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CD40 ligand–binding protein safely lowered RA disease activity
A nonantibody scaffold protein that targets the CD40 ligand appears to dampen down autoimmune responses without the thromboembolic complications seen in trials of monoclonal antibodies against the CD40 ligand.
In a paper published in Science Translational Medicine, researchers presented the results of a phase 1a study in 59 healthy volunteers and phase 1b proof-of-concept study in 57 individuals with rheumatoid arthritis. Participants received either varying dosages of CD40 ligand (CD40L)–binding protein VIB4920 – a single dose in the healthy volunteers and seven doses in the phase 1b study – or placebo.
Jodi L. Karnell, PhD, of Viela Bio in Gaithersburg, Md., and coauthors, wrote that the CD40/CD40L pathway is known to play a key role in humoral immune responses and in the pathogenesis of several autoimmune diseases.
However, previous clinical trials of compounds targeting CD40L were stopped early because of an increased risk of adverse thromboembolic events related to platelet aggregation, despite showing potential benefits in lupus and immune thrombocytopenic purpura.
Preclinical studies of VIB4920 found that it blocked the expansion of CD40L-dependent human B cells without showing any signs of platelet aggregation. The authors said the platelet aggregation had been linked to a particular region of anti-CD40L monoclonal antibodies, but VIB4920 was engineered using a protein scaffold that did not contain that region.
In healthy volunteers, researchers saw a dose-dependent suppression of antibody production and reductions in B-cell proliferation, in recall response to a T cell–dependent antigen.
In individuals with rheumatoid arthritis, more than half of those treated with the two highest dosages of VIB4920 achieved low disease activity state or clinical remission by 12 weeks. Overall, there was also a significant decrease in disease activity, and dose-dependent decreases in rheumatoid factor autoantibodies and Vectra DA biomarker score, which is a composite of twelve rheumatoid arthritis–related biomarkers.
“The consistency of improvement across a variety of clinical and laboratory outcome measures further supports the potential clinical efficacy of VIB4920,” the authors wrote.
Researchers saw a similar rate of adverse events in the placebo and treatment arms of the study.
“VIB4920 represents an alternative to monoclonal antibody–based targeting of CD40L, which does not induce platelet aggregation in vitro and demonstrates a favorable safety profile in early clinical evaluation.”
The study was funded by MedImmune. All but one author were employees of MedImmune/AstraZeneca or of Viela Bio.
SOURCE: Karnell J et al. Sci Transl Med. 2019 April 24. doi: 10.1126/scitranslmed.aar6584
A nonantibody scaffold protein that targets the CD40 ligand appears to dampen down autoimmune responses without the thromboembolic complications seen in trials of monoclonal antibodies against the CD40 ligand.
In a paper published in Science Translational Medicine, researchers presented the results of a phase 1a study in 59 healthy volunteers and phase 1b proof-of-concept study in 57 individuals with rheumatoid arthritis. Participants received either varying dosages of CD40 ligand (CD40L)–binding protein VIB4920 – a single dose in the healthy volunteers and seven doses in the phase 1b study – or placebo.
Jodi L. Karnell, PhD, of Viela Bio in Gaithersburg, Md., and coauthors, wrote that the CD40/CD40L pathway is known to play a key role in humoral immune responses and in the pathogenesis of several autoimmune diseases.
However, previous clinical trials of compounds targeting CD40L were stopped early because of an increased risk of adverse thromboembolic events related to platelet aggregation, despite showing potential benefits in lupus and immune thrombocytopenic purpura.
Preclinical studies of VIB4920 found that it blocked the expansion of CD40L-dependent human B cells without showing any signs of platelet aggregation. The authors said the platelet aggregation had been linked to a particular region of anti-CD40L monoclonal antibodies, but VIB4920 was engineered using a protein scaffold that did not contain that region.
In healthy volunteers, researchers saw a dose-dependent suppression of antibody production and reductions in B-cell proliferation, in recall response to a T cell–dependent antigen.
In individuals with rheumatoid arthritis, more than half of those treated with the two highest dosages of VIB4920 achieved low disease activity state or clinical remission by 12 weeks. Overall, there was also a significant decrease in disease activity, and dose-dependent decreases in rheumatoid factor autoantibodies and Vectra DA biomarker score, which is a composite of twelve rheumatoid arthritis–related biomarkers.
“The consistency of improvement across a variety of clinical and laboratory outcome measures further supports the potential clinical efficacy of VIB4920,” the authors wrote.
Researchers saw a similar rate of adverse events in the placebo and treatment arms of the study.
“VIB4920 represents an alternative to monoclonal antibody–based targeting of CD40L, which does not induce platelet aggregation in vitro and demonstrates a favorable safety profile in early clinical evaluation.”
The study was funded by MedImmune. All but one author were employees of MedImmune/AstraZeneca or of Viela Bio.
SOURCE: Karnell J et al. Sci Transl Med. 2019 April 24. doi: 10.1126/scitranslmed.aar6584
A nonantibody scaffold protein that targets the CD40 ligand appears to dampen down autoimmune responses without the thromboembolic complications seen in trials of monoclonal antibodies against the CD40 ligand.
In a paper published in Science Translational Medicine, researchers presented the results of a phase 1a study in 59 healthy volunteers and phase 1b proof-of-concept study in 57 individuals with rheumatoid arthritis. Participants received either varying dosages of CD40 ligand (CD40L)–binding protein VIB4920 – a single dose in the healthy volunteers and seven doses in the phase 1b study – or placebo.
Jodi L. Karnell, PhD, of Viela Bio in Gaithersburg, Md., and coauthors, wrote that the CD40/CD40L pathway is known to play a key role in humoral immune responses and in the pathogenesis of several autoimmune diseases.
However, previous clinical trials of compounds targeting CD40L were stopped early because of an increased risk of adverse thromboembolic events related to platelet aggregation, despite showing potential benefits in lupus and immune thrombocytopenic purpura.
Preclinical studies of VIB4920 found that it blocked the expansion of CD40L-dependent human B cells without showing any signs of platelet aggregation. The authors said the platelet aggregation had been linked to a particular region of anti-CD40L monoclonal antibodies, but VIB4920 was engineered using a protein scaffold that did not contain that region.
In healthy volunteers, researchers saw a dose-dependent suppression of antibody production and reductions in B-cell proliferation, in recall response to a T cell–dependent antigen.
In individuals with rheumatoid arthritis, more than half of those treated with the two highest dosages of VIB4920 achieved low disease activity state or clinical remission by 12 weeks. Overall, there was also a significant decrease in disease activity, and dose-dependent decreases in rheumatoid factor autoantibodies and Vectra DA biomarker score, which is a composite of twelve rheumatoid arthritis–related biomarkers.
“The consistency of improvement across a variety of clinical and laboratory outcome measures further supports the potential clinical efficacy of VIB4920,” the authors wrote.
Researchers saw a similar rate of adverse events in the placebo and treatment arms of the study.
“VIB4920 represents an alternative to monoclonal antibody–based targeting of CD40L, which does not induce platelet aggregation in vitro and demonstrates a favorable safety profile in early clinical evaluation.”
The study was funded by MedImmune. All but one author were employees of MedImmune/AstraZeneca or of Viela Bio.
SOURCE: Karnell J et al. Sci Transl Med. 2019 April 24. doi: 10.1126/scitranslmed.aar6584
FROM SCIENCE TRANSLATIONAL MEDICINE
Key clinical point:
Major finding: Treatment with higher doses of VIB4920 is associated with low disease activity or remission in 50% of rheumatoid arthritis patients.
Study details: Phase 1a and 1b study in 59 healthy individuals and 57 people with rheumatoid arthritis.
Disclosures: The study was funded by MedImmune. All but one author were employees of MedImmune/AstraZeneca or Viela Bio.
Source: Karnell J et al. Sci Transl Med. 2019 April 24. doi: 10.1126/scitranslmed.aar6584.
Atorvastatin appears to lower cardiovascular risk in RA patients
Atorvastatin proved safe and potentially effective in preventing cardiovascular events in RA patients, according to the prematurely terminated TRACE RA trial.
“TRACE RA suggests that atorvastatin 40 mg daily is safe for the primary prevention of [CV events] in patients with RA and appears to confer a similar degree of risk reduction in these patients as in other populations,” wrote George D. Kitas, MD, of the Dudley (England) Group NHS Foundation Trust. The study was published in Arthritis & Rheumatology.
TRACE RA was a multicenter, double-blind, randomized trial that compared atorvastatin with placebo in preventing CV events by reducing LDL cholesterol. Its 3,002 patients with RA were randomized to receive either atorvastatin (1,504) or placebo (1,498). The goal was to follow the participants for 5 years. However, because of an unexpectedly low event rate, the trial was terminated early, resulting in a mean follow-up of 2.5 years.
At the end of the trial, those in the atorvastatin group had 0.77 mmol/L lower LDL cholesterol levels, compared with the placebo group (P less than .0001). Of the patients who received atorvastatin, 24 (1.6%) had a cardiac event versus 36 (2.4%) for placebo (hazard ratio, 0.66; 95% confidence interval, 0.39-1.11; P = .115). The estimated CV event risk reduction per 1 mmol/L reduction in LDL cholesterol was 42% (95% CI, –14% to 70%).
The coauthors acknowledged the study’s limitations, including the fact that it was terminated early because of a lower-than-expected CV event rate. This led to their results not being deemed statistically significant. They noted several reasons why this might have occurred – among them TRACE RA purposely excluding patients with the highest CV event risk – but also recognized that “the low event rate shows that there is a sizeable population of RA patients who have a relatively low CVD risk.”
“This does not support prescribing statins to all RA patients,” they added. “Instead, the decision to prescribe should be based on assessment of the individual RA patient’s risk using, at present, the relevant national or international recommendations and risk assessment tools.”
The study was funded by Arthritis Research UK and the British Heart Foundation. The coauthors report numerous potential conflicts of interest, including receiving honoraria for lectures and advisory boards participation, grant support, and consulting fees from various pharmaceutical companies.
SOURCE: Kitas GD et al. Arthritis Rheumatol. 2019 Apr 15. doi: 10.1002/art.40892.
Although it did not accomplish exactly what it set out to do, the TRACE RA study is a firm step in the right direction, according to Katherine P. Liao, MD, and Daniel H. Solomon, MD, of Brigham and Women’s Hospital in Boston.
To illustrate their point, Dr. Liao and Dr. Solomon presented a hypothetical RA patient called TR. She is firmly “average,” especially among the population represented in this study. Though she doesn’t seem like a glaring candidate for a statin, we can rightfully assume that – because of RA and a C-reactive protein above 2 mg/dL – her cardiovascular risk is higher than a member of the general population. The next step is determining if a statin will benefit such a patient, something relatively unexplored thus far.
Despite its abrupt termination, the coauthors “laud the investigators of TRACE RA, as this is the first trial among RA patients that was designed to study hard CVD endpoints.” At the very least, the study reinforced that statins are not associated with side effects when paired with typical RA treatments. In the future, Dr. Liao and Dr. Solomon suggested a focus on “better methods for identifying the appropriate patient population in RA to target for CV risk reduction strategies.”
These comments are adapted from an accompanying editorial (Arthritis Rheumatol. 2019 Apr 15. doi: 10.1002/art.40891). Dr. Solomon reported receiving salary support through research contracts from AbbVie, Amgen, Corrona, Genentech, Janssen, and Pfizer.
Although it did not accomplish exactly what it set out to do, the TRACE RA study is a firm step in the right direction, according to Katherine P. Liao, MD, and Daniel H. Solomon, MD, of Brigham and Women’s Hospital in Boston.
To illustrate their point, Dr. Liao and Dr. Solomon presented a hypothetical RA patient called TR. She is firmly “average,” especially among the population represented in this study. Though she doesn’t seem like a glaring candidate for a statin, we can rightfully assume that – because of RA and a C-reactive protein above 2 mg/dL – her cardiovascular risk is higher than a member of the general population. The next step is determining if a statin will benefit such a patient, something relatively unexplored thus far.
Despite its abrupt termination, the coauthors “laud the investigators of TRACE RA, as this is the first trial among RA patients that was designed to study hard CVD endpoints.” At the very least, the study reinforced that statins are not associated with side effects when paired with typical RA treatments. In the future, Dr. Liao and Dr. Solomon suggested a focus on “better methods for identifying the appropriate patient population in RA to target for CV risk reduction strategies.”
These comments are adapted from an accompanying editorial (Arthritis Rheumatol. 2019 Apr 15. doi: 10.1002/art.40891). Dr. Solomon reported receiving salary support through research contracts from AbbVie, Amgen, Corrona, Genentech, Janssen, and Pfizer.
Although it did not accomplish exactly what it set out to do, the TRACE RA study is a firm step in the right direction, according to Katherine P. Liao, MD, and Daniel H. Solomon, MD, of Brigham and Women’s Hospital in Boston.
To illustrate their point, Dr. Liao and Dr. Solomon presented a hypothetical RA patient called TR. She is firmly “average,” especially among the population represented in this study. Though she doesn’t seem like a glaring candidate for a statin, we can rightfully assume that – because of RA and a C-reactive protein above 2 mg/dL – her cardiovascular risk is higher than a member of the general population. The next step is determining if a statin will benefit such a patient, something relatively unexplored thus far.
Despite its abrupt termination, the coauthors “laud the investigators of TRACE RA, as this is the first trial among RA patients that was designed to study hard CVD endpoints.” At the very least, the study reinforced that statins are not associated with side effects when paired with typical RA treatments. In the future, Dr. Liao and Dr. Solomon suggested a focus on “better methods for identifying the appropriate patient population in RA to target for CV risk reduction strategies.”
These comments are adapted from an accompanying editorial (Arthritis Rheumatol. 2019 Apr 15. doi: 10.1002/art.40891). Dr. Solomon reported receiving salary support through research contracts from AbbVie, Amgen, Corrona, Genentech, Janssen, and Pfizer.
Atorvastatin proved safe and potentially effective in preventing cardiovascular events in RA patients, according to the prematurely terminated TRACE RA trial.
“TRACE RA suggests that atorvastatin 40 mg daily is safe for the primary prevention of [CV events] in patients with RA and appears to confer a similar degree of risk reduction in these patients as in other populations,” wrote George D. Kitas, MD, of the Dudley (England) Group NHS Foundation Trust. The study was published in Arthritis & Rheumatology.
TRACE RA was a multicenter, double-blind, randomized trial that compared atorvastatin with placebo in preventing CV events by reducing LDL cholesterol. Its 3,002 patients with RA were randomized to receive either atorvastatin (1,504) or placebo (1,498). The goal was to follow the participants for 5 years. However, because of an unexpectedly low event rate, the trial was terminated early, resulting in a mean follow-up of 2.5 years.
At the end of the trial, those in the atorvastatin group had 0.77 mmol/L lower LDL cholesterol levels, compared with the placebo group (P less than .0001). Of the patients who received atorvastatin, 24 (1.6%) had a cardiac event versus 36 (2.4%) for placebo (hazard ratio, 0.66; 95% confidence interval, 0.39-1.11; P = .115). The estimated CV event risk reduction per 1 mmol/L reduction in LDL cholesterol was 42% (95% CI, –14% to 70%).
The coauthors acknowledged the study’s limitations, including the fact that it was terminated early because of a lower-than-expected CV event rate. This led to their results not being deemed statistically significant. They noted several reasons why this might have occurred – among them TRACE RA purposely excluding patients with the highest CV event risk – but also recognized that “the low event rate shows that there is a sizeable population of RA patients who have a relatively low CVD risk.”
“This does not support prescribing statins to all RA patients,” they added. “Instead, the decision to prescribe should be based on assessment of the individual RA patient’s risk using, at present, the relevant national or international recommendations and risk assessment tools.”
The study was funded by Arthritis Research UK and the British Heart Foundation. The coauthors report numerous potential conflicts of interest, including receiving honoraria for lectures and advisory boards participation, grant support, and consulting fees from various pharmaceutical companies.
SOURCE: Kitas GD et al. Arthritis Rheumatol. 2019 Apr 15. doi: 10.1002/art.40892.
Atorvastatin proved safe and potentially effective in preventing cardiovascular events in RA patients, according to the prematurely terminated TRACE RA trial.
“TRACE RA suggests that atorvastatin 40 mg daily is safe for the primary prevention of [CV events] in patients with RA and appears to confer a similar degree of risk reduction in these patients as in other populations,” wrote George D. Kitas, MD, of the Dudley (England) Group NHS Foundation Trust. The study was published in Arthritis & Rheumatology.
TRACE RA was a multicenter, double-blind, randomized trial that compared atorvastatin with placebo in preventing CV events by reducing LDL cholesterol. Its 3,002 patients with RA were randomized to receive either atorvastatin (1,504) or placebo (1,498). The goal was to follow the participants for 5 years. However, because of an unexpectedly low event rate, the trial was terminated early, resulting in a mean follow-up of 2.5 years.
At the end of the trial, those in the atorvastatin group had 0.77 mmol/L lower LDL cholesterol levels, compared with the placebo group (P less than .0001). Of the patients who received atorvastatin, 24 (1.6%) had a cardiac event versus 36 (2.4%) for placebo (hazard ratio, 0.66; 95% confidence interval, 0.39-1.11; P = .115). The estimated CV event risk reduction per 1 mmol/L reduction in LDL cholesterol was 42% (95% CI, –14% to 70%).
The coauthors acknowledged the study’s limitations, including the fact that it was terminated early because of a lower-than-expected CV event rate. This led to their results not being deemed statistically significant. They noted several reasons why this might have occurred – among them TRACE RA purposely excluding patients with the highest CV event risk – but also recognized that “the low event rate shows that there is a sizeable population of RA patients who have a relatively low CVD risk.”
“This does not support prescribing statins to all RA patients,” they added. “Instead, the decision to prescribe should be based on assessment of the individual RA patient’s risk using, at present, the relevant national or international recommendations and risk assessment tools.”
The study was funded by Arthritis Research UK and the British Heart Foundation. The coauthors report numerous potential conflicts of interest, including receiving honoraria for lectures and advisory boards participation, grant support, and consulting fees from various pharmaceutical companies.
SOURCE: Kitas GD et al. Arthritis Rheumatol. 2019 Apr 15. doi: 10.1002/art.40892.
FROM ARTHRITIS & RHEUMATOLOGY
Bronchiolitis is a feared complication of connective tissue disease
MAUI, HAWAII – who develop shortness of breath and cough or a precipitous drop in their forced expiratory volume on pulmonary function testing, Aryeh Fischer, MD, said at the 2019 Rheumatology Winter Clinical Symposium.
“This is an underappreciated – and I think among the most potentially devastating – of the lung diseases we as rheumatologists will encounter in our patients,” said Dr. Fischer, a rheumatologist at the University of Colorado at Denver, Aurora, with a special interest in autoimmune lung disease.
“If you’re seeing patients with rheumatoid arthritis, SLE, or Sjögren’s and they’ve got bad asthma they can’t get under control, you’ve got to think about bronchiolitis because I can tell you your lung doc quite often is not thinking about this,” he added.
Bronchiolitis involves inflammation, narrowing, or obliteration of the small airways. The diagnosis is often missed because of the false sense of reassurance provided by the normal chest x-ray and regular CT findings, which are a feature of the disease.
“This is really important: You have to get a high-resolution CT that includes expiratory images, because that’s the only way you’re going to be able to tell if your patient has small airways disease,” he explained. “You must, must, must do an expiratory CT.”
A normal expiratory CT image should be gray, since the lungs are empty. Air is black on CT, so large areas of black intermixed with gray on an expiratory CT – a finding known as mosaicism – indicate air trapping due to small airways disease, Dr. Fischer noted.
Surgical lung biopsy will yield a pathologic report documenting isolated constrictive, follicular, and/or lymphocytic bronchiolitis. However, the terminology can be confusing: What pathologists describe as constrictive bronchiolitis is called obliterative by pulmonologists and radiologists.
Pulmonary function testing shows an obstructive defect. The diffusing capacity of the lungs for carbon monoxide (DLCO) is fairly normal, the forced expiratory volume in 1 second (FEV1) is sharply reduced, and the forced vital capacity (FVC) is near normal, with a resultant abnormally low FEV1/FVC ratio. A patient with bronchiolitis may or may not have a response to bronchodilators.
“I tell you, I’ve seen a bunch of these patients. They typically have a precipitous drop in their FEV1 and then stay stable at a very low level of lung function without much opportunity for improvement,” Dr. Fischer said. “Stability equals success in these patients. It’s really unusual to see much improvement.”
In theory, patients with follicular or lymphocytic bronchiolitis have an ongoing inflammatory process that should be amenable to rheumatologic ministrations. But there is no convincing evidence of treatment efficacy to date. And in obliterative bronchiolitis, marked by airway scarring, there is no reason to think anti-inflammatory therapies should be helpful. Anecdotally, Dr. Fischer said, he has seen immunosuppression help patients with obliterative bronchiolitis.
“Actually, the only proven therapy is lung transplantation,” he said.
He recommended that his fellow rheumatologists periodically use office spirometry to check the FEV1 in their patients with rheumatoid arthritis, Sjögren’s, or SLE, the forms of connective tissue disease most often associated with bronchiolitis. Compared with all the other testing rheumatologists routinely order in their patients, having them blow into a tube is a simple enough matter.
“We really don’t have anything to impact the natural history, but I like the notion of not being surprised. What are you going to do with that [abnormal] FEV1 data? I have no idea. But maybe it’s better to know earlier,” he said.
Dr. Fischer reported having no financial conflicts of interest regarding his presentation.
MAUI, HAWAII – who develop shortness of breath and cough or a precipitous drop in their forced expiratory volume on pulmonary function testing, Aryeh Fischer, MD, said at the 2019 Rheumatology Winter Clinical Symposium.
“This is an underappreciated – and I think among the most potentially devastating – of the lung diseases we as rheumatologists will encounter in our patients,” said Dr. Fischer, a rheumatologist at the University of Colorado at Denver, Aurora, with a special interest in autoimmune lung disease.
“If you’re seeing patients with rheumatoid arthritis, SLE, or Sjögren’s and they’ve got bad asthma they can’t get under control, you’ve got to think about bronchiolitis because I can tell you your lung doc quite often is not thinking about this,” he added.
Bronchiolitis involves inflammation, narrowing, or obliteration of the small airways. The diagnosis is often missed because of the false sense of reassurance provided by the normal chest x-ray and regular CT findings, which are a feature of the disease.
“This is really important: You have to get a high-resolution CT that includes expiratory images, because that’s the only way you’re going to be able to tell if your patient has small airways disease,” he explained. “You must, must, must do an expiratory CT.”
A normal expiratory CT image should be gray, since the lungs are empty. Air is black on CT, so large areas of black intermixed with gray on an expiratory CT – a finding known as mosaicism – indicate air trapping due to small airways disease, Dr. Fischer noted.
Surgical lung biopsy will yield a pathologic report documenting isolated constrictive, follicular, and/or lymphocytic bronchiolitis. However, the terminology can be confusing: What pathologists describe as constrictive bronchiolitis is called obliterative by pulmonologists and radiologists.
Pulmonary function testing shows an obstructive defect. The diffusing capacity of the lungs for carbon monoxide (DLCO) is fairly normal, the forced expiratory volume in 1 second (FEV1) is sharply reduced, and the forced vital capacity (FVC) is near normal, with a resultant abnormally low FEV1/FVC ratio. A patient with bronchiolitis may or may not have a response to bronchodilators.
“I tell you, I’ve seen a bunch of these patients. They typically have a precipitous drop in their FEV1 and then stay stable at a very low level of lung function without much opportunity for improvement,” Dr. Fischer said. “Stability equals success in these patients. It’s really unusual to see much improvement.”
In theory, patients with follicular or lymphocytic bronchiolitis have an ongoing inflammatory process that should be amenable to rheumatologic ministrations. But there is no convincing evidence of treatment efficacy to date. And in obliterative bronchiolitis, marked by airway scarring, there is no reason to think anti-inflammatory therapies should be helpful. Anecdotally, Dr. Fischer said, he has seen immunosuppression help patients with obliterative bronchiolitis.
“Actually, the only proven therapy is lung transplantation,” he said.
He recommended that his fellow rheumatologists periodically use office spirometry to check the FEV1 in their patients with rheumatoid arthritis, Sjögren’s, or SLE, the forms of connective tissue disease most often associated with bronchiolitis. Compared with all the other testing rheumatologists routinely order in their patients, having them blow into a tube is a simple enough matter.
“We really don’t have anything to impact the natural history, but I like the notion of not being surprised. What are you going to do with that [abnormal] FEV1 data? I have no idea. But maybe it’s better to know earlier,” he said.
Dr. Fischer reported having no financial conflicts of interest regarding his presentation.
MAUI, HAWAII – who develop shortness of breath and cough or a precipitous drop in their forced expiratory volume on pulmonary function testing, Aryeh Fischer, MD, said at the 2019 Rheumatology Winter Clinical Symposium.
“This is an underappreciated – and I think among the most potentially devastating – of the lung diseases we as rheumatologists will encounter in our patients,” said Dr. Fischer, a rheumatologist at the University of Colorado at Denver, Aurora, with a special interest in autoimmune lung disease.
“If you’re seeing patients with rheumatoid arthritis, SLE, or Sjögren’s and they’ve got bad asthma they can’t get under control, you’ve got to think about bronchiolitis because I can tell you your lung doc quite often is not thinking about this,” he added.
Bronchiolitis involves inflammation, narrowing, or obliteration of the small airways. The diagnosis is often missed because of the false sense of reassurance provided by the normal chest x-ray and regular CT findings, which are a feature of the disease.
“This is really important: You have to get a high-resolution CT that includes expiratory images, because that’s the only way you’re going to be able to tell if your patient has small airways disease,” he explained. “You must, must, must do an expiratory CT.”
A normal expiratory CT image should be gray, since the lungs are empty. Air is black on CT, so large areas of black intermixed with gray on an expiratory CT – a finding known as mosaicism – indicate air trapping due to small airways disease, Dr. Fischer noted.
Surgical lung biopsy will yield a pathologic report documenting isolated constrictive, follicular, and/or lymphocytic bronchiolitis. However, the terminology can be confusing: What pathologists describe as constrictive bronchiolitis is called obliterative by pulmonologists and radiologists.
Pulmonary function testing shows an obstructive defect. The diffusing capacity of the lungs for carbon monoxide (DLCO) is fairly normal, the forced expiratory volume in 1 second (FEV1) is sharply reduced, and the forced vital capacity (FVC) is near normal, with a resultant abnormally low FEV1/FVC ratio. A patient with bronchiolitis may or may not have a response to bronchodilators.
“I tell you, I’ve seen a bunch of these patients. They typically have a precipitous drop in their FEV1 and then stay stable at a very low level of lung function without much opportunity for improvement,” Dr. Fischer said. “Stability equals success in these patients. It’s really unusual to see much improvement.”
In theory, patients with follicular or lymphocytic bronchiolitis have an ongoing inflammatory process that should be amenable to rheumatologic ministrations. But there is no convincing evidence of treatment efficacy to date. And in obliterative bronchiolitis, marked by airway scarring, there is no reason to think anti-inflammatory therapies should be helpful. Anecdotally, Dr. Fischer said, he has seen immunosuppression help patients with obliterative bronchiolitis.
“Actually, the only proven therapy is lung transplantation,” he said.
He recommended that his fellow rheumatologists periodically use office spirometry to check the FEV1 in their patients with rheumatoid arthritis, Sjögren’s, or SLE, the forms of connective tissue disease most often associated with bronchiolitis. Compared with all the other testing rheumatologists routinely order in their patients, having them blow into a tube is a simple enough matter.
“We really don’t have anything to impact the natural history, but I like the notion of not being surprised. What are you going to do with that [abnormal] FEV1 data? I have no idea. But maybe it’s better to know earlier,” he said.
Dr. Fischer reported having no financial conflicts of interest regarding his presentation.
REPORTING FROM RWCS 2019
Abatacept appears safe for RA patients with COPD
Concerns about abatacept (Orencia)-related lung disease in patients with rheumatoid arthritis appear to be unfounded, a large U.S. database review has determined.
Safety signals seen in a small subset of patients in the 2006 ASSURE study likely arose from chance, Samy Suissa, PhD, and his colleagues wrote in Seminars in Arthritis & Rheumatism. Patients in that study with preexisting chronic obstructive pulmonary disease (COPD) were 84% more likely to develop an exacerbation or other lung disorder than were those taking a placebo comparator.
The new database study contradicted that finding.
“Our study suggests that these numerical differences in ASSURE are expected results of random variation and thus compatible with chance,” Dr. Suissa of Jewish General Hospital and McGill University, both in Montreal, and his coauthors wrote. “Moreover, our findings are consistent with two studies of the safety of abatacept in the context of interstitial lung disease, albeit a different respiratory disease than COPD.”
The year-long ASSURE trial reported on the safety of abatacept in 959 patients versus 482 assigned to placebo. The safety signal arose in a subgroup of 54 patients with COPD, 37 of whom were assigned to abatacept and 17 to placebo. Among these were four serious respiratory adverse events (COPD exacerbation, worsening of COPD, bronchitis, and pneumonia) in four patients taking abatacept and none in the placebo arm.
“It is useful to note that this difference of 11% versus 0% rate is compatible with chance [exact P = .31], while the exact 95% confidence interval for the odds ratio is wide and includes unity ... The trial also reported more mild-moderate respiratory events with abatacept than with placebo [43.2% vs. 23.5%], including cough, rhonchi, COPD exacerbation, COPD, dyspnea, and nasal congestion. This difference resulted in an odds ration of 1.84,” with a wide confidence interval that included unity (0.48-8.63).
Nevertheless, these findings led to the addition of a warning in the prescribing insert: “Adult COPD patients treated with Orencia developed adverse events more frequently than those treated with placebo, including COPD exacerbations, cough, rhonchi, and dyspnea. Use of Orencia in patients with RA and COPD should be undertaken with caution and such patients should be monitored for worsening of their respiratory status.”
Dr. Suissa’s team used the U.S. MarketScan prescribing database to asses the risk of respiratory adverse events associated with abatacept, compared with other biologic disease-modifying antirheumatic drugs (DMARDs) in a real-world setting.
The cohort comprised 1,807 patients with rheumatoid arthritis and COPD who started a new prescription for abatacept, matched in time to 3,547 who initiated another biologic DMARD. The primary endpoint was the combined risk of hospitalization for COPD exacerbation, bronchitis, and hospitalized pneumonia or influenza.
The most common comparator biologic DMARDs were etanercept, adalimumab, rituximab, and infliximab.
For patients with COPD and comparator patients, the incidence rates for COPD exacerbation were 1.2 per 100 person-years with abatacept and 2.1 per 100 person-years with a different biologic DMARD; for bronchitis, the respective rates were 4.2 and 5.3; for hospitalized pneumonia or influenza, 3.6 and 2.6; and for outpatient pneumonia or flu, 14.7 and 14.4. For the combined endpoint, the incidence rate was 8.7 per 100 person-years with abatacept and 9.9 per 100 person-years with other biologic DMARDs.
The adjusted hazard ratio of the combined endpoint with abatacept versus that with other biologic DMARDs was a nonsignificant risk of 0.87. The hazard ratio with abatacept was 0.60 for hospitalized COPD; 0.80 for bronchitis; 1.39 for hospitalized pneumonia and flu; and 1.05 for outpatient pneumonia and flu. None of these associations was statistically significant.
“One exception was the risk of hospitalization for pneumonia or influenza, which was higher with abatacept among patients with more severe COPD,” at 6.99, than it was with other biologic DMARDs, the authors noted.
Dr. Suissa disclosed relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Novartis.
SOURCE: Suissa S et al. Semin Arthritis Rheum. 2019 Mar 16. doi: 10.1016j.semarthrit.2019.03.007.
Concerns about abatacept (Orencia)-related lung disease in patients with rheumatoid arthritis appear to be unfounded, a large U.S. database review has determined.
Safety signals seen in a small subset of patients in the 2006 ASSURE study likely arose from chance, Samy Suissa, PhD, and his colleagues wrote in Seminars in Arthritis & Rheumatism. Patients in that study with preexisting chronic obstructive pulmonary disease (COPD) were 84% more likely to develop an exacerbation or other lung disorder than were those taking a placebo comparator.
The new database study contradicted that finding.
“Our study suggests that these numerical differences in ASSURE are expected results of random variation and thus compatible with chance,” Dr. Suissa of Jewish General Hospital and McGill University, both in Montreal, and his coauthors wrote. “Moreover, our findings are consistent with two studies of the safety of abatacept in the context of interstitial lung disease, albeit a different respiratory disease than COPD.”
The year-long ASSURE trial reported on the safety of abatacept in 959 patients versus 482 assigned to placebo. The safety signal arose in a subgroup of 54 patients with COPD, 37 of whom were assigned to abatacept and 17 to placebo. Among these were four serious respiratory adverse events (COPD exacerbation, worsening of COPD, bronchitis, and pneumonia) in four patients taking abatacept and none in the placebo arm.
“It is useful to note that this difference of 11% versus 0% rate is compatible with chance [exact P = .31], while the exact 95% confidence interval for the odds ratio is wide and includes unity ... The trial also reported more mild-moderate respiratory events with abatacept than with placebo [43.2% vs. 23.5%], including cough, rhonchi, COPD exacerbation, COPD, dyspnea, and nasal congestion. This difference resulted in an odds ration of 1.84,” with a wide confidence interval that included unity (0.48-8.63).
Nevertheless, these findings led to the addition of a warning in the prescribing insert: “Adult COPD patients treated with Orencia developed adverse events more frequently than those treated with placebo, including COPD exacerbations, cough, rhonchi, and dyspnea. Use of Orencia in patients with RA and COPD should be undertaken with caution and such patients should be monitored for worsening of their respiratory status.”
Dr. Suissa’s team used the U.S. MarketScan prescribing database to asses the risk of respiratory adverse events associated with abatacept, compared with other biologic disease-modifying antirheumatic drugs (DMARDs) in a real-world setting.
The cohort comprised 1,807 patients with rheumatoid arthritis and COPD who started a new prescription for abatacept, matched in time to 3,547 who initiated another biologic DMARD. The primary endpoint was the combined risk of hospitalization for COPD exacerbation, bronchitis, and hospitalized pneumonia or influenza.
The most common comparator biologic DMARDs were etanercept, adalimumab, rituximab, and infliximab.
For patients with COPD and comparator patients, the incidence rates for COPD exacerbation were 1.2 per 100 person-years with abatacept and 2.1 per 100 person-years with a different biologic DMARD; for bronchitis, the respective rates were 4.2 and 5.3; for hospitalized pneumonia or influenza, 3.6 and 2.6; and for outpatient pneumonia or flu, 14.7 and 14.4. For the combined endpoint, the incidence rate was 8.7 per 100 person-years with abatacept and 9.9 per 100 person-years with other biologic DMARDs.
The adjusted hazard ratio of the combined endpoint with abatacept versus that with other biologic DMARDs was a nonsignificant risk of 0.87. The hazard ratio with abatacept was 0.60 for hospitalized COPD; 0.80 for bronchitis; 1.39 for hospitalized pneumonia and flu; and 1.05 for outpatient pneumonia and flu. None of these associations was statistically significant.
“One exception was the risk of hospitalization for pneumonia or influenza, which was higher with abatacept among patients with more severe COPD,” at 6.99, than it was with other biologic DMARDs, the authors noted.
Dr. Suissa disclosed relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Novartis.
SOURCE: Suissa S et al. Semin Arthritis Rheum. 2019 Mar 16. doi: 10.1016j.semarthrit.2019.03.007.
Concerns about abatacept (Orencia)-related lung disease in patients with rheumatoid arthritis appear to be unfounded, a large U.S. database review has determined.
Safety signals seen in a small subset of patients in the 2006 ASSURE study likely arose from chance, Samy Suissa, PhD, and his colleagues wrote in Seminars in Arthritis & Rheumatism. Patients in that study with preexisting chronic obstructive pulmonary disease (COPD) were 84% more likely to develop an exacerbation or other lung disorder than were those taking a placebo comparator.
The new database study contradicted that finding.
“Our study suggests that these numerical differences in ASSURE are expected results of random variation and thus compatible with chance,” Dr. Suissa of Jewish General Hospital and McGill University, both in Montreal, and his coauthors wrote. “Moreover, our findings are consistent with two studies of the safety of abatacept in the context of interstitial lung disease, albeit a different respiratory disease than COPD.”
The year-long ASSURE trial reported on the safety of abatacept in 959 patients versus 482 assigned to placebo. The safety signal arose in a subgroup of 54 patients with COPD, 37 of whom were assigned to abatacept and 17 to placebo. Among these were four serious respiratory adverse events (COPD exacerbation, worsening of COPD, bronchitis, and pneumonia) in four patients taking abatacept and none in the placebo arm.
“It is useful to note that this difference of 11% versus 0% rate is compatible with chance [exact P = .31], while the exact 95% confidence interval for the odds ratio is wide and includes unity ... The trial also reported more mild-moderate respiratory events with abatacept than with placebo [43.2% vs. 23.5%], including cough, rhonchi, COPD exacerbation, COPD, dyspnea, and nasal congestion. This difference resulted in an odds ration of 1.84,” with a wide confidence interval that included unity (0.48-8.63).
Nevertheless, these findings led to the addition of a warning in the prescribing insert: “Adult COPD patients treated with Orencia developed adverse events more frequently than those treated with placebo, including COPD exacerbations, cough, rhonchi, and dyspnea. Use of Orencia in patients with RA and COPD should be undertaken with caution and such patients should be monitored for worsening of their respiratory status.”
Dr. Suissa’s team used the U.S. MarketScan prescribing database to asses the risk of respiratory adverse events associated with abatacept, compared with other biologic disease-modifying antirheumatic drugs (DMARDs) in a real-world setting.
The cohort comprised 1,807 patients with rheumatoid arthritis and COPD who started a new prescription for abatacept, matched in time to 3,547 who initiated another biologic DMARD. The primary endpoint was the combined risk of hospitalization for COPD exacerbation, bronchitis, and hospitalized pneumonia or influenza.
The most common comparator biologic DMARDs were etanercept, adalimumab, rituximab, and infliximab.
For patients with COPD and comparator patients, the incidence rates for COPD exacerbation were 1.2 per 100 person-years with abatacept and 2.1 per 100 person-years with a different biologic DMARD; for bronchitis, the respective rates were 4.2 and 5.3; for hospitalized pneumonia or influenza, 3.6 and 2.6; and for outpatient pneumonia or flu, 14.7 and 14.4. For the combined endpoint, the incidence rate was 8.7 per 100 person-years with abatacept and 9.9 per 100 person-years with other biologic DMARDs.
The adjusted hazard ratio of the combined endpoint with abatacept versus that with other biologic DMARDs was a nonsignificant risk of 0.87. The hazard ratio with abatacept was 0.60 for hospitalized COPD; 0.80 for bronchitis; 1.39 for hospitalized pneumonia and flu; and 1.05 for outpatient pneumonia and flu. None of these associations was statistically significant.
“One exception was the risk of hospitalization for pneumonia or influenza, which was higher with abatacept among patients with more severe COPD,” at 6.99, than it was with other biologic DMARDs, the authors noted.
Dr. Suissa disclosed relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Novartis.
SOURCE: Suissa S et al. Semin Arthritis Rheum. 2019 Mar 16. doi: 10.1016j.semarthrit.2019.03.007.
FROM SEMINARS IN ARTHRITIS & RHEUMATISM
Flu shot can be given irrespective of the time of last methotrexate dose
Immune response to influenza vaccination in rheumatoid arthritis patients taking methotrexate appears to depend most on stopping the next two weekly doses of the drug rather than any effect from the timing of the last dose, new research concludes.
The new finding, reported in Annals of the Rheumatic Diseases, stems from a post hoc analysis of a randomized, controlled trial that Jin Kyun Park, MD, of Seoul (Korea) National University, and his colleagues had conducted earlier on immune response when patients stopped methotrexate for either 2 or 4 weeks after vaccination. While the main endpoint of that study showed no difference in the improvement in vaccine response with either stopping methotrexate for 2 or 4 weeks and no increase in disease activity with stopping for 2 weeks, it was unclear whether the timing of the last dose mattered when stopping for 2 weeks.
In a bid to identify the optimal time between the last dose of methotrexate and administration of a flu vaccine, Dr. Park and his colleagues conducted a post hoc analysis of the trial, which involved 316 patients with RA receiving methotrexate for 6 weeks or longer to continue (n = 156) or to hold methotrexate (n = 160) for 2 weeks after receiving a quadrivalent influenza vaccine containing H1N1, H3N2, B-Yamagata, and B-Victoria.
The study authors defined a positive vaccine response as a fourfold or greater increase in hemagglutination inhibition (HI) antibody titer. A satisfactory vaccine response was a positive response to two or more of four vaccine antigens.
Patients who stopped taking methotrexate were divided into eight subgroups according to the number of days between their last dose and their vaccination.
The research team reported that response to vaccine, fold increase in HI antibody titers, and postvaccination seroprotection rates were not associated with the time between the last methotrexate dose and the time of vaccination.
However, they conceded that “the absence of impact of the number of days between the last methotrexate dose and vaccination could be due to the small patient numbers in eight subgroups.”
Vaccine response also did not differ between patients who received the influenza vaccination within 3 days of the last methotrexate dose (n = 65) and those who received it between 4-7 days of the last methotrexate dose (n = 95).
Furthermore, RA disease activity, seropositivity, or use of conventional or biologic disease-modifying antirheumatic drugs did not have an impact on methotrexate discontinuation.
The authors concluded that vaccinations could be given irrespective of the time of the last methotrexate dose, and patients should be advised to skip two weekly doses following vaccination.
“This supports the notion that the effects of methotrexate on humeral immunity occur rapidly, despite the delayed effects on arthritis; therefore, the absence of methotrexate during the first 2 weeks postvaccination is critical for humoral immunity,” they wrote.
The study was sponsored by GC Pharma. One author disclosed serving as a consultant to Pfizer and receiving research grants from GC Pharma and Hanmi Pharma.
SOURCE: Park JK et al. Ann Rheum Dis. 2019 Mar 23. doi: 10.1136/annrheumdis-2019-215187.
Immune response to influenza vaccination in rheumatoid arthritis patients taking methotrexate appears to depend most on stopping the next two weekly doses of the drug rather than any effect from the timing of the last dose, new research concludes.
The new finding, reported in Annals of the Rheumatic Diseases, stems from a post hoc analysis of a randomized, controlled trial that Jin Kyun Park, MD, of Seoul (Korea) National University, and his colleagues had conducted earlier on immune response when patients stopped methotrexate for either 2 or 4 weeks after vaccination. While the main endpoint of that study showed no difference in the improvement in vaccine response with either stopping methotrexate for 2 or 4 weeks and no increase in disease activity with stopping for 2 weeks, it was unclear whether the timing of the last dose mattered when stopping for 2 weeks.
In a bid to identify the optimal time between the last dose of methotrexate and administration of a flu vaccine, Dr. Park and his colleagues conducted a post hoc analysis of the trial, which involved 316 patients with RA receiving methotrexate for 6 weeks or longer to continue (n = 156) or to hold methotrexate (n = 160) for 2 weeks after receiving a quadrivalent influenza vaccine containing H1N1, H3N2, B-Yamagata, and B-Victoria.
The study authors defined a positive vaccine response as a fourfold or greater increase in hemagglutination inhibition (HI) antibody titer. A satisfactory vaccine response was a positive response to two or more of four vaccine antigens.
Patients who stopped taking methotrexate were divided into eight subgroups according to the number of days between their last dose and their vaccination.
The research team reported that response to vaccine, fold increase in HI antibody titers, and postvaccination seroprotection rates were not associated with the time between the last methotrexate dose and the time of vaccination.
However, they conceded that “the absence of impact of the number of days between the last methotrexate dose and vaccination could be due to the small patient numbers in eight subgroups.”
Vaccine response also did not differ between patients who received the influenza vaccination within 3 days of the last methotrexate dose (n = 65) and those who received it between 4-7 days of the last methotrexate dose (n = 95).
Furthermore, RA disease activity, seropositivity, or use of conventional or biologic disease-modifying antirheumatic drugs did not have an impact on methotrexate discontinuation.
The authors concluded that vaccinations could be given irrespective of the time of the last methotrexate dose, and patients should be advised to skip two weekly doses following vaccination.
“This supports the notion that the effects of methotrexate on humeral immunity occur rapidly, despite the delayed effects on arthritis; therefore, the absence of methotrexate during the first 2 weeks postvaccination is critical for humoral immunity,” they wrote.
The study was sponsored by GC Pharma. One author disclosed serving as a consultant to Pfizer and receiving research grants from GC Pharma and Hanmi Pharma.
SOURCE: Park JK et al. Ann Rheum Dis. 2019 Mar 23. doi: 10.1136/annrheumdis-2019-215187.
Immune response to influenza vaccination in rheumatoid arthritis patients taking methotrexate appears to depend most on stopping the next two weekly doses of the drug rather than any effect from the timing of the last dose, new research concludes.
The new finding, reported in Annals of the Rheumatic Diseases, stems from a post hoc analysis of a randomized, controlled trial that Jin Kyun Park, MD, of Seoul (Korea) National University, and his colleagues had conducted earlier on immune response when patients stopped methotrexate for either 2 or 4 weeks after vaccination. While the main endpoint of that study showed no difference in the improvement in vaccine response with either stopping methotrexate for 2 or 4 weeks and no increase in disease activity with stopping for 2 weeks, it was unclear whether the timing of the last dose mattered when stopping for 2 weeks.
In a bid to identify the optimal time between the last dose of methotrexate and administration of a flu vaccine, Dr. Park and his colleagues conducted a post hoc analysis of the trial, which involved 316 patients with RA receiving methotrexate for 6 weeks or longer to continue (n = 156) or to hold methotrexate (n = 160) for 2 weeks after receiving a quadrivalent influenza vaccine containing H1N1, H3N2, B-Yamagata, and B-Victoria.
The study authors defined a positive vaccine response as a fourfold or greater increase in hemagglutination inhibition (HI) antibody titer. A satisfactory vaccine response was a positive response to two or more of four vaccine antigens.
Patients who stopped taking methotrexate were divided into eight subgroups according to the number of days between their last dose and their vaccination.
The research team reported that response to vaccine, fold increase in HI antibody titers, and postvaccination seroprotection rates were not associated with the time between the last methotrexate dose and the time of vaccination.
However, they conceded that “the absence of impact of the number of days between the last methotrexate dose and vaccination could be due to the small patient numbers in eight subgroups.”
Vaccine response also did not differ between patients who received the influenza vaccination within 3 days of the last methotrexate dose (n = 65) and those who received it between 4-7 days of the last methotrexate dose (n = 95).
Furthermore, RA disease activity, seropositivity, or use of conventional or biologic disease-modifying antirheumatic drugs did not have an impact on methotrexate discontinuation.
The authors concluded that vaccinations could be given irrespective of the time of the last methotrexate dose, and patients should be advised to skip two weekly doses following vaccination.
“This supports the notion that the effects of methotrexate on humeral immunity occur rapidly, despite the delayed effects on arthritis; therefore, the absence of methotrexate during the first 2 weeks postvaccination is critical for humoral immunity,” they wrote.
The study was sponsored by GC Pharma. One author disclosed serving as a consultant to Pfizer and receiving research grants from GC Pharma and Hanmi Pharma.
SOURCE: Park JK et al. Ann Rheum Dis. 2019 Mar 23. doi: 10.1136/annrheumdis-2019-215187.
FROM ANNALS OF THE RHEUMATIC DISEASES
Key clinical point:
Major finding: Response to vaccine, fold increase in HI antibody titers, and postvaccination seroprotection rates were not associated with the time between the last methotrexate dose and the time of vaccination.
Study details: A post hoc analysis of a randomized, controlled trial involving 316 patients with rheumatoid arthritis who continued or stopped methotrexate for 2 weeks following influenza vaccination.
Disclosures: The study was sponsored by GC Pharma. One author disclosed serving as a consultant to Pfizer and receiving research grants from GC Pharma and Hanmi Pharma.
Source: Park JK et al. Ann Rheum Dis. 2019 Mar 23. doi: 10.1136/annrheumdis-2019-215187
Industry-funded rheumatology RCTs are higher quality
MAUI, HAWAII – Industry-funded randomized, controlled clinical trials published in the three top-rated rheumatology journals during the past 20 years are of significantly higher overall quality than the nonindustry-funded ones, Michael Putman, MD, said at the 2019 Rheumatology Winter Clinical Symposium.
Dr. Putman, a second-year rheumatology fellow at Northwestern University, Chicago, analyzed all randomized, controlled trials (RCTs) of pharmacotherapy featuring a comparator – either placebo or an active agent – published in 1998, 2008, and 2018 in Annals of the Rheumatic Diseases, Rheumatology, and Arthritis & Rheumatology.
His main takeaway: “Rheumatologic interventions seem to work pretty well. The mean absolute risk reduction in the trials is 17.5%, so the average number of patients who need to be treated with a rheumatologic intervention is about five. This is why it’s such a great specialty to be a part of: A lot of our patients get better.”
He created an RCT quality rating scale that captured the strength of study design, methodology, and findings based upon whether a randomized trial used a double-blind design; identified a prespecified primary outcome; and featured patient-reported outcomes, power calculations, sensitivity analysis, adjustment for multiple hypotheses, and intention-to-treat analysis. He then applied the rating scale to the 85 published RCTs in the three study years.
Of note, 84% of the trials published in 2018 were industry funded, up from 74% in 2008 and 1998.
“Industry funds the vast majority of studies. Industry studies are significantly more likely to be appropriately double blinded, report patient-reported outcome measures, use intention to treat, and they have a higher overall quality,” according to Dr. Putman.
Indeed, the industry-funded studies averaged a 66% score on his quality grading scale, compared with 45% for nonindustry-funded studies.
Utilization of most of the quality metrics remained stable over time. The exceptions: Incorporation of intent-to-treat analysis increased from 58% in 1998 to 87% in 2018, and sensitivity analysis was employed in just 5% of the trials published in 1998, compared with 37% in 2008 and 26% in 2018.
The most important change over the past 2 decades, in his view, has been the shrinking proportion of RCTs featuring an active-drug, head-to-head comparator arm. In 1998, 42% of studies featured that design; for example, comparing methotrexate to sulfasalazine. By 2018, that figure had dropped to just 13%.
“Most of our trials today compare an active compound, such an interleukin-17 inhibitor, to a placebo. I think that’s a big change in how we do things,” Dr. Putman observed. “With 84% of our studies being funded by industry, the incentives in medicine right now don’t support active comparator research. It’s harder to show a difference between two things that work than it is to show a difference between something and nothing.”
However, he’d welcome a revival of head-to-head active comparator trials.
“I’d really love to have that happen,” he said. “We have basic questions we haven’t answered yet about a lot of our basic drugs: Like in myositis, should you start with Imuran [azathioprine], CellCept [mycophenolate mofetil], or methotrexate?”
Another striking change over time has been the dwindling proportion of published trials with a statistically significant finding for the primary outcome: 79% in 1998, 46% in 2008, and 36% last year. Dr. Putman suspects the explanation lies in the steady improvement in the effectiveness of standard background therapy for many conditions, which makes it tougher to show a striking difference between the add-on study drug and add-on placebo.
“We’re a victim of our own success,” he commented.
In any event, many key secondary outcomes in the RCTs were positive, even when the primary endpoint wasn’t, according to Dr. Putman, and there was a notable dearth of completely negative clinical RCTs published in the three top journals.
“The more cynical interpretation is there’s an incredible amount of publication bias, where we’re only publishing studies that show an effect and the journals or investigators are censoring the ones that don’t. The more charitable explanation, which is probably also true, is that by the time you get to putting on an RCT you kind of think, ‘This thing works.’ You’re not testing random stuff, so your pretest probability of a drug being effective when it enters into an RCT is probably shifted toward effectiveness,” Dr. Putman speculated.
He reported having no financial conflicts regarding his study.
MAUI, HAWAII – Industry-funded randomized, controlled clinical trials published in the three top-rated rheumatology journals during the past 20 years are of significantly higher overall quality than the nonindustry-funded ones, Michael Putman, MD, said at the 2019 Rheumatology Winter Clinical Symposium.
Dr. Putman, a second-year rheumatology fellow at Northwestern University, Chicago, analyzed all randomized, controlled trials (RCTs) of pharmacotherapy featuring a comparator – either placebo or an active agent – published in 1998, 2008, and 2018 in Annals of the Rheumatic Diseases, Rheumatology, and Arthritis & Rheumatology.
His main takeaway: “Rheumatologic interventions seem to work pretty well. The mean absolute risk reduction in the trials is 17.5%, so the average number of patients who need to be treated with a rheumatologic intervention is about five. This is why it’s such a great specialty to be a part of: A lot of our patients get better.”
He created an RCT quality rating scale that captured the strength of study design, methodology, and findings based upon whether a randomized trial used a double-blind design; identified a prespecified primary outcome; and featured patient-reported outcomes, power calculations, sensitivity analysis, adjustment for multiple hypotheses, and intention-to-treat analysis. He then applied the rating scale to the 85 published RCTs in the three study years.
Of note, 84% of the trials published in 2018 were industry funded, up from 74% in 2008 and 1998.
“Industry funds the vast majority of studies. Industry studies are significantly more likely to be appropriately double blinded, report patient-reported outcome measures, use intention to treat, and they have a higher overall quality,” according to Dr. Putman.
Indeed, the industry-funded studies averaged a 66% score on his quality grading scale, compared with 45% for nonindustry-funded studies.
Utilization of most of the quality metrics remained stable over time. The exceptions: Incorporation of intent-to-treat analysis increased from 58% in 1998 to 87% in 2018, and sensitivity analysis was employed in just 5% of the trials published in 1998, compared with 37% in 2008 and 26% in 2018.
The most important change over the past 2 decades, in his view, has been the shrinking proportion of RCTs featuring an active-drug, head-to-head comparator arm. In 1998, 42% of studies featured that design; for example, comparing methotrexate to sulfasalazine. By 2018, that figure had dropped to just 13%.
“Most of our trials today compare an active compound, such an interleukin-17 inhibitor, to a placebo. I think that’s a big change in how we do things,” Dr. Putman observed. “With 84% of our studies being funded by industry, the incentives in medicine right now don’t support active comparator research. It’s harder to show a difference between two things that work than it is to show a difference between something and nothing.”
However, he’d welcome a revival of head-to-head active comparator trials.
“I’d really love to have that happen,” he said. “We have basic questions we haven’t answered yet about a lot of our basic drugs: Like in myositis, should you start with Imuran [azathioprine], CellCept [mycophenolate mofetil], or methotrexate?”
Another striking change over time has been the dwindling proportion of published trials with a statistically significant finding for the primary outcome: 79% in 1998, 46% in 2008, and 36% last year. Dr. Putman suspects the explanation lies in the steady improvement in the effectiveness of standard background therapy for many conditions, which makes it tougher to show a striking difference between the add-on study drug and add-on placebo.
“We’re a victim of our own success,” he commented.
In any event, many key secondary outcomes in the RCTs were positive, even when the primary endpoint wasn’t, according to Dr. Putman, and there was a notable dearth of completely negative clinical RCTs published in the three top journals.
“The more cynical interpretation is there’s an incredible amount of publication bias, where we’re only publishing studies that show an effect and the journals or investigators are censoring the ones that don’t. The more charitable explanation, which is probably also true, is that by the time you get to putting on an RCT you kind of think, ‘This thing works.’ You’re not testing random stuff, so your pretest probability of a drug being effective when it enters into an RCT is probably shifted toward effectiveness,” Dr. Putman speculated.
He reported having no financial conflicts regarding his study.
MAUI, HAWAII – Industry-funded randomized, controlled clinical trials published in the three top-rated rheumatology journals during the past 20 years are of significantly higher overall quality than the nonindustry-funded ones, Michael Putman, MD, said at the 2019 Rheumatology Winter Clinical Symposium.
Dr. Putman, a second-year rheumatology fellow at Northwestern University, Chicago, analyzed all randomized, controlled trials (RCTs) of pharmacotherapy featuring a comparator – either placebo or an active agent – published in 1998, 2008, and 2018 in Annals of the Rheumatic Diseases, Rheumatology, and Arthritis & Rheumatology.
His main takeaway: “Rheumatologic interventions seem to work pretty well. The mean absolute risk reduction in the trials is 17.5%, so the average number of patients who need to be treated with a rheumatologic intervention is about five. This is why it’s such a great specialty to be a part of: A lot of our patients get better.”
He created an RCT quality rating scale that captured the strength of study design, methodology, and findings based upon whether a randomized trial used a double-blind design; identified a prespecified primary outcome; and featured patient-reported outcomes, power calculations, sensitivity analysis, adjustment for multiple hypotheses, and intention-to-treat analysis. He then applied the rating scale to the 85 published RCTs in the three study years.
Of note, 84% of the trials published in 2018 were industry funded, up from 74% in 2008 and 1998.
“Industry funds the vast majority of studies. Industry studies are significantly more likely to be appropriately double blinded, report patient-reported outcome measures, use intention to treat, and they have a higher overall quality,” according to Dr. Putman.
Indeed, the industry-funded studies averaged a 66% score on his quality grading scale, compared with 45% for nonindustry-funded studies.
Utilization of most of the quality metrics remained stable over time. The exceptions: Incorporation of intent-to-treat analysis increased from 58% in 1998 to 87% in 2018, and sensitivity analysis was employed in just 5% of the trials published in 1998, compared with 37% in 2008 and 26% in 2018.
The most important change over the past 2 decades, in his view, has been the shrinking proportion of RCTs featuring an active-drug, head-to-head comparator arm. In 1998, 42% of studies featured that design; for example, comparing methotrexate to sulfasalazine. By 2018, that figure had dropped to just 13%.
“Most of our trials today compare an active compound, such an interleukin-17 inhibitor, to a placebo. I think that’s a big change in how we do things,” Dr. Putman observed. “With 84% of our studies being funded by industry, the incentives in medicine right now don’t support active comparator research. It’s harder to show a difference between two things that work than it is to show a difference between something and nothing.”
However, he’d welcome a revival of head-to-head active comparator trials.
“I’d really love to have that happen,” he said. “We have basic questions we haven’t answered yet about a lot of our basic drugs: Like in myositis, should you start with Imuran [azathioprine], CellCept [mycophenolate mofetil], or methotrexate?”
Another striking change over time has been the dwindling proportion of published trials with a statistically significant finding for the primary outcome: 79% in 1998, 46% in 2008, and 36% last year. Dr. Putman suspects the explanation lies in the steady improvement in the effectiveness of standard background therapy for many conditions, which makes it tougher to show a striking difference between the add-on study drug and add-on placebo.
“We’re a victim of our own success,” he commented.
In any event, many key secondary outcomes in the RCTs were positive, even when the primary endpoint wasn’t, according to Dr. Putman, and there was a notable dearth of completely negative clinical RCTs published in the three top journals.
“The more cynical interpretation is there’s an incredible amount of publication bias, where we’re only publishing studies that show an effect and the journals or investigators are censoring the ones that don’t. The more charitable explanation, which is probably also true, is that by the time you get to putting on an RCT you kind of think, ‘This thing works.’ You’re not testing random stuff, so your pretest probability of a drug being effective when it enters into an RCT is probably shifted toward effectiveness,” Dr. Putman speculated.
He reported having no financial conflicts regarding his study.
REPORTING FROM RWCS 2019
No biological benefits from alcohol seen in rheumatoid arthritis
, according to a study published online March 20 in Arthritis Care & Research.
Joshua F. Baker, MD, of the University of Pennsylvania, Philadelphia, and his coauthors wrote that previous studies had suggested a link between moderate alcohol consumption and lower disease activity, better quality of life, and better functional status in people with rheumatoid arthritis. This link may tempt clinicians “to encourage moderate alcohol consumption among patients with RA,” the researchers wrote, and so it prompted them to examine the relationship more closely.
The researchers studied 16,762 individuals with rheumatoid arthritis in the National Databank for Rheumatic Diseases who had been asked about alcohol use and disease activity in a series of semiannual surveys, providing a total of 121,280 observations, at which 53% reported using alcohol.
Across the observations taken from the semiannual surveys, a total of 8.2% reported discontinuing alcohol consumption from one survey to the next, and 8.4% of abstainers reported initiating alcohol use. Importantly, individuals with high disease activity had a significantly shorter time to discontinuation of alcohol, and those with a moderate or high Patient Activity Scale-II (PAS-II) score were 36% more likely to stop alcohol consumption, compared with individuals who had a low PAS-II score.
Individuals who were older or obese or had more comorbidities or greater work disability were all independently more likely to discontinue alcohol use, while those less likely to give up alcohol tended to be white, male, and have higher physical and mental quality of life, higher educational level, and greater household income.
Participants with moderate or high PAS-II scores were also less likely to start consuming alcohol in comparison to those with low scores.
“Overall, these observations suggest that patients with RA are substantially less likely to use alcohol when their disease activity is high and their health and quality of life are poor,” the authors wrote. “This study also found that active drinking, recent discontinuation of drinking, and recent initiation of drinking were not associated with disease activity or death in this population when considering the reasons for the changes in behavior.”
They said this offered a different explanation for the previously observed association between alcohol use and lower disease activity by showing an effect of reverse causality rather than any biologically protective effect of alcohol.
While the study also found a strong link between discontinuation of alcohol use and increased subsequent mortality, they suggested this was also likely a function of disease activity and disability, rather than the effect of giving up alcohol.
The study was funded by grants to several authors from the Department of Veterans Affairs, the National Institutes of Health, and the Rheumatology Research Foundation. Dr. Baker reported receiving consulting fees from Bristol-Myers Squibb outside of the current work.
SOURCE: Baker J et al. Arthritis Care Res. 2019 Mar 20. doi: 10.1002/acr.23847.
, according to a study published online March 20 in Arthritis Care & Research.
Joshua F. Baker, MD, of the University of Pennsylvania, Philadelphia, and his coauthors wrote that previous studies had suggested a link between moderate alcohol consumption and lower disease activity, better quality of life, and better functional status in people with rheumatoid arthritis. This link may tempt clinicians “to encourage moderate alcohol consumption among patients with RA,” the researchers wrote, and so it prompted them to examine the relationship more closely.
The researchers studied 16,762 individuals with rheumatoid arthritis in the National Databank for Rheumatic Diseases who had been asked about alcohol use and disease activity in a series of semiannual surveys, providing a total of 121,280 observations, at which 53% reported using alcohol.
Across the observations taken from the semiannual surveys, a total of 8.2% reported discontinuing alcohol consumption from one survey to the next, and 8.4% of abstainers reported initiating alcohol use. Importantly, individuals with high disease activity had a significantly shorter time to discontinuation of alcohol, and those with a moderate or high Patient Activity Scale-II (PAS-II) score were 36% more likely to stop alcohol consumption, compared with individuals who had a low PAS-II score.
Individuals who were older or obese or had more comorbidities or greater work disability were all independently more likely to discontinue alcohol use, while those less likely to give up alcohol tended to be white, male, and have higher physical and mental quality of life, higher educational level, and greater household income.
Participants with moderate or high PAS-II scores were also less likely to start consuming alcohol in comparison to those with low scores.
“Overall, these observations suggest that patients with RA are substantially less likely to use alcohol when their disease activity is high and their health and quality of life are poor,” the authors wrote. “This study also found that active drinking, recent discontinuation of drinking, and recent initiation of drinking were not associated with disease activity or death in this population when considering the reasons for the changes in behavior.”
They said this offered a different explanation for the previously observed association between alcohol use and lower disease activity by showing an effect of reverse causality rather than any biologically protective effect of alcohol.
While the study also found a strong link between discontinuation of alcohol use and increased subsequent mortality, they suggested this was also likely a function of disease activity and disability, rather than the effect of giving up alcohol.
The study was funded by grants to several authors from the Department of Veterans Affairs, the National Institutes of Health, and the Rheumatology Research Foundation. Dr. Baker reported receiving consulting fees from Bristol-Myers Squibb outside of the current work.
SOURCE: Baker J et al. Arthritis Care Res. 2019 Mar 20. doi: 10.1002/acr.23847.
, according to a study published online March 20 in Arthritis Care & Research.
Joshua F. Baker, MD, of the University of Pennsylvania, Philadelphia, and his coauthors wrote that previous studies had suggested a link between moderate alcohol consumption and lower disease activity, better quality of life, and better functional status in people with rheumatoid arthritis. This link may tempt clinicians “to encourage moderate alcohol consumption among patients with RA,” the researchers wrote, and so it prompted them to examine the relationship more closely.
The researchers studied 16,762 individuals with rheumatoid arthritis in the National Databank for Rheumatic Diseases who had been asked about alcohol use and disease activity in a series of semiannual surveys, providing a total of 121,280 observations, at which 53% reported using alcohol.
Across the observations taken from the semiannual surveys, a total of 8.2% reported discontinuing alcohol consumption from one survey to the next, and 8.4% of abstainers reported initiating alcohol use. Importantly, individuals with high disease activity had a significantly shorter time to discontinuation of alcohol, and those with a moderate or high Patient Activity Scale-II (PAS-II) score were 36% more likely to stop alcohol consumption, compared with individuals who had a low PAS-II score.
Individuals who were older or obese or had more comorbidities or greater work disability were all independently more likely to discontinue alcohol use, while those less likely to give up alcohol tended to be white, male, and have higher physical and mental quality of life, higher educational level, and greater household income.
Participants with moderate or high PAS-II scores were also less likely to start consuming alcohol in comparison to those with low scores.
“Overall, these observations suggest that patients with RA are substantially less likely to use alcohol when their disease activity is high and their health and quality of life are poor,” the authors wrote. “This study also found that active drinking, recent discontinuation of drinking, and recent initiation of drinking were not associated with disease activity or death in this population when considering the reasons for the changes in behavior.”
They said this offered a different explanation for the previously observed association between alcohol use and lower disease activity by showing an effect of reverse causality rather than any biologically protective effect of alcohol.
While the study also found a strong link between discontinuation of alcohol use and increased subsequent mortality, they suggested this was also likely a function of disease activity and disability, rather than the effect of giving up alcohol.
The study was funded by grants to several authors from the Department of Veterans Affairs, the National Institutes of Health, and the Rheumatology Research Foundation. Dr. Baker reported receiving consulting fees from Bristol-Myers Squibb outside of the current work.
SOURCE: Baker J et al. Arthritis Care Res. 2019 Mar 20. doi: 10.1002/acr.23847.
FROM ARTHRITIS CARE & RESEARCH
Disease burden in OA worse than RA 6 months post presentation
Patients with osteoarthritis (OA) have RAPID3 scores at their initial visit (16.0) similar to patients with rheumatoid arthritis (RA) and either prior use of disease-modifying antirheumatic drugs (DMARDs) or no exposure to DMARDs (15.6 and 15.5, respectively). After 6 months of treatment, the RAPID3 (Routine Assessment of Patient Index Data 3) score fell by just 1.7 points for patients with OA, compared with 5.7 points in RA patients naive to DMARDs and 4.3 points in those with prior DMARD exposure. These findings were published March 20 in Arthritis & Rheumatology (doi: 10.1002/art.40869).
We reported this story at the 2018 World Congress on Osteoarthritis before it was published in the journal. Read the story at the link above.
Patients with osteoarthritis (OA) have RAPID3 scores at their initial visit (16.0) similar to patients with rheumatoid arthritis (RA) and either prior use of disease-modifying antirheumatic drugs (DMARDs) or no exposure to DMARDs (15.6 and 15.5, respectively). After 6 months of treatment, the RAPID3 (Routine Assessment of Patient Index Data 3) score fell by just 1.7 points for patients with OA, compared with 5.7 points in RA patients naive to DMARDs and 4.3 points in those with prior DMARD exposure. These findings were published March 20 in Arthritis & Rheumatology (doi: 10.1002/art.40869).
We reported this story at the 2018 World Congress on Osteoarthritis before it was published in the journal. Read the story at the link above.
Patients with osteoarthritis (OA) have RAPID3 scores at their initial visit (16.0) similar to patients with rheumatoid arthritis (RA) and either prior use of disease-modifying antirheumatic drugs (DMARDs) or no exposure to DMARDs (15.6 and 15.5, respectively). After 6 months of treatment, the RAPID3 (Routine Assessment of Patient Index Data 3) score fell by just 1.7 points for patients with OA, compared with 5.7 points in RA patients naive to DMARDs and 4.3 points in those with prior DMARD exposure. These findings were published March 20 in Arthritis & Rheumatology (doi: 10.1002/art.40869).
We reported this story at the 2018 World Congress on Osteoarthritis before it was published in the journal. Read the story at the link above.
FROM ARTHRITIS & RHEUMATOLOGY
Patients at risk of RA may already have abnormal aortic stiffness
according to a study of potential RA patients who underwent cardiac MRI.
“To our knowledge, this is the first study showing subclinical increase in aortic stiffness in at-risk individuals for RA, with values numerically close to those seen in early, treatment-naive RA,” wrote Graham Fent, MBChB, of the University of Leeds (England) and his associates. The study was published in Annals of the Rheumatic Diseases.
Hypothesizing that patients with no systemic inflammation but circulating anti–cyclic citrullinated peptide (CCP) antibodies may already have cardiovascular concerns, Dr. Fent and his colleagues recruited 18 individuals at risk of developing RA and 30 healthy controls. The groups were matched for age and gender and then underwent multiparametric 3.0 Tesla cardiac MRI with late gadolinium enhancement. The at-risk individuals were classified as being at either low (n = 10) or high (n = 8) risk of RA. Over 12 months, five of the at-risk patients progressed to RA.
According to the cardiac MRI findings, aortic distensibility was lower – and thus arterial stiffness was greater – in the at-risk group (3.6 x 10–3 per mm Hg) versus the healthy controls (4.9 x 10–3 per mm Hg). The difference was even more distinct in the high-risk group (3.1 x 10–3 per mm Hg), compared with the low-risk group (4.2 x 10–3 per mm Hg). The group who eventually progressed to RA also showed lower levels of distensibility (3.2 x 10–3 per mm Hg).
The coauthors acknowledged that the major limitation of their study was a lack of control groups. However, they noted that such a pronounced level of aortic stiffness in the high-risk and RA groups should be seen as “implying a particular role of CCP antibodies.”
The study was supported by the U.K. National Institute for Health Research. One author reported being funded by a National Institute for Health Research grant; another reported being funded by a British Heart Foundation Personal Chair.
SOURCE: Fent G et al. Ann Rheum Dis. 2019 Mar 9. doi: 10.1136/annrheumdis-2018-214975.
according to a study of potential RA patients who underwent cardiac MRI.
“To our knowledge, this is the first study showing subclinical increase in aortic stiffness in at-risk individuals for RA, with values numerically close to those seen in early, treatment-naive RA,” wrote Graham Fent, MBChB, of the University of Leeds (England) and his associates. The study was published in Annals of the Rheumatic Diseases.
Hypothesizing that patients with no systemic inflammation but circulating anti–cyclic citrullinated peptide (CCP) antibodies may already have cardiovascular concerns, Dr. Fent and his colleagues recruited 18 individuals at risk of developing RA and 30 healthy controls. The groups were matched for age and gender and then underwent multiparametric 3.0 Tesla cardiac MRI with late gadolinium enhancement. The at-risk individuals were classified as being at either low (n = 10) or high (n = 8) risk of RA. Over 12 months, five of the at-risk patients progressed to RA.
According to the cardiac MRI findings, aortic distensibility was lower – and thus arterial stiffness was greater – in the at-risk group (3.6 x 10–3 per mm Hg) versus the healthy controls (4.9 x 10–3 per mm Hg). The difference was even more distinct in the high-risk group (3.1 x 10–3 per mm Hg), compared with the low-risk group (4.2 x 10–3 per mm Hg). The group who eventually progressed to RA also showed lower levels of distensibility (3.2 x 10–3 per mm Hg).
The coauthors acknowledged that the major limitation of their study was a lack of control groups. However, they noted that such a pronounced level of aortic stiffness in the high-risk and RA groups should be seen as “implying a particular role of CCP antibodies.”
The study was supported by the U.K. National Institute for Health Research. One author reported being funded by a National Institute for Health Research grant; another reported being funded by a British Heart Foundation Personal Chair.
SOURCE: Fent G et al. Ann Rheum Dis. 2019 Mar 9. doi: 10.1136/annrheumdis-2018-214975.
according to a study of potential RA patients who underwent cardiac MRI.
“To our knowledge, this is the first study showing subclinical increase in aortic stiffness in at-risk individuals for RA, with values numerically close to those seen in early, treatment-naive RA,” wrote Graham Fent, MBChB, of the University of Leeds (England) and his associates. The study was published in Annals of the Rheumatic Diseases.
Hypothesizing that patients with no systemic inflammation but circulating anti–cyclic citrullinated peptide (CCP) antibodies may already have cardiovascular concerns, Dr. Fent and his colleagues recruited 18 individuals at risk of developing RA and 30 healthy controls. The groups were matched for age and gender and then underwent multiparametric 3.0 Tesla cardiac MRI with late gadolinium enhancement. The at-risk individuals were classified as being at either low (n = 10) or high (n = 8) risk of RA. Over 12 months, five of the at-risk patients progressed to RA.
According to the cardiac MRI findings, aortic distensibility was lower – and thus arterial stiffness was greater – in the at-risk group (3.6 x 10–3 per mm Hg) versus the healthy controls (4.9 x 10–3 per mm Hg). The difference was even more distinct in the high-risk group (3.1 x 10–3 per mm Hg), compared with the low-risk group (4.2 x 10–3 per mm Hg). The group who eventually progressed to RA also showed lower levels of distensibility (3.2 x 10–3 per mm Hg).
The coauthors acknowledged that the major limitation of their study was a lack of control groups. However, they noted that such a pronounced level of aortic stiffness in the high-risk and RA groups should be seen as “implying a particular role of CCP antibodies.”
The study was supported by the U.K. National Institute for Health Research. One author reported being funded by a National Institute for Health Research grant; another reported being funded by a British Heart Foundation Personal Chair.
SOURCE: Fent G et al. Ann Rheum Dis. 2019 Mar 9. doi: 10.1136/annrheumdis-2018-214975.
FROM ANNALS OF THE RHEUMATIC DISEASES
Novel RA strategy: Target first-line biologics for likely methotrexate nonresponders
MAUI, HAWAII – An ongoing proof-of-concept study in the United Kingdom uses T-cell subset analysis to identify those patients with early rheumatoid arthritis who are unlikely to experience remission with methotrexate alone and therefore warrant more potent first-line therapy with a tumor necrosis factor (TNF) inhibitor in combination with methotrexate, Paul Emery, MD, said at the 2019 Rheumatology Winter Clinical Symposium.
“When we get the readout from this study, if we get the results we expect, we could actually put it to the National Health Service that it would be cost saving to use biologics as first-line therapy in a proportion, which will be about 40% of patients. But we won’t necessarily need to use them for a year, and we’ll get a 70%-plus remission rate, which I think is the sort of level we should be asking for in our patients,” according to Dr. Emery, professor of rheumatology and director of the University of Leeds (England) Musculoskeletal Biomedical Research Center.
This proof-of-concept study capitalizes on earlier work by Dr. Emery and coinvestigators, who showed in 70 patients with early rheumatoid arthritis given methotrexate as their first-ever disease-modifying antirheumatic drug (DMARD) that those with a normal pretreatment frequency of naive CD4+ T cells had an 83% remission rate at 6 months as defined by a Disease Activity Score in 28 joints (DAS28) of less than 2.6. In contrast, only 21% of those with a reduced naive CD4+ T-cell frequency experienced remission when compared with healthy controls. In an analysis adjusted for age and the presence of anti–citrullinated protein antibodies (ACPA), a normal baseline naive CD4+ T-cell frequency was associated with a 5.9-fold increased likelihood of remission on methotrexate (Ann Rheum Dis. 2014 Nov;73[11]:2047-53).
In the new proof-of-concept study, DMARD-naive, ACPA-positive patients with early RA undergo T-cell subset quantification by flow cytometry. Thirty patients with a normal test result are assigned to methotrexate with treat-to-target dose escalation. Based upon the investigators’ earlier work, it’s anticipated that about 80% of these patients will be in remission at 6 months.
Sixty patients with an abnormal baseline T-cell test result are being randomized to methotrexate plus either placebo or biosimilar etanercept. Again based upon the earlier study, the expected remission rate at 6 months in the methotrexate-plus-placebo group is about 20%. In contrast, the anticipated remission rate in the patients on an anti-TNF biologic plus methotrexate as first-line therapy is about 70% on the basis of the results of previous clinical trials, including PRIZE (N Engl J Med. 2014 Nov 6;371[19]:1781-92) and COMET (Ann Rheum Dis. 2012 Jun;71[6]:989-92).
Meanwhile, the price tag for biosimilar TNF inhibitors in the United Kingdom has come down to the point that routine across-the-board use of biologics as first-line therapy is arguably cost effective, a situation Dr. Emery described as hitherto “the unthinkable.”
The cost of biosimilar adalimumab in the coming year will be less than $3,000 annually in the U.K. health care system. So if 100 patients with early RA and no contraindication to biologic therapy are placed on biosimilar adalimumab and methotrexate for 1 year, the total cost for the biologic in this cohort will be less than $300,000, and roughly 70 of the 100 patients will have achieved remission. This approach makes much more sense than current standard practice, which is to reserve biologics as second-line therapy for patients who have failed to achieve remission on nonbiologic DMARDs, thereby allowing their joint damage to advance in the interim to the point that they need to stay on biologic therapy for decades, the rheumatologist argued.
“Once one accepts that remission has become the aim of therapy, then the facts, I think, speak for themselves: There’s absolutely no doubt that the rate of remission is best with the first DMARD. So if our aim is remission, we should use that one opportunity with the best agent first, because we’re not going to get the same response later,” Dr. Emery said.
Also, “there’s no doubt” that the dose of biologics can be halved with no loss of efficacy in patients who achieve remission on full-dose therapy, as previously demonstrated in PRIZE and other trials. This strategy further reduces the overall cost of biologic therapy, he added.
Dr. Emery, who recently received the Order of the British Empire from Queen Elizabeth personally in recognition of his career achievements in rheumatology, reported having no financial conflicts of interest regarding his presentation.
MAUI, HAWAII – An ongoing proof-of-concept study in the United Kingdom uses T-cell subset analysis to identify those patients with early rheumatoid arthritis who are unlikely to experience remission with methotrexate alone and therefore warrant more potent first-line therapy with a tumor necrosis factor (TNF) inhibitor in combination with methotrexate, Paul Emery, MD, said at the 2019 Rheumatology Winter Clinical Symposium.
“When we get the readout from this study, if we get the results we expect, we could actually put it to the National Health Service that it would be cost saving to use biologics as first-line therapy in a proportion, which will be about 40% of patients. But we won’t necessarily need to use them for a year, and we’ll get a 70%-plus remission rate, which I think is the sort of level we should be asking for in our patients,” according to Dr. Emery, professor of rheumatology and director of the University of Leeds (England) Musculoskeletal Biomedical Research Center.
This proof-of-concept study capitalizes on earlier work by Dr. Emery and coinvestigators, who showed in 70 patients with early rheumatoid arthritis given methotrexate as their first-ever disease-modifying antirheumatic drug (DMARD) that those with a normal pretreatment frequency of naive CD4+ T cells had an 83% remission rate at 6 months as defined by a Disease Activity Score in 28 joints (DAS28) of less than 2.6. In contrast, only 21% of those with a reduced naive CD4+ T-cell frequency experienced remission when compared with healthy controls. In an analysis adjusted for age and the presence of anti–citrullinated protein antibodies (ACPA), a normal baseline naive CD4+ T-cell frequency was associated with a 5.9-fold increased likelihood of remission on methotrexate (Ann Rheum Dis. 2014 Nov;73[11]:2047-53).
In the new proof-of-concept study, DMARD-naive, ACPA-positive patients with early RA undergo T-cell subset quantification by flow cytometry. Thirty patients with a normal test result are assigned to methotrexate with treat-to-target dose escalation. Based upon the investigators’ earlier work, it’s anticipated that about 80% of these patients will be in remission at 6 months.
Sixty patients with an abnormal baseline T-cell test result are being randomized to methotrexate plus either placebo or biosimilar etanercept. Again based upon the earlier study, the expected remission rate at 6 months in the methotrexate-plus-placebo group is about 20%. In contrast, the anticipated remission rate in the patients on an anti-TNF biologic plus methotrexate as first-line therapy is about 70% on the basis of the results of previous clinical trials, including PRIZE (N Engl J Med. 2014 Nov 6;371[19]:1781-92) and COMET (Ann Rheum Dis. 2012 Jun;71[6]:989-92).
Meanwhile, the price tag for biosimilar TNF inhibitors in the United Kingdom has come down to the point that routine across-the-board use of biologics as first-line therapy is arguably cost effective, a situation Dr. Emery described as hitherto “the unthinkable.”
The cost of biosimilar adalimumab in the coming year will be less than $3,000 annually in the U.K. health care system. So if 100 patients with early RA and no contraindication to biologic therapy are placed on biosimilar adalimumab and methotrexate for 1 year, the total cost for the biologic in this cohort will be less than $300,000, and roughly 70 of the 100 patients will have achieved remission. This approach makes much more sense than current standard practice, which is to reserve biologics as second-line therapy for patients who have failed to achieve remission on nonbiologic DMARDs, thereby allowing their joint damage to advance in the interim to the point that they need to stay on biologic therapy for decades, the rheumatologist argued.
“Once one accepts that remission has become the aim of therapy, then the facts, I think, speak for themselves: There’s absolutely no doubt that the rate of remission is best with the first DMARD. So if our aim is remission, we should use that one opportunity with the best agent first, because we’re not going to get the same response later,” Dr. Emery said.
Also, “there’s no doubt” that the dose of biologics can be halved with no loss of efficacy in patients who achieve remission on full-dose therapy, as previously demonstrated in PRIZE and other trials. This strategy further reduces the overall cost of biologic therapy, he added.
Dr. Emery, who recently received the Order of the British Empire from Queen Elizabeth personally in recognition of his career achievements in rheumatology, reported having no financial conflicts of interest regarding his presentation.
MAUI, HAWAII – An ongoing proof-of-concept study in the United Kingdom uses T-cell subset analysis to identify those patients with early rheumatoid arthritis who are unlikely to experience remission with methotrexate alone and therefore warrant more potent first-line therapy with a tumor necrosis factor (TNF) inhibitor in combination with methotrexate, Paul Emery, MD, said at the 2019 Rheumatology Winter Clinical Symposium.
“When we get the readout from this study, if we get the results we expect, we could actually put it to the National Health Service that it would be cost saving to use biologics as first-line therapy in a proportion, which will be about 40% of patients. But we won’t necessarily need to use them for a year, and we’ll get a 70%-plus remission rate, which I think is the sort of level we should be asking for in our patients,” according to Dr. Emery, professor of rheumatology and director of the University of Leeds (England) Musculoskeletal Biomedical Research Center.
This proof-of-concept study capitalizes on earlier work by Dr. Emery and coinvestigators, who showed in 70 patients with early rheumatoid arthritis given methotrexate as their first-ever disease-modifying antirheumatic drug (DMARD) that those with a normal pretreatment frequency of naive CD4+ T cells had an 83% remission rate at 6 months as defined by a Disease Activity Score in 28 joints (DAS28) of less than 2.6. In contrast, only 21% of those with a reduced naive CD4+ T-cell frequency experienced remission when compared with healthy controls. In an analysis adjusted for age and the presence of anti–citrullinated protein antibodies (ACPA), a normal baseline naive CD4+ T-cell frequency was associated with a 5.9-fold increased likelihood of remission on methotrexate (Ann Rheum Dis. 2014 Nov;73[11]:2047-53).
In the new proof-of-concept study, DMARD-naive, ACPA-positive patients with early RA undergo T-cell subset quantification by flow cytometry. Thirty patients with a normal test result are assigned to methotrexate with treat-to-target dose escalation. Based upon the investigators’ earlier work, it’s anticipated that about 80% of these patients will be in remission at 6 months.
Sixty patients with an abnormal baseline T-cell test result are being randomized to methotrexate plus either placebo or biosimilar etanercept. Again based upon the earlier study, the expected remission rate at 6 months in the methotrexate-plus-placebo group is about 20%. In contrast, the anticipated remission rate in the patients on an anti-TNF biologic plus methotrexate as first-line therapy is about 70% on the basis of the results of previous clinical trials, including PRIZE (N Engl J Med. 2014 Nov 6;371[19]:1781-92) and COMET (Ann Rheum Dis. 2012 Jun;71[6]:989-92).
Meanwhile, the price tag for biosimilar TNF inhibitors in the United Kingdom has come down to the point that routine across-the-board use of biologics as first-line therapy is arguably cost effective, a situation Dr. Emery described as hitherto “the unthinkable.”
The cost of biosimilar adalimumab in the coming year will be less than $3,000 annually in the U.K. health care system. So if 100 patients with early RA and no contraindication to biologic therapy are placed on biosimilar adalimumab and methotrexate for 1 year, the total cost for the biologic in this cohort will be less than $300,000, and roughly 70 of the 100 patients will have achieved remission. This approach makes much more sense than current standard practice, which is to reserve biologics as second-line therapy for patients who have failed to achieve remission on nonbiologic DMARDs, thereby allowing their joint damage to advance in the interim to the point that they need to stay on biologic therapy for decades, the rheumatologist argued.
“Once one accepts that remission has become the aim of therapy, then the facts, I think, speak for themselves: There’s absolutely no doubt that the rate of remission is best with the first DMARD. So if our aim is remission, we should use that one opportunity with the best agent first, because we’re not going to get the same response later,” Dr. Emery said.
Also, “there’s no doubt” that the dose of biologics can be halved with no loss of efficacy in patients who achieve remission on full-dose therapy, as previously demonstrated in PRIZE and other trials. This strategy further reduces the overall cost of biologic therapy, he added.
Dr. Emery, who recently received the Order of the British Empire from Queen Elizabeth personally in recognition of his career achievements in rheumatology, reported having no financial conflicts of interest regarding his presentation.
REPORTING FROM RWCS 2019