything seem broken here?’ even though such a trial to test moderate drinking effects on cardiovascular health should very likely involve the programmatic division to which this senior staff member belongs. In response to receiving the forwarded discussion, NIAAA senior leadership communicates among one other, ‘Best not to respond right now but we can’t keep him totally in the dark.’ "
The trial was also funded in part by NIAAA, which expected to commit $20 million to the overall project over 10 years, of which $4 million has been spent.
“The integrity of the NIH grants administrative process, peer review, and the quality of NIH-supported research must always be above reproach,” Dr. Collins said in the statement. “When any problems are uncovered, however, efforts to correct them must be swift and comprehensive.”
NIH Francis Collins, MD, said the ethical violations resulted in a fundamentally flawed study that could not proceed.
“NIH has strong policies that detail the standards of conduct for NIH employees, including prohibiting the solicitation of gifts and promoting fairness in grant competitions. We take very seriously any violations of these standards,” Dr. Collins said in a statement, which added that the agency will take appropriate personnel actions.
While testifying before the Senate Appropriations Committee in mid-May on NIH’s budget request for 2019, Dr. Collins vowed not only to appropriately close the Moderate Alcohol and Cardiovascular Health (MACH) study, but to investigate whether other potential conflicts exist in other NIH-funded studies.
The story broke in mid-March, when The New York Times reported that scientists and officials from the National Institute on Alcohol Abuse and Alcoholism who were working on the MACH trial met at informational sessions with five liquor and beer companies in 2013 and 2014. The officials suggested that “the research might reflect favorably on moderate drinking, while institute officials pressed the groups for support,” according to documents obtained by the Times.
In all, the Times reported, the alcohol companies agreed to foot $67 million of the trial’s total $100 million bill. Such action violates NIH policy. An NIH report named those companies as Anheuser-Busch InBev, Carlsberg Breweries A/S, Diageo plc, Heineken, and Pernod Ricard USA LLC.
The MACH study was a multicenter, randomized clinical trial to determine the effects of one serving of alcohol (approximately 15 grams) daily, compared to no alcohol intake, on the rate of new cases of cardiovascular disease and the rate of new cases of diabetes among participants free of diabetes at baseline.
“The study was launched because some epidemiological studies have shown that moderate alcohol consumption has health benefits by reducing risk for coronary artery disease, type 2 diabetes, and rheumatoid arthritis,” according to the NIH statement. “The study aimed to enroll 7,800 participants. After a planning phase, it began enrollment on Feb. 5, 2018, and was suspended on May 10, 2018, at which time there were 105 participants enrolled.”
The trial was being led by researchers at Beth Israel Deaconess Medical Center, Boston.
In response to the public disclosure of the study’s funding, NIH convened a working group to ascertain:
- the circumstances that led to securing private funding for MACH trial
- the scientific premise of and planning for the MACH trial
- the process used to decide to support the MACH trial
- program development and oversight once funding was secured by the secured by the Foundation for NIH (FNIH)
- a review of the NIAAA portfolio prior to and during the leadership of the current NIAAA Director to assess what programmatic shifts, if any, could be discerned.
While noting that public-private partnerships are key to advancing science, the committee found that soliciting funds from alcoholic beverage companies for a study that could prove such beverages are beneficial, crossed the “firewall” between public funds and private resources. The committee recommended terminating the study.
The committee also recommended an expanded investigation into measures that would prevent NIH staff from soliciting external funds to support research programs.
The committee uncovered an email trail strongly suggesting that the solicitation of funds was planned and intended to be secretive.
According to the working group report, there was “frequent email correspondence among members of NIAAA senior staff, select extramural investigators (including the eventual PI of the MACH trial), and industry representatives occurred prior to involvement of the FNIH and the development of the NIH funding opportunity announcement for a multi-site clinical trial on moderate drinking and cardiovascular health. These communications appear to be an attempt to persuade industry to provide funding for the MACH trial. Moreover, these senior members of NIAAA staff appear to have purposefully kept other key members of NIAAA staff and the FNIH ignorant of these efforts. For example, correspondence between NIAAA staff draws attention to a February 2014 wine industry blog that reports that FNIH is initiating a search for industry funding to support a major clinical study on the health effects of moderate alcohol consumption. One senior staff member at NIAAA is unaware of any such potential planning, asking another senior staff member about the article. ‘... Anything seem broken here?’ even though such a trial to test moderate drinking effects on cardiovascular health should very likely involve the programmatic division to which this senior staff member belongs. In response to receiving the forwarded discussion, NIAAA senior leadership communicates among one other, ‘Best not to respond right now but we can’t keep him totally in the dark.’ "
The trial was also funded in part by NIAAA, which expected to commit $20 million to the overall project over 10 years, of which $4 million has been spent.
“The integrity of the NIH grants administrative process, peer review, and the quality of NIH-supported research must always be above reproach,” Dr. Collins said in the statement. “When any problems are uncovered, however, efforts to correct them must be swift and comprehensive.”
NIH Francis Collins, MD, said the ethical violations resulted in a fundamentally flawed study that could not proceed.
“NIH has strong policies that detail the standards of conduct for NIH employees, including prohibiting the solicitation of gifts and promoting fairness in grant competitions. We take very seriously any violations of these standards,” Dr. Collins said in a statement, which added that the agency will take appropriate personnel actions.
While testifying before the Senate Appropriations Committee in mid-May on NIH’s budget request for 2019, Dr. Collins vowed not only to appropriately close the Moderate Alcohol and Cardiovascular Health (MACH) study, but to investigate whether other potential conflicts exist in other NIH-funded studies.
The story broke in mid-March, when The New York Times reported that scientists and officials from the National Institute on Alcohol Abuse and Alcoholism who were working on the MACH trial met at informational sessions with five liquor and beer companies in 2013 and 2014. The officials suggested that “the research might reflect favorably on moderate drinking, while institute officials pressed the groups for support,” according to documents obtained by the Times.
In all, the Times reported, the alcohol companies agreed to foot $67 million of the trial’s total $100 million bill. Such action violates NIH policy. An NIH report named those companies as Anheuser-Busch InBev, Carlsberg Breweries A/S, Diageo plc, Heineken, and Pernod Ricard USA LLC.
The MACH study was a multicenter, randomized clinical trial to determine the effects of one serving of alcohol (approximately 15 grams) daily, compared to no alcohol intake, on the rate of new cases of cardiovascular disease and the rate of new cases of diabetes among participants free of diabetes at baseline.
“The study was launched because some epidemiological studies have shown that moderate alcohol consumption has health benefits by reducing risk for coronary artery disease, type 2 diabetes, and rheumatoid arthritis,” according to the NIH statement. “The study aimed to enroll 7,800 participants. After a planning phase, it began enrollment on Feb. 5, 2018, and was suspended on May 10, 2018, at which time there were 105 participants enrolled.”
The trial was being led by researchers at Beth Israel Deaconess Medical Center, Boston.
In response to the public disclosure of the study’s funding, NIH convened a working group to ascertain:
- the circumstances that led to securing private funding for MACH trial
- the scientific premise of and planning for the MACH trial
- the process used to decide to support the MACH trial
- program development and oversight once funding was secured by the secured by the Foundation for NIH (FNIH)
- a review of the NIAAA portfolio prior to and during the leadership of the current NIAAA Director to assess what programmatic shifts, if any, could be discerned.
While noting that public-private partnerships are key to advancing science, the committee found that soliciting funds from alcoholic beverage companies for a study that could prove such beverages are beneficial, crossed the “firewall” between public funds and private resources. The committee recommended terminating the study.
The committee also recommended an expanded investigation into measures that would prevent NIH staff from soliciting external funds to support research programs.
The committee uncovered an email trail strongly suggesting that the solicitation of funds was planned and intended to be secretive.
According to the working group report, there was “frequent email correspondence among members of NIAAA senior staff, select extramural investigators (including the eventual PI of the MACH trial), and industry representatives occurred prior to involvement of the FNIH and the development of the NIH funding opportunity announcement for a multi-site clinical trial on moderate drinking and cardiovascular health. These communications appear to be an attempt to persuade industry to provide funding for the MACH trial. Moreover, these senior members of NIAAA staff appear to have purposefully kept other key members of NIAAA staff and the FNIH ignorant of these efforts. For example, correspondence between NIAAA staff draws attention to a February 2014 wine industry blog that reports that FNIH is initiating a search for industry funding to support a major clinical study on the health effects of moderate alcohol consumption. One senior staff member at NIAAA is unaware of any such potential planning, asking another senior staff member about the article. ‘... Anything seem broken here?’ even though such a trial to test moderate drinking effects on cardiovascular health should very likely involve the programmatic division to which this senior staff member belongs. In response to receiving the forwarded discussion, NIAAA senior leadership communicates among one other, ‘Best not to respond right now but we can’t keep him totally in the dark.’ "
The trial was also funded in part by NIAAA, which expected to commit $20 million to the overall project over 10 years, of which $4 million has been spent.
“The integrity of the NIH grants administrative process, peer review, and the quality of NIH-supported research must always be above reproach,” Dr. Collins said in the statement. “When any problems are uncovered, however, efforts to correct them must be swift and comprehensive.”
Functional disability prevails despite rheumatoid arthritis treatment
AMSTERDAM – Functional disability remains a significant problem for people with rheumatoid arthritis, with the prevalence remaining at least 15% higher over time than in individuals without the disease.
“We found a higher prevalence of functional disability in patients with RA versus non-RA,” the presenting study investigator Elena Myasoedova, MD, PhD, said at the European Congress of Rheumatology.
Dr. Myasoedova, who is a clinical fellow in rheumatology at the Mayo Clinic in Rochester, Minn., added that the increase in prevalence over time was significantly higher in subjects with RA than in those without RA (P = .003), but that there was no difference in the pace of this increase with adjustment for the duration of RA disease (P = .51).
There was also no difference in functional disability between the two groups of patients by about the 8th or 9th decade.
RA remains one of the most common conditions associated with functional disability, Dr. Myasoedova said, with several risk factors for physical impairment identified, including being female, of older age, smoking, and the use of certain medications (glucocorticoids and antidepressants), as well as sociodemographic factors.
A discrepancy between improved RA disease control and persistent impairment in physical function has been noted in prior studies, but there are few data on how this might change over time. Dr. Myasoedova and her associates investigated this by analyzing data from the Rochester Epidemiology Project, which collects medical data on individuals living in Olmsted County, Minnesota. They identified two populations of adults aged 18 and older: one diagnosed with RA according to 1987 American College of Rheumatology criteria between 1999 and 2013, and one without RA but who were of a similar age and sex and enrolled in the project around the same time.
As part of the project, participants completed an annual questionnaire asking about their health and ability to perform six activities of daily living (ADL). These include the ability to wash, dress, feed, and toilet oneself without assistance, as well as perform normal household chores and walk unaided. Over the course of study, 7,466 questionnaires have been completed by the participants and functional disability was defined as having difficulty with at least one of these six ADLs, Dr. Myasoedova explained.
At baseline, subjects with and without RA were aged a mean of 55 and 56 years, respectively, and 70% in both groups were female. Similar percentages were current (about 15%), former (about 30%), or never smokers (about 55%), and about 40% were obese.
Just under two-thirds (64.4%) of patients in the RA cohort were positive for rheumatoid factor (RF) or anti–cyclic citrullinated peptide (CCP) antibodies. While there was a similar prevalence of functional disability in RA patients who were or were not RF or CCP positive (both 25%, P = .67), there was an increasing prevalence noted in those who were positive versus those who were negative over time (P = .027).
Although the investigators did not conduct an objective assessment for functional disability, these findings highlight the need for vigilant management of patients with RA, Dr. Myasoedova proposed.
“Early and aggressive treatment regimens aimed at tight inflammation control can help prevent the disabling effects of high disease activity and joint damage, thereby lowering functional disability,” she said in an interview ahead of the congress.
Future work, she observed, should look at how the pattern of functional disability changes and the use of transition modeling to understand the bidirectional pattern of potential change and accumulation of functional disability in RA. The investigators also plan to look at risk factors for persistent and worsening functional disability and how treatment – including “treat to target” and biologics – might affect this.
The National Institute of Arthritis and Musculoskeletal and Skin Diseases supported the study. Dr. Myasoedova had no conflicts of interest.
SOURCE: Myasoedova E et al. Ann Rheum Dis. 2018;77(Suppl 2):54. Abstract OP0009.
AMSTERDAM – Functional disability remains a significant problem for people with rheumatoid arthritis, with the prevalence remaining at least 15% higher over time than in individuals without the disease.
“We found a higher prevalence of functional disability in patients with RA versus non-RA,” the presenting study investigator Elena Myasoedova, MD, PhD, said at the European Congress of Rheumatology.
Dr. Myasoedova, who is a clinical fellow in rheumatology at the Mayo Clinic in Rochester, Minn., added that the increase in prevalence over time was significantly higher in subjects with RA than in those without RA (P = .003), but that there was no difference in the pace of this increase with adjustment for the duration of RA disease (P = .51).
There was also no difference in functional disability between the two groups of patients by about the 8th or 9th decade.
RA remains one of the most common conditions associated with functional disability, Dr. Myasoedova said, with several risk factors for physical impairment identified, including being female, of older age, smoking, and the use of certain medications (glucocorticoids and antidepressants), as well as sociodemographic factors.
A discrepancy between improved RA disease control and persistent impairment in physical function has been noted in prior studies, but there are few data on how this might change over time. Dr. Myasoedova and her associates investigated this by analyzing data from the Rochester Epidemiology Project, which collects medical data on individuals living in Olmsted County, Minnesota. They identified two populations of adults aged 18 and older: one diagnosed with RA according to 1987 American College of Rheumatology criteria between 1999 and 2013, and one without RA but who were of a similar age and sex and enrolled in the project around the same time.
As part of the project, participants completed an annual questionnaire asking about their health and ability to perform six activities of daily living (ADL). These include the ability to wash, dress, feed, and toilet oneself without assistance, as well as perform normal household chores and walk unaided. Over the course of study, 7,466 questionnaires have been completed by the participants and functional disability was defined as having difficulty with at least one of these six ADLs, Dr. Myasoedova explained.
At baseline, subjects with and without RA were aged a mean of 55 and 56 years, respectively, and 70% in both groups were female. Similar percentages were current (about 15%), former (about 30%), or never smokers (about 55%), and about 40% were obese.
Just under two-thirds (64.4%) of patients in the RA cohort were positive for rheumatoid factor (RF) or anti–cyclic citrullinated peptide (CCP) antibodies. While there was a similar prevalence of functional disability in RA patients who were or were not RF or CCP positive (both 25%, P = .67), there was an increasing prevalence noted in those who were positive versus those who were negative over time (P = .027).
Although the investigators did not conduct an objective assessment for functional disability, these findings highlight the need for vigilant management of patients with RA, Dr. Myasoedova proposed.
“Early and aggressive treatment regimens aimed at tight inflammation control can help prevent the disabling effects of high disease activity and joint damage, thereby lowering functional disability,” she said in an interview ahead of the congress.
Future work, she observed, should look at how the pattern of functional disability changes and the use of transition modeling to understand the bidirectional pattern of potential change and accumulation of functional disability in RA. The investigators also plan to look at risk factors for persistent and worsening functional disability and how treatment – including “treat to target” and biologics – might affect this.
The National Institute of Arthritis and Musculoskeletal and Skin Diseases supported the study. Dr. Myasoedova had no conflicts of interest.
SOURCE: Myasoedova E et al. Ann Rheum Dis. 2018;77(Suppl 2):54. Abstract OP0009.
AMSTERDAM – Functional disability remains a significant problem for people with rheumatoid arthritis, with the prevalence remaining at least 15% higher over time than in individuals without the disease.
“We found a higher prevalence of functional disability in patients with RA versus non-RA,” the presenting study investigator Elena Myasoedova, MD, PhD, said at the European Congress of Rheumatology.
Dr. Myasoedova, who is a clinical fellow in rheumatology at the Mayo Clinic in Rochester, Minn., added that the increase in prevalence over time was significantly higher in subjects with RA than in those without RA (P = .003), but that there was no difference in the pace of this increase with adjustment for the duration of RA disease (P = .51).
There was also no difference in functional disability between the two groups of patients by about the 8th or 9th decade.
RA remains one of the most common conditions associated with functional disability, Dr. Myasoedova said, with several risk factors for physical impairment identified, including being female, of older age, smoking, and the use of certain medications (glucocorticoids and antidepressants), as well as sociodemographic factors.
A discrepancy between improved RA disease control and persistent impairment in physical function has been noted in prior studies, but there are few data on how this might change over time. Dr. Myasoedova and her associates investigated this by analyzing data from the Rochester Epidemiology Project, which collects medical data on individuals living in Olmsted County, Minnesota. They identified two populations of adults aged 18 and older: one diagnosed with RA according to 1987 American College of Rheumatology criteria between 1999 and 2013, and one without RA but who were of a similar age and sex and enrolled in the project around the same time.
As part of the project, participants completed an annual questionnaire asking about their health and ability to perform six activities of daily living (ADL). These include the ability to wash, dress, feed, and toilet oneself without assistance, as well as perform normal household chores and walk unaided. Over the course of study, 7,466 questionnaires have been completed by the participants and functional disability was defined as having difficulty with at least one of these six ADLs, Dr. Myasoedova explained.
At baseline, subjects with and without RA were aged a mean of 55 and 56 years, respectively, and 70% in both groups were female. Similar percentages were current (about 15%), former (about 30%), or never smokers (about 55%), and about 40% were obese.
Just under two-thirds (64.4%) of patients in the RA cohort were positive for rheumatoid factor (RF) or anti–cyclic citrullinated peptide (CCP) antibodies. While there was a similar prevalence of functional disability in RA patients who were or were not RF or CCP positive (both 25%, P = .67), there was an increasing prevalence noted in those who were positive versus those who were negative over time (P = .027).
Although the investigators did not conduct an objective assessment for functional disability, these findings highlight the need for vigilant management of patients with RA, Dr. Myasoedova proposed.
“Early and aggressive treatment regimens aimed at tight inflammation control can help prevent the disabling effects of high disease activity and joint damage, thereby lowering functional disability,” she said in an interview ahead of the congress.
Future work, she observed, should look at how the pattern of functional disability changes and the use of transition modeling to understand the bidirectional pattern of potential change and accumulation of functional disability in RA. The investigators also plan to look at risk factors for persistent and worsening functional disability and how treatment – including “treat to target” and biologics – might affect this.
The National Institute of Arthritis and Musculoskeletal and Skin Diseases supported the study. Dr. Myasoedova had no conflicts of interest.
SOURCE: Myasoedova E et al. Ann Rheum Dis. 2018;77(Suppl 2):54. Abstract OP0009.
REPORTING FROM THE EULAR 2018 CONGRESS
Key clinical point: Functional disability remains higher over time in patients with rheumatoid arthritis, compared with people without the disease.
Major finding: The prevalence of functional disability was 26% vs. 11% at baseline, a 15% difference that persisted over more than 18 years of follow-up.
Study details: Retrospective, longitudinal, population-based cohort study of 586 individuals with RA, and 531 without.
Disclosures: The National Institute of Arthritis and Musculoskeletal and Skin Diseases supported the study. Dr. Myasoedova had no conflicts of interest.
Source: Myasoedova E et al. Ann Rheum Dis. 2018;77(Suppl 2):54. Abstract OP0009.
Malignancy risk of tocilizumab and TNF inhibitors found similar
AMSTERDAM – , according to an analysis of three large databases presented at the European Congress of Rheumatology.
“When we combined the databases, the incidence of any malignancy excluding nonmelanoma skin cancer was 13.09 per 1,000 patient years in the tocilizumab group and 13.46 in the TNF-inhibitor group,” reported Seoyoung C. Kim, MD, ScD, of the division of pharmacoepidemiology & pharmacoeconomics at Brigham and Women’s Hospital, Boston.
The study was conducted with data from 10,393 adult RA patients treated with tocilizumab and 26,357 patients treated with TNFi in the Medicare, QuintilesIMS PharMetrics Plus, and Truven Health MarketScan databases. All patients were new starts on tocilizumab or the TNFi on which they were evaluated, but all were required to have been exposed to at least one different biologic prior to starting the treatment. A diagnosis of RA at least 365 days prior to inclusion in this analysis was required to rule out prevalent cancers, which was an exclusion criterion.
More than 60 covariates were employed in the analysis to minimize the risk of confounders. These included demographics, RA characteristics, comorbidities, and other medications.
There also was no difference in the rates of the 12 most common cancer types when those exposed to tocilizumab were compared with those exposed to TNFi in a secondary analysis of these data, according to Dr. Kim. When expressed as hazard ratios, there were some numerical differences in relative risk among these cancers on both as-treated and intention-to-treat analyses, but confidence intervals were large, and none approached significance.
RA itself has been associated with an increased risk of some malignancies, such as lung cancer, but the relationship between the proinflammatory state of RA, its treatments, and the risk of cancer has been unclear, according to Dr. Kim. She said, “There is some concern relative to use of TNFi or other biologics in regard to developing malignancy, but studies have been inconsistent.”
Dr. Kim conceded that a lack of data on patients’ disease duration or activity is one limitation of this analysis. Another is that residual confounding can never be ruled out from a retrospective analysis. However, she said that, because the two biologics were compared for the same indication in patients exposed to at least one previous biologic, the confounding may be less than it would be if tocilizumab was compared with a conventional synthetic disease modifying antirheumatic drug (csDMARD), such as methotrexate. Again, there also was a requirement for exposure to at least one prior biologic, and this also is reassuring for the final conclusion.
“In other words, even among RA patients who were exposed to more than one biologic, the risk of cancer was similar between tocilizumab and TNF-inhibitor initiators,” Dr. Kim reported.
Roche provided funding for the study. Dr. Kim reports financial relationships with Bristol-Myers Squibb, Pfizer, and Roche.
AMSTERDAM – , according to an analysis of three large databases presented at the European Congress of Rheumatology.
“When we combined the databases, the incidence of any malignancy excluding nonmelanoma skin cancer was 13.09 per 1,000 patient years in the tocilizumab group and 13.46 in the TNF-inhibitor group,” reported Seoyoung C. Kim, MD, ScD, of the division of pharmacoepidemiology & pharmacoeconomics at Brigham and Women’s Hospital, Boston.
The study was conducted with data from 10,393 adult RA patients treated with tocilizumab and 26,357 patients treated with TNFi in the Medicare, QuintilesIMS PharMetrics Plus, and Truven Health MarketScan databases. All patients were new starts on tocilizumab or the TNFi on which they were evaluated, but all were required to have been exposed to at least one different biologic prior to starting the treatment. A diagnosis of RA at least 365 days prior to inclusion in this analysis was required to rule out prevalent cancers, which was an exclusion criterion.
More than 60 covariates were employed in the analysis to minimize the risk of confounders. These included demographics, RA characteristics, comorbidities, and other medications.
There also was no difference in the rates of the 12 most common cancer types when those exposed to tocilizumab were compared with those exposed to TNFi in a secondary analysis of these data, according to Dr. Kim. When expressed as hazard ratios, there were some numerical differences in relative risk among these cancers on both as-treated and intention-to-treat analyses, but confidence intervals were large, and none approached significance.
RA itself has been associated with an increased risk of some malignancies, such as lung cancer, but the relationship between the proinflammatory state of RA, its treatments, and the risk of cancer has been unclear, according to Dr. Kim. She said, “There is some concern relative to use of TNFi or other biologics in regard to developing malignancy, but studies have been inconsistent.”
Dr. Kim conceded that a lack of data on patients’ disease duration or activity is one limitation of this analysis. Another is that residual confounding can never be ruled out from a retrospective analysis. However, she said that, because the two biologics were compared for the same indication in patients exposed to at least one previous biologic, the confounding may be less than it would be if tocilizumab was compared with a conventional synthetic disease modifying antirheumatic drug (csDMARD), such as methotrexate. Again, there also was a requirement for exposure to at least one prior biologic, and this also is reassuring for the final conclusion.
“In other words, even among RA patients who were exposed to more than one biologic, the risk of cancer was similar between tocilizumab and TNF-inhibitor initiators,” Dr. Kim reported.
Roche provided funding for the study. Dr. Kim reports financial relationships with Bristol-Myers Squibb, Pfizer, and Roche.
AMSTERDAM – , according to an analysis of three large databases presented at the European Congress of Rheumatology.
“When we combined the databases, the incidence of any malignancy excluding nonmelanoma skin cancer was 13.09 per 1,000 patient years in the tocilizumab group and 13.46 in the TNF-inhibitor group,” reported Seoyoung C. Kim, MD, ScD, of the division of pharmacoepidemiology & pharmacoeconomics at Brigham and Women’s Hospital, Boston.
The study was conducted with data from 10,393 adult RA patients treated with tocilizumab and 26,357 patients treated with TNFi in the Medicare, QuintilesIMS PharMetrics Plus, and Truven Health MarketScan databases. All patients were new starts on tocilizumab or the TNFi on which they were evaluated, but all were required to have been exposed to at least one different biologic prior to starting the treatment. A diagnosis of RA at least 365 days prior to inclusion in this analysis was required to rule out prevalent cancers, which was an exclusion criterion.
More than 60 covariates were employed in the analysis to minimize the risk of confounders. These included demographics, RA characteristics, comorbidities, and other medications.
There also was no difference in the rates of the 12 most common cancer types when those exposed to tocilizumab were compared with those exposed to TNFi in a secondary analysis of these data, according to Dr. Kim. When expressed as hazard ratios, there were some numerical differences in relative risk among these cancers on both as-treated and intention-to-treat analyses, but confidence intervals were large, and none approached significance.
RA itself has been associated with an increased risk of some malignancies, such as lung cancer, but the relationship between the proinflammatory state of RA, its treatments, and the risk of cancer has been unclear, according to Dr. Kim. She said, “There is some concern relative to use of TNFi or other biologics in regard to developing malignancy, but studies have been inconsistent.”
Dr. Kim conceded that a lack of data on patients’ disease duration or activity is one limitation of this analysis. Another is that residual confounding can never be ruled out from a retrospective analysis. However, she said that, because the two biologics were compared for the same indication in patients exposed to at least one previous biologic, the confounding may be less than it would be if tocilizumab was compared with a conventional synthetic disease modifying antirheumatic drug (csDMARD), such as methotrexate. Again, there also was a requirement for exposure to at least one prior biologic, and this also is reassuring for the final conclusion.
“In other words, even among RA patients who were exposed to more than one biologic, the risk of cancer was similar between tocilizumab and TNF-inhibitor initiators,” Dr. Kim reported.
Roche provided funding for the study. Dr. Kim reports financial relationships with Bristol-Myers Squibb, Pfizer, and Roche.
REPORTING FROM THE EULAR 2018 CONGRESS
Key clinical point: Tocilizumab was not associated with a higher cancer risk in rheumatoid arthritis than TNFi treatment in a cohort study.
Major finding: Relative to TNFI, the hazard ratio for malignancy was 0.98 (95% CI, 0.80-1.19) for tocilizumab relative to TNFi.
Study details: Cohort study with propensity matching with data from 10,393 adult RA patients treated with tocilizumab and 26,357 patients treated with TNFi.
Disclosures: Roche provided funding for the study. Dr. Kim reports financial relationships with Bristol-Myers Squibb, Pfizer, and Roche.
New JAK-1 inhibitor had high, early efficacy in rheumatoid arthritis trial
LIVERPOOL, ENGLAND – Treatment with the investigational drug upadacitinib resulted in higher percentages of patients with active rheumatoid arthritis achieving good disease control within 12 weeks than did treatment with placebo in a phase 3 trial.
Two-thirds of patients met American College of Rheumatology 20% (ACR 20) response criteria, and almost half (48%) achieved a Disease Activity Score in 28 Joints–C-reactive protein (DAS28-CRP) of 3.2 or less versus 17% of placebo-treated patients (P less than .001).
All patients had been given upadacitinib on top of their existing conventional synthetic disease-modifying antirheumatic drug therapy because they had not been fully responding to csDMARDs alone.
“Onset of action was rapid: By week 1 significantly more patients achieved ACR 20 on upadacitinib at both doses versus placebo,” the study’s investigators noted in a poster presentation given at the British Society for Rheumatology annual conference. Significant improvements in DAS28-CRP and Clinical Disease Activity Index (CDAI) were also seen as early as week 1.
Gerd R. Burmester, MD, of Charité-Universitätsmedizin, Berlin, and associates reported the results of the SELECT-NEXT study, one of six global phase 3 studies testing the efficacy and safety of upadacitinib targeting “a range of different patient populations” with RA; together the trials include more than 4,500 patients.
Upadacitinib (ABT-494) is a selective Janus kinase (JAK)-1 inhibitor and is also in phase 3 trials for the treatment of psoriatic arthritis and Crohn’s disease, as well as being tested as a potential treatment for axial spondyloarthritis, giant cell arteritis, ulcerative colitis, and atopic dermatitis.
SELECT-NEXT consists of two phases, the first of which has been completed and was reported at the meeting. Phase 1 consisted of randomized, double-blind treatment with upadacitinib 15 mg or 30 mg once daily or matching placebo. After the coprimary endpoint assessment of ACR 20 and DAS28-CRP was undertaken at 12 weeks, the trial entered its second phase: This is a blinded-extension phase that will last up to 5 years and during which patients randomized to upadacitinib will continue their treatment, and the patients randomized to placebo will split into two groups and be treated with one or the other dose of upadacitinib.
The study included 661 patients who had been treated with csDMARDs for at least 3 months but still had swollen and tender joint counts of six or higher and high-sensitivity CRP levels of 3 mg/L or higher. At entry, patients were allowed to continue on up to two csDMARDs; stable-dose steroids (less than 10 mg/week), nonsteroidal anti-inflammatory drugs, and acetaminophen were also allowed.
“Significant changes from baseline in several patient-reported outcomes were observed,” with the active treatment versus placebo, the investigators observed. Indeed, by week 12, morning stiffness was reduced by an average of 85 minutes in patients taking upadacitinib versus a decrease of 34 minutes in the placebo group. Significant (P less than .01) improvements were also seen in Short-Form 36–Mental Component scores, they reported.
Furthermore, more patients taking the active treatment than placebo achieved clinical remission by 12 weeks.
“The safety and tolerability profile was consistent with observations in the phase 2 studies,” Dr. Burmester and associates observed. The most frequently reported adverse events in more than 3% of patients were nasopharyngitis, upper respiratory infection, headache, urinary tract infection, cough, nausea, and diarrhea.
Serious adverse events and those leading to discontinuation were both higher in the two upadacitinib groups versus placebo, at 2.7% and 5.9% for the 30-mg dose, 4.1% and 3.2% for the 15-mg dose, and 2.3% and 3.2% for placebo. Of note, infections occurred in a 31.5% of patients on 30 mg, 29.0% on 15 mg, and 21.3% on placebo, and hepatic disorders occurred in 2.7% of patients on 30 mg, 1.8% on 15 mg, and 2.3% on placebo. One (0.5%) patient taking the 30-mg dose had a major cardiovascular event and two (0.9%) patients in the 15-mg group had other adjudicated cardiovascular events.
The study was sponsored and run by Abbvie. The study authors acknowledged receiving research support or consulting fees from Abbvie or being employees of the company.
SOURCE: Burmester GR et al.; BSR 2018 Rheumatology. 2018;57[Suppl. 3]:key075.466.
LIVERPOOL, ENGLAND – Treatment with the investigational drug upadacitinib resulted in higher percentages of patients with active rheumatoid arthritis achieving good disease control within 12 weeks than did treatment with placebo in a phase 3 trial.
Two-thirds of patients met American College of Rheumatology 20% (ACR 20) response criteria, and almost half (48%) achieved a Disease Activity Score in 28 Joints–C-reactive protein (DAS28-CRP) of 3.2 or less versus 17% of placebo-treated patients (P less than .001).
All patients had been given upadacitinib on top of their existing conventional synthetic disease-modifying antirheumatic drug therapy because they had not been fully responding to csDMARDs alone.
“Onset of action was rapid: By week 1 significantly more patients achieved ACR 20 on upadacitinib at both doses versus placebo,” the study’s investigators noted in a poster presentation given at the British Society for Rheumatology annual conference. Significant improvements in DAS28-CRP and Clinical Disease Activity Index (CDAI) were also seen as early as week 1.
Gerd R. Burmester, MD, of Charité-Universitätsmedizin, Berlin, and associates reported the results of the SELECT-NEXT study, one of six global phase 3 studies testing the efficacy and safety of upadacitinib targeting “a range of different patient populations” with RA; together the trials include more than 4,500 patients.
Upadacitinib (ABT-494) is a selective Janus kinase (JAK)-1 inhibitor and is also in phase 3 trials for the treatment of psoriatic arthritis and Crohn’s disease, as well as being tested as a potential treatment for axial spondyloarthritis, giant cell arteritis, ulcerative colitis, and atopic dermatitis.
SELECT-NEXT consists of two phases, the first of which has been completed and was reported at the meeting. Phase 1 consisted of randomized, double-blind treatment with upadacitinib 15 mg or 30 mg once daily or matching placebo. After the coprimary endpoint assessment of ACR 20 and DAS28-CRP was undertaken at 12 weeks, the trial entered its second phase: This is a blinded-extension phase that will last up to 5 years and during which patients randomized to upadacitinib will continue their treatment, and the patients randomized to placebo will split into two groups and be treated with one or the other dose of upadacitinib.
The study included 661 patients who had been treated with csDMARDs for at least 3 months but still had swollen and tender joint counts of six or higher and high-sensitivity CRP levels of 3 mg/L or higher. At entry, patients were allowed to continue on up to two csDMARDs; stable-dose steroids (less than 10 mg/week), nonsteroidal anti-inflammatory drugs, and acetaminophen were also allowed.
“Significant changes from baseline in several patient-reported outcomes were observed,” with the active treatment versus placebo, the investigators observed. Indeed, by week 12, morning stiffness was reduced by an average of 85 minutes in patients taking upadacitinib versus a decrease of 34 minutes in the placebo group. Significant (P less than .01) improvements were also seen in Short-Form 36–Mental Component scores, they reported.
Furthermore, more patients taking the active treatment than placebo achieved clinical remission by 12 weeks.
“The safety and tolerability profile was consistent with observations in the phase 2 studies,” Dr. Burmester and associates observed. The most frequently reported adverse events in more than 3% of patients were nasopharyngitis, upper respiratory infection, headache, urinary tract infection, cough, nausea, and diarrhea.
Serious adverse events and those leading to discontinuation were both higher in the two upadacitinib groups versus placebo, at 2.7% and 5.9% for the 30-mg dose, 4.1% and 3.2% for the 15-mg dose, and 2.3% and 3.2% for placebo. Of note, infections occurred in a 31.5% of patients on 30 mg, 29.0% on 15 mg, and 21.3% on placebo, and hepatic disorders occurred in 2.7% of patients on 30 mg, 1.8% on 15 mg, and 2.3% on placebo. One (0.5%) patient taking the 30-mg dose had a major cardiovascular event and two (0.9%) patients in the 15-mg group had other adjudicated cardiovascular events.
The study was sponsored and run by Abbvie. The study authors acknowledged receiving research support or consulting fees from Abbvie or being employees of the company.
SOURCE: Burmester GR et al.; BSR 2018 Rheumatology. 2018;57[Suppl. 3]:key075.466.
LIVERPOOL, ENGLAND – Treatment with the investigational drug upadacitinib resulted in higher percentages of patients with active rheumatoid arthritis achieving good disease control within 12 weeks than did treatment with placebo in a phase 3 trial.
Two-thirds of patients met American College of Rheumatology 20% (ACR 20) response criteria, and almost half (48%) achieved a Disease Activity Score in 28 Joints–C-reactive protein (DAS28-CRP) of 3.2 or less versus 17% of placebo-treated patients (P less than .001).
All patients had been given upadacitinib on top of their existing conventional synthetic disease-modifying antirheumatic drug therapy because they had not been fully responding to csDMARDs alone.
“Onset of action was rapid: By week 1 significantly more patients achieved ACR 20 on upadacitinib at both doses versus placebo,” the study’s investigators noted in a poster presentation given at the British Society for Rheumatology annual conference. Significant improvements in DAS28-CRP and Clinical Disease Activity Index (CDAI) were also seen as early as week 1.
Gerd R. Burmester, MD, of Charité-Universitätsmedizin, Berlin, and associates reported the results of the SELECT-NEXT study, one of six global phase 3 studies testing the efficacy and safety of upadacitinib targeting “a range of different patient populations” with RA; together the trials include more than 4,500 patients.
Upadacitinib (ABT-494) is a selective Janus kinase (JAK)-1 inhibitor and is also in phase 3 trials for the treatment of psoriatic arthritis and Crohn’s disease, as well as being tested as a potential treatment for axial spondyloarthritis, giant cell arteritis, ulcerative colitis, and atopic dermatitis.
SELECT-NEXT consists of two phases, the first of which has been completed and was reported at the meeting. Phase 1 consisted of randomized, double-blind treatment with upadacitinib 15 mg or 30 mg once daily or matching placebo. After the coprimary endpoint assessment of ACR 20 and DAS28-CRP was undertaken at 12 weeks, the trial entered its second phase: This is a blinded-extension phase that will last up to 5 years and during which patients randomized to upadacitinib will continue their treatment, and the patients randomized to placebo will split into two groups and be treated with one or the other dose of upadacitinib.
The study included 661 patients who had been treated with csDMARDs for at least 3 months but still had swollen and tender joint counts of six or higher and high-sensitivity CRP levels of 3 mg/L or higher. At entry, patients were allowed to continue on up to two csDMARDs; stable-dose steroids (less than 10 mg/week), nonsteroidal anti-inflammatory drugs, and acetaminophen were also allowed.
“Significant changes from baseline in several patient-reported outcomes were observed,” with the active treatment versus placebo, the investigators observed. Indeed, by week 12, morning stiffness was reduced by an average of 85 minutes in patients taking upadacitinib versus a decrease of 34 minutes in the placebo group. Significant (P less than .01) improvements were also seen in Short-Form 36–Mental Component scores, they reported.
Furthermore, more patients taking the active treatment than placebo achieved clinical remission by 12 weeks.
“The safety and tolerability profile was consistent with observations in the phase 2 studies,” Dr. Burmester and associates observed. The most frequently reported adverse events in more than 3% of patients were nasopharyngitis, upper respiratory infection, headache, urinary tract infection, cough, nausea, and diarrhea.
Serious adverse events and those leading to discontinuation were both higher in the two upadacitinib groups versus placebo, at 2.7% and 5.9% for the 30-mg dose, 4.1% and 3.2% for the 15-mg dose, and 2.3% and 3.2% for placebo. Of note, infections occurred in a 31.5% of patients on 30 mg, 29.0% on 15 mg, and 21.3% on placebo, and hepatic disorders occurred in 2.7% of patients on 30 mg, 1.8% on 15 mg, and 2.3% on placebo. One (0.5%) patient taking the 30-mg dose had a major cardiovascular event and two (0.9%) patients in the 15-mg group had other adjudicated cardiovascular events.
The study was sponsored and run by Abbvie. The study authors acknowledged receiving research support or consulting fees from Abbvie or being employees of the company.
SOURCE: Burmester GR et al.; BSR 2018 Rheumatology. 2018;57[Suppl. 3]:key075.466.
REPORTING FROM Rheumatology 2018
Key clinical point: Upadacitinib met both of the coprimary endpoints in the trial – ACR 20 response and low disease activity at 12 weeks.
Major finding: ACR 20 was achieved by 64%/66%/36% of patients taking upadacitinib 15 mg once daily, patients taking upadacitinib 30 mg once daily, and placebo-treated patients, respectively. Low disease activity was achieved by 48%/48%/17% of patients taking upadacitinib 15 mg once daily, patients taking upadacitinib 30 mg once daily, and placebo-treated patients, respectively (P less than .001).
Study details: SELECT-NEXT, a phase 3, randomized, double-blind, placebo-controlled trial of two doses of upadacitinib in 661 patients with rheumatoid arthritis who were not responding to conventional disease-modifying drug treatment.
Disclosures: The study was sponsored by Abbvie. The study authors acknowledged receiving research support or consulting fees from Abbvie or being employees of the company.
Source: Burmester GR et al. BSR 2018; Rheumatology. 2018;57[Suppl. 3]:key075.466.