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Intramuscular steroid injection reduced hip OA pain up to 12 weeks
Systemic treatment with an intramuscular glucocorticoid injection is effective, compared with placebo, in reducing pain in people with hip osteoarthritis for up to 12 weeks, a double-blinded, placebo-controlled, randomized trial suggests.
However, the study found benefit with intramuscular (IM) glucocorticoid injection at 2 weeks only when patients were at rest, and did not find any significant benefit with the injection in reducing pain while walking or in reducing Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain subscale scores. The report was published in Annals of the Rheumatic Diseases.
The multicenter, double-blinded, superiority trial randomized 106 patients with painful hip OA who were not responding to oral analgesics to either 40 mg triamcinolone acetate (n = 52) or placebo injection (n = 54) into the gluteus muscle. Overall, 73 patients (68%) were women, and the average age of the cohort was 64 years. Hip OA symptoms had occurred for at least 1 year in 70% of the patients.
The study’s three primary outcomes of hip pain severity 2 weeks after the injection on a 0-10 scale at rest and during walking and on the WOMAC pain subscale revealed inconsistent results with the treatment.
At the 2-week follow-up, patients who had received the IM glucocorticoid injection had a significant and clinically relevant difference in hip pain at rest (between-group difference = –1.3; 95% confidence interval, –2.3 to –0.3; P = .01). But at this time point there were no significant associations between glucocorticoid injection and hip pain during walking (difference = –0.9; 95% CI, –1.9 to 0.1; P = .07) and WOMAC pain subscale score (difference = –6.1; 95% CI, –13.4 to 1.2; P = .10), the researchers reported.
At 2-week follow-up, recipients of the glucocorticoid injection were significantly more likely to perceive improvement (relative risk = 1.7; 95% CI, 1.1 to 2.7; P = .02) or achieve OMERACT-OARSI level of response (RR = 2.0; 95% CI, 1.1 to 3.6; P = .03).
The authors described this finding as “surprising,” speculating that the 7-point Likert scale used to measure perceived improvement could have resulted in less power.
Nineteen patients in the glucocorticoid group reported 27 nonserious adverse events, compared with 13 patients in the placebo group who reported 18 adverse events.
The authors said the greatest effects of the glucocorticoid injection were seen at 4- to 12-week follow-up (the secondary outcomes of the study), instead of at the 2-week follow-up. For example, at 4-week follow-up, the glucocorticoid injection was associated with a significant hip pain reduction at rest (between-group difference = –1.2; 95% CI, –2.1 to –0.2; P = .01) and during walking (difference = –1.1; 95% CI, –2.0 to –0.2; P = .01). At 6 weeks, the corresponding figures for hip pain reduction were –1.4 at rest (95% CI, –2.4 to –0.5; P = .005) and –1.4 while walking (95% CI, –2.3 to –0.4; P = .004). The between-group differences were still significant at 12 weeks while at rest (difference = –1.2; 95% CI, –2.3 to –0.2; P = .02) and during walking (difference = –1.3; 95% CI, –2.2 to –0.3; P = .01).
Significant differences in favor of the glucocorticoid injection overall occurred on the WOMAC subscale scores for pain, function, and stiffness, as well as total Hip disability and Osteoarthritis Outcome Score for pain and total, intermittent, and constant pain measures on the Intermittent and Constant Osteoarthritis Pain scale. At 12 weeks, the between-group difference on the WOMAC total score was –9.4 (95% CI, –17.8 to –0.9; P = .03).
The researchers said it was surprising that hip pain reduction after IM glucocorticoid injection was still present at a similar degree at 12 weeks since previous studies had shown the effect usually peaked after 1-3 weeks.
“Our findings should be replicated in future research,” they said.
“An IM glucocorticoid injection showed effectiveness in patients with hip OA on one of the three primary outcomes at a 2 weeks post injection ... The effect is probably clinically relevant,” the authors concluded.
The investigators noted that in clinical practice patients are sometimes offered multiple injections per year, whereas in the current study patients received only one injection. There has also been concern that intra-articular glucocorticoid injections could cause toxicity to chondrocytes and potentially lead to OA progression, but the effect of a single IM injection is unknown.
Financial support for the study came from the Dutch Arthritis Foundation and the NutsOhra fund. Two of the authors reported receiving grants from several pharmaceutical companies, research consortia, and foundations.
SOURCE: Dorleijn D et al. Ann Rheum Dis. 2018 March 7. doi: 10.1136/annrheumdis-2017-212628
Systemic treatment with an intramuscular glucocorticoid injection is effective, compared with placebo, in reducing pain in people with hip osteoarthritis for up to 12 weeks, a double-blinded, placebo-controlled, randomized trial suggests.
However, the study found benefit with intramuscular (IM) glucocorticoid injection at 2 weeks only when patients were at rest, and did not find any significant benefit with the injection in reducing pain while walking or in reducing Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain subscale scores. The report was published in Annals of the Rheumatic Diseases.
The multicenter, double-blinded, superiority trial randomized 106 patients with painful hip OA who were not responding to oral analgesics to either 40 mg triamcinolone acetate (n = 52) or placebo injection (n = 54) into the gluteus muscle. Overall, 73 patients (68%) were women, and the average age of the cohort was 64 years. Hip OA symptoms had occurred for at least 1 year in 70% of the patients.
The study’s three primary outcomes of hip pain severity 2 weeks after the injection on a 0-10 scale at rest and during walking and on the WOMAC pain subscale revealed inconsistent results with the treatment.
At the 2-week follow-up, patients who had received the IM glucocorticoid injection had a significant and clinically relevant difference in hip pain at rest (between-group difference = –1.3; 95% confidence interval, –2.3 to –0.3; P = .01). But at this time point there were no significant associations between glucocorticoid injection and hip pain during walking (difference = –0.9; 95% CI, –1.9 to 0.1; P = .07) and WOMAC pain subscale score (difference = –6.1; 95% CI, –13.4 to 1.2; P = .10), the researchers reported.
At 2-week follow-up, recipients of the glucocorticoid injection were significantly more likely to perceive improvement (relative risk = 1.7; 95% CI, 1.1 to 2.7; P = .02) or achieve OMERACT-OARSI level of response (RR = 2.0; 95% CI, 1.1 to 3.6; P = .03).
The authors described this finding as “surprising,” speculating that the 7-point Likert scale used to measure perceived improvement could have resulted in less power.
Nineteen patients in the glucocorticoid group reported 27 nonserious adverse events, compared with 13 patients in the placebo group who reported 18 adverse events.
The authors said the greatest effects of the glucocorticoid injection were seen at 4- to 12-week follow-up (the secondary outcomes of the study), instead of at the 2-week follow-up. For example, at 4-week follow-up, the glucocorticoid injection was associated with a significant hip pain reduction at rest (between-group difference = –1.2; 95% CI, –2.1 to –0.2; P = .01) and during walking (difference = –1.1; 95% CI, –2.0 to –0.2; P = .01). At 6 weeks, the corresponding figures for hip pain reduction were –1.4 at rest (95% CI, –2.4 to –0.5; P = .005) and –1.4 while walking (95% CI, –2.3 to –0.4; P = .004). The between-group differences were still significant at 12 weeks while at rest (difference = –1.2; 95% CI, –2.3 to –0.2; P = .02) and during walking (difference = –1.3; 95% CI, –2.2 to –0.3; P = .01).
Significant differences in favor of the glucocorticoid injection overall occurred on the WOMAC subscale scores for pain, function, and stiffness, as well as total Hip disability and Osteoarthritis Outcome Score for pain and total, intermittent, and constant pain measures on the Intermittent and Constant Osteoarthritis Pain scale. At 12 weeks, the between-group difference on the WOMAC total score was –9.4 (95% CI, –17.8 to –0.9; P = .03).
The researchers said it was surprising that hip pain reduction after IM glucocorticoid injection was still present at a similar degree at 12 weeks since previous studies had shown the effect usually peaked after 1-3 weeks.
“Our findings should be replicated in future research,” they said.
“An IM glucocorticoid injection showed effectiveness in patients with hip OA on one of the three primary outcomes at a 2 weeks post injection ... The effect is probably clinically relevant,” the authors concluded.
The investigators noted that in clinical practice patients are sometimes offered multiple injections per year, whereas in the current study patients received only one injection. There has also been concern that intra-articular glucocorticoid injections could cause toxicity to chondrocytes and potentially lead to OA progression, but the effect of a single IM injection is unknown.
Financial support for the study came from the Dutch Arthritis Foundation and the NutsOhra fund. Two of the authors reported receiving grants from several pharmaceutical companies, research consortia, and foundations.
SOURCE: Dorleijn D et al. Ann Rheum Dis. 2018 March 7. doi: 10.1136/annrheumdis-2017-212628
Systemic treatment with an intramuscular glucocorticoid injection is effective, compared with placebo, in reducing pain in people with hip osteoarthritis for up to 12 weeks, a double-blinded, placebo-controlled, randomized trial suggests.
However, the study found benefit with intramuscular (IM) glucocorticoid injection at 2 weeks only when patients were at rest, and did not find any significant benefit with the injection in reducing pain while walking or in reducing Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain subscale scores. The report was published in Annals of the Rheumatic Diseases.
The multicenter, double-blinded, superiority trial randomized 106 patients with painful hip OA who were not responding to oral analgesics to either 40 mg triamcinolone acetate (n = 52) or placebo injection (n = 54) into the gluteus muscle. Overall, 73 patients (68%) were women, and the average age of the cohort was 64 years. Hip OA symptoms had occurred for at least 1 year in 70% of the patients.
The study’s three primary outcomes of hip pain severity 2 weeks after the injection on a 0-10 scale at rest and during walking and on the WOMAC pain subscale revealed inconsistent results with the treatment.
At the 2-week follow-up, patients who had received the IM glucocorticoid injection had a significant and clinically relevant difference in hip pain at rest (between-group difference = –1.3; 95% confidence interval, –2.3 to –0.3; P = .01). But at this time point there were no significant associations between glucocorticoid injection and hip pain during walking (difference = –0.9; 95% CI, –1.9 to 0.1; P = .07) and WOMAC pain subscale score (difference = –6.1; 95% CI, –13.4 to 1.2; P = .10), the researchers reported.
At 2-week follow-up, recipients of the glucocorticoid injection were significantly more likely to perceive improvement (relative risk = 1.7; 95% CI, 1.1 to 2.7; P = .02) or achieve OMERACT-OARSI level of response (RR = 2.0; 95% CI, 1.1 to 3.6; P = .03).
The authors described this finding as “surprising,” speculating that the 7-point Likert scale used to measure perceived improvement could have resulted in less power.
Nineteen patients in the glucocorticoid group reported 27 nonserious adverse events, compared with 13 patients in the placebo group who reported 18 adverse events.
The authors said the greatest effects of the glucocorticoid injection were seen at 4- to 12-week follow-up (the secondary outcomes of the study), instead of at the 2-week follow-up. For example, at 4-week follow-up, the glucocorticoid injection was associated with a significant hip pain reduction at rest (between-group difference = –1.2; 95% CI, –2.1 to –0.2; P = .01) and during walking (difference = –1.1; 95% CI, –2.0 to –0.2; P = .01). At 6 weeks, the corresponding figures for hip pain reduction were –1.4 at rest (95% CI, –2.4 to –0.5; P = .005) and –1.4 while walking (95% CI, –2.3 to –0.4; P = .004). The between-group differences were still significant at 12 weeks while at rest (difference = –1.2; 95% CI, –2.3 to –0.2; P = .02) and during walking (difference = –1.3; 95% CI, –2.2 to –0.3; P = .01).
Significant differences in favor of the glucocorticoid injection overall occurred on the WOMAC subscale scores for pain, function, and stiffness, as well as total Hip disability and Osteoarthritis Outcome Score for pain and total, intermittent, and constant pain measures on the Intermittent and Constant Osteoarthritis Pain scale. At 12 weeks, the between-group difference on the WOMAC total score was –9.4 (95% CI, –17.8 to –0.9; P = .03).
The researchers said it was surprising that hip pain reduction after IM glucocorticoid injection was still present at a similar degree at 12 weeks since previous studies had shown the effect usually peaked after 1-3 weeks.
“Our findings should be replicated in future research,” they said.
“An IM glucocorticoid injection showed effectiveness in patients with hip OA on one of the three primary outcomes at a 2 weeks post injection ... The effect is probably clinically relevant,” the authors concluded.
The investigators noted that in clinical practice patients are sometimes offered multiple injections per year, whereas in the current study patients received only one injection. There has also been concern that intra-articular glucocorticoid injections could cause toxicity to chondrocytes and potentially lead to OA progression, but the effect of a single IM injection is unknown.
Financial support for the study came from the Dutch Arthritis Foundation and the NutsOhra fund. Two of the authors reported receiving grants from several pharmaceutical companies, research consortia, and foundations.
SOURCE: Dorleijn D et al. Ann Rheum Dis. 2018 March 7. doi: 10.1136/annrheumdis-2017-212628
FROM ANNALS OF THE RHEUMATIC DISEASES
Key clinical point:
Major finding: At 2 weeks, patients who had received the intramuscular glucocorticoid injection had a significant and clinically relevant difference in hip pain at rest (between-group difference = –1.3; 95% CI, –2.3 to –0.3; P = .01).
Study details: A 12-week, double blinded, placebo-controlled trial of 106 patients with hip OA randomized to 40 mg triamcinolone acetate or placebo injection.
Disclosures: Financial support for the study came from the Dutch Arthritis Foundation and the NutsOhra fund. Two of the authors reported receiving grants from several pharmaceutical companies, research consortia, and foundations.
Source: Dorleijn D et al. Ann Rheum Dis. 2018 Mar 7. doi: 10.1136/annrheumdis-2017-212628.
Gut bacteria could drive autoimmune response in genetically predisposed
Gut bacteria found in the small intestines could play a role in triggering an autoimmune response in genetically predisposed individuals, such as those with lupus, a research report suggests.
Recent studies have shown that gut commensals can reside within gastrointestinal-associated lymph tissues of healthy hosts, but it has been unclear whether pathobiont translocation was involved in systemic autoimmunity. Silvio Manfredo Vieira, PhD, and his colleagues at Yale University, New Haven, Conn., addressed this knowledge gap by studying the Gram-positive gut commensal Enterococcus gallinarum, which was identified in mesenteric lymph nodes, liver, and spleen cultures from genetically susceptible mouse models.
The researchers found that they could suppress the autoimmunity with antibiotics or an intramuscular vaccine targeted at E. gallinarum. The vaccine reduced levels of serum autoantibodies, prolonged survival in the mice, and also prevented translocation, as no growth of E. gallinarum was observed in internal organs.
“Pathobiont-specific treatment can abrogate host autoimmune processes without needing to suppress the immune system, which can lead to systemic adverse events in current clinical practice,” they wrote.
The researchers then tested for E. gallinarum translocation to human livers in patients with systemic lupus erythematosus (SLE) and autoimmune hepatitis (AIH) with serologic features of lupus, including antinuclear antibodies and anti-dsDNA immunoglobulin G antibodies.
Liver biopsies from three SLE patients were positive for E. gallinarum, whereas samples from four of six healthy liver transplant donors with normal liver histology tested positive for the presence of other Enterococcus species but not E. gallinarum.
“Consistent with enhanced adaptive immune responses to E. gallinarum, the majority of SLE and AIH patients also showed increased serum antibody titers against E. gallinarum and particularly its RNA,” they said.
The authors said their findings showed that E. gallinarum translocates into systemic organs as a result of the breakdown of the gut barrier in autoimmune-prone hosts to drive autoimmune pathogenesis. They suggested that the translocating bacteria skewed T helper cell differentiation but also acted directly on colonized tissues such as the liver to induce autoantigens, endogenous retrovirus proteins, cytokines, and other autoimmune-promoting factors.
“If the complexity of host-tissue microbiota interactions is considered in chronic autoimmunity, it may offer new therapeutic avenues for these debilitating and potentially lethal diseases,” they concluded.
The study was supported by grants from various institutes and initiatives within the National Institutes of Health as well as from the Arthritis National Research Foundation, the Arthritis Foundation, and the Lupus Research Institute. Dr. Vieira and the senior author, Martin A. Kriegel, MD, PhD, are inventors on a patent application filed by Yale University related to the use of antibiotics and commensal vaccination to treat autoimmunity.
SOURCE: Vieira S et al. Science. 2018;359(6380):1156-61.
Gut bacteria found in the small intestines could play a role in triggering an autoimmune response in genetically predisposed individuals, such as those with lupus, a research report suggests.
Recent studies have shown that gut commensals can reside within gastrointestinal-associated lymph tissues of healthy hosts, but it has been unclear whether pathobiont translocation was involved in systemic autoimmunity. Silvio Manfredo Vieira, PhD, and his colleagues at Yale University, New Haven, Conn., addressed this knowledge gap by studying the Gram-positive gut commensal Enterococcus gallinarum, which was identified in mesenteric lymph nodes, liver, and spleen cultures from genetically susceptible mouse models.
The researchers found that they could suppress the autoimmunity with antibiotics or an intramuscular vaccine targeted at E. gallinarum. The vaccine reduced levels of serum autoantibodies, prolonged survival in the mice, and also prevented translocation, as no growth of E. gallinarum was observed in internal organs.
“Pathobiont-specific treatment can abrogate host autoimmune processes without needing to suppress the immune system, which can lead to systemic adverse events in current clinical practice,” they wrote.
The researchers then tested for E. gallinarum translocation to human livers in patients with systemic lupus erythematosus (SLE) and autoimmune hepatitis (AIH) with serologic features of lupus, including antinuclear antibodies and anti-dsDNA immunoglobulin G antibodies.
Liver biopsies from three SLE patients were positive for E. gallinarum, whereas samples from four of six healthy liver transplant donors with normal liver histology tested positive for the presence of other Enterococcus species but not E. gallinarum.
“Consistent with enhanced adaptive immune responses to E. gallinarum, the majority of SLE and AIH patients also showed increased serum antibody titers against E. gallinarum and particularly its RNA,” they said.
The authors said their findings showed that E. gallinarum translocates into systemic organs as a result of the breakdown of the gut barrier in autoimmune-prone hosts to drive autoimmune pathogenesis. They suggested that the translocating bacteria skewed T helper cell differentiation but also acted directly on colonized tissues such as the liver to induce autoantigens, endogenous retrovirus proteins, cytokines, and other autoimmune-promoting factors.
“If the complexity of host-tissue microbiota interactions is considered in chronic autoimmunity, it may offer new therapeutic avenues for these debilitating and potentially lethal diseases,” they concluded.
The study was supported by grants from various institutes and initiatives within the National Institutes of Health as well as from the Arthritis National Research Foundation, the Arthritis Foundation, and the Lupus Research Institute. Dr. Vieira and the senior author, Martin A. Kriegel, MD, PhD, are inventors on a patent application filed by Yale University related to the use of antibiotics and commensal vaccination to treat autoimmunity.
SOURCE: Vieira S et al. Science. 2018;359(6380):1156-61.
Gut bacteria found in the small intestines could play a role in triggering an autoimmune response in genetically predisposed individuals, such as those with lupus, a research report suggests.
Recent studies have shown that gut commensals can reside within gastrointestinal-associated lymph tissues of healthy hosts, but it has been unclear whether pathobiont translocation was involved in systemic autoimmunity. Silvio Manfredo Vieira, PhD, and his colleagues at Yale University, New Haven, Conn., addressed this knowledge gap by studying the Gram-positive gut commensal Enterococcus gallinarum, which was identified in mesenteric lymph nodes, liver, and spleen cultures from genetically susceptible mouse models.
The researchers found that they could suppress the autoimmunity with antibiotics or an intramuscular vaccine targeted at E. gallinarum. The vaccine reduced levels of serum autoantibodies, prolonged survival in the mice, and also prevented translocation, as no growth of E. gallinarum was observed in internal organs.
“Pathobiont-specific treatment can abrogate host autoimmune processes without needing to suppress the immune system, which can lead to systemic adverse events in current clinical practice,” they wrote.
The researchers then tested for E. gallinarum translocation to human livers in patients with systemic lupus erythematosus (SLE) and autoimmune hepatitis (AIH) with serologic features of lupus, including antinuclear antibodies and anti-dsDNA immunoglobulin G antibodies.
Liver biopsies from three SLE patients were positive for E. gallinarum, whereas samples from four of six healthy liver transplant donors with normal liver histology tested positive for the presence of other Enterococcus species but not E. gallinarum.
“Consistent with enhanced adaptive immune responses to E. gallinarum, the majority of SLE and AIH patients also showed increased serum antibody titers against E. gallinarum and particularly its RNA,” they said.
The authors said their findings showed that E. gallinarum translocates into systemic organs as a result of the breakdown of the gut barrier in autoimmune-prone hosts to drive autoimmune pathogenesis. They suggested that the translocating bacteria skewed T helper cell differentiation but also acted directly on colonized tissues such as the liver to induce autoantigens, endogenous retrovirus proteins, cytokines, and other autoimmune-promoting factors.
“If the complexity of host-tissue microbiota interactions is considered in chronic autoimmunity, it may offer new therapeutic avenues for these debilitating and potentially lethal diseases,” they concluded.
The study was supported by grants from various institutes and initiatives within the National Institutes of Health as well as from the Arthritis National Research Foundation, the Arthritis Foundation, and the Lupus Research Institute. Dr. Vieira and the senior author, Martin A. Kriegel, MD, PhD, are inventors on a patent application filed by Yale University related to the use of antibiotics and commensal vaccination to treat autoimmunity.
SOURCE: Vieira S et al. Science. 2018;359(6380):1156-61.
FROM SCIENCE
Key clinical point: The discovery that gut bacteria found in the small intestines can trigger autoimmune responses in predisposed individuals could lead to new therapeutic avenues for autoimmune diseases.
Major finding: In mice and humans, the Gram-positive gut bacteria pathobiont E. gallinarum translocated into systemic organs in autoimmune-prone hosts to drive autoimmune pathogenesis.
Study details: A mouse model that was replicated in cultured liver cells of healthy controls and patients with autoimmune disease.
Disclosures: The study was supported by grants from various institutes and initiatives within the National Institutes of Health as well as from the Arthritis National Research Foundation, the Arthritis Foundation, and the Lupus Research Institute. The first author and senior author are inventors on a patent application filed by Yale University related to the use of antibiotics and commensal vaccination to treat autoimmunity.
Source: Vieira S et al. Science. 2018;359(6380):1156-61.
Phosphodiesterase-5 inhibitors often prescribed inappropriately
While most veterans with pulmonary hypertension are treated in accordance with clinical guidelines, almost two-thirds who are prescribed therapy are being treated with pulmonary vasodilators inappropriately, an analysis of veteran prescription data reveals.
Little was known about how pulmonary vasodilators were used in practice prior to the publication of this study. While pulmonary vasodilators are considered effective for group 1 pulmonary hypertension (PH), clinical guidelines and advice from the Choosing Wisely campaign recommend against their routine use for PH patients classified into the most common types of PH – groups 2 and 3 – because of a lack of benefit, potential for harm, and high cost, the authors wrote. The report was published in Annals of the American Thoracic Society.
The new analysis shows that patients with PH are potentially being exposed to unnecessary harm, according to study author Renda Soylemez Wiener, MD, MPH, of the Center for Healthcare Organization & Implementation Research at Bedford (Mass.) Veterans Affairs Medical Center, and her colleagues. Their findings also reveal that inappropriate prescribing of pulmonary vasodilators, mostly by specialist clinicians, is contributing to the financial burden of an already stretched health system.
The research team looked at prescription data for veterans prescribed a phosphodiesterase-5 inhibitor (PDE5i), which causes pulmonary vasodilation, between 2005 and 2012 at any VA site. The primary outcome of the study was the proportion of patients who received potentially inappropriate PDE5i as classified in guideline recommendations. Patients with group 1 PH were deemed to have been treated appropriately, while those with group 2 and 3 PH were deemed to have been potentially treated inappropriately. Those with groups 4 and 5 PH were thought to have received treatment of “uncertain value.”
In a chart abstraction analysis from a randomly selected subset of PDE5i-treated patients, half (110/230, 47.8% [41.3%-54.5%]) had documented right heart catheterization to confirm the presence of PH. After factoring this into their algorithm, the investigators determined that only 11.7% [8.0%-16.8%] of these patients received clearly appropriate treatment.
Over the 8-year study period, the number of patients with PH group 2 or 3 prescribed PDE5i rose more than 14-fold, the researchers said. They speculated that this figure was likely to continue to rise with the increasing use of echocardiography and detection of PH.
According to the authors, the cost of treating one PH patient for 1 year with PDE5i therapy was between $10,000 and $13,000.
The 1,711 PH patients classified as being treated inappropriately in the study translated into a cost of over $20 million, if each patient were treated for only 1 year, but many of the patients were treated for a longer period of time.
The researchers suggested that there were several reasons why clinicians might choose to deviate from the guidelines, including lacking familiarity with them or disagreeing with them.
“While guidelines do allow trials of PDE5i in treatment for groups 2 or 3 PH on a case-by-case basis after consultation with a PH expert and a confirmatory [right heart catheterization], even PH experts disagree about whether a trial of PDE5i therapy is reasonable and appropriate for patients with group 3 PH,” they wrote.
They may also overestimate the potential benefits of treatment and/or underestimate potential harm.
Clinicians may believe that guidelines developed for a general population do not apply to the patients they are treating.
“It is understandable why clinicians may offer unproven therapies like PDE5i in hopes of providing relief to very sick patients with groups 2 or 3 PH, especially if they do not believe the recommendation applies to their individual patient or they are not convinced about the potential harms of pulmonary vasodilators,” they said.
The authors expressed concern about VA clinicians’ allowing patients to take PDE5i therapy that had been initially prescribed by clinicians outside of VA hospitals. The researchers said such drugs, which potentially had been prescribed inappropriately, “were continued by VA clinicians without much apparent scrutiny.”
The chart abstraction analysis also showed that specialists prescribed the majority of potentially inappropriate PDE5i treatment, suggesting “that other interventions to prevent inappropriate use may be required.”
The researchers concluded that “[the] time has come to develop interventions to optimize prescribing for PH in order to improve the value, quality, and safety of care.”
One potential intervention suggested by the researchers was to require patients with PH to be evaluated at a PH expert center, as recommended by treatment guidelines.
The study was funded by the Department of Veterans Affairs with resources from the Edith Nourse Rogers Memorial VA Hospital. Elizabeth S. Klings, MD, one of the study’s authors, declared receiving research support from several pharmaceutical companies.
SOURCE: Wiener RS et al. Ann Am Thorac Soc. 2018 Feb 27. doi: 10.1513/AnnalsATS.201710-762OC.
While most veterans with pulmonary hypertension are treated in accordance with clinical guidelines, almost two-thirds who are prescribed therapy are being treated with pulmonary vasodilators inappropriately, an analysis of veteran prescription data reveals.
Little was known about how pulmonary vasodilators were used in practice prior to the publication of this study. While pulmonary vasodilators are considered effective for group 1 pulmonary hypertension (PH), clinical guidelines and advice from the Choosing Wisely campaign recommend against their routine use for PH patients classified into the most common types of PH – groups 2 and 3 – because of a lack of benefit, potential for harm, and high cost, the authors wrote. The report was published in Annals of the American Thoracic Society.
The new analysis shows that patients with PH are potentially being exposed to unnecessary harm, according to study author Renda Soylemez Wiener, MD, MPH, of the Center for Healthcare Organization & Implementation Research at Bedford (Mass.) Veterans Affairs Medical Center, and her colleagues. Their findings also reveal that inappropriate prescribing of pulmonary vasodilators, mostly by specialist clinicians, is contributing to the financial burden of an already stretched health system.
The research team looked at prescription data for veterans prescribed a phosphodiesterase-5 inhibitor (PDE5i), which causes pulmonary vasodilation, between 2005 and 2012 at any VA site. The primary outcome of the study was the proportion of patients who received potentially inappropriate PDE5i as classified in guideline recommendations. Patients with group 1 PH were deemed to have been treated appropriately, while those with group 2 and 3 PH were deemed to have been potentially treated inappropriately. Those with groups 4 and 5 PH were thought to have received treatment of “uncertain value.”
In a chart abstraction analysis from a randomly selected subset of PDE5i-treated patients, half (110/230, 47.8% [41.3%-54.5%]) had documented right heart catheterization to confirm the presence of PH. After factoring this into their algorithm, the investigators determined that only 11.7% [8.0%-16.8%] of these patients received clearly appropriate treatment.
Over the 8-year study period, the number of patients with PH group 2 or 3 prescribed PDE5i rose more than 14-fold, the researchers said. They speculated that this figure was likely to continue to rise with the increasing use of echocardiography and detection of PH.
According to the authors, the cost of treating one PH patient for 1 year with PDE5i therapy was between $10,000 and $13,000.
The 1,711 PH patients classified as being treated inappropriately in the study translated into a cost of over $20 million, if each patient were treated for only 1 year, but many of the patients were treated for a longer period of time.
The researchers suggested that there were several reasons why clinicians might choose to deviate from the guidelines, including lacking familiarity with them or disagreeing with them.
“While guidelines do allow trials of PDE5i in treatment for groups 2 or 3 PH on a case-by-case basis after consultation with a PH expert and a confirmatory [right heart catheterization], even PH experts disagree about whether a trial of PDE5i therapy is reasonable and appropriate for patients with group 3 PH,” they wrote.
They may also overestimate the potential benefits of treatment and/or underestimate potential harm.
Clinicians may believe that guidelines developed for a general population do not apply to the patients they are treating.
“It is understandable why clinicians may offer unproven therapies like PDE5i in hopes of providing relief to very sick patients with groups 2 or 3 PH, especially if they do not believe the recommendation applies to their individual patient or they are not convinced about the potential harms of pulmonary vasodilators,” they said.
The authors expressed concern about VA clinicians’ allowing patients to take PDE5i therapy that had been initially prescribed by clinicians outside of VA hospitals. The researchers said such drugs, which potentially had been prescribed inappropriately, “were continued by VA clinicians without much apparent scrutiny.”
The chart abstraction analysis also showed that specialists prescribed the majority of potentially inappropriate PDE5i treatment, suggesting “that other interventions to prevent inappropriate use may be required.”
The researchers concluded that “[the] time has come to develop interventions to optimize prescribing for PH in order to improve the value, quality, and safety of care.”
One potential intervention suggested by the researchers was to require patients with PH to be evaluated at a PH expert center, as recommended by treatment guidelines.
The study was funded by the Department of Veterans Affairs with resources from the Edith Nourse Rogers Memorial VA Hospital. Elizabeth S. Klings, MD, one of the study’s authors, declared receiving research support from several pharmaceutical companies.
SOURCE: Wiener RS et al. Ann Am Thorac Soc. 2018 Feb 27. doi: 10.1513/AnnalsATS.201710-762OC.
While most veterans with pulmonary hypertension are treated in accordance with clinical guidelines, almost two-thirds who are prescribed therapy are being treated with pulmonary vasodilators inappropriately, an analysis of veteran prescription data reveals.
Little was known about how pulmonary vasodilators were used in practice prior to the publication of this study. While pulmonary vasodilators are considered effective for group 1 pulmonary hypertension (PH), clinical guidelines and advice from the Choosing Wisely campaign recommend against their routine use for PH patients classified into the most common types of PH – groups 2 and 3 – because of a lack of benefit, potential for harm, and high cost, the authors wrote. The report was published in Annals of the American Thoracic Society.
The new analysis shows that patients with PH are potentially being exposed to unnecessary harm, according to study author Renda Soylemez Wiener, MD, MPH, of the Center for Healthcare Organization & Implementation Research at Bedford (Mass.) Veterans Affairs Medical Center, and her colleagues. Their findings also reveal that inappropriate prescribing of pulmonary vasodilators, mostly by specialist clinicians, is contributing to the financial burden of an already stretched health system.
The research team looked at prescription data for veterans prescribed a phosphodiesterase-5 inhibitor (PDE5i), which causes pulmonary vasodilation, between 2005 and 2012 at any VA site. The primary outcome of the study was the proportion of patients who received potentially inappropriate PDE5i as classified in guideline recommendations. Patients with group 1 PH were deemed to have been treated appropriately, while those with group 2 and 3 PH were deemed to have been potentially treated inappropriately. Those with groups 4 and 5 PH were thought to have received treatment of “uncertain value.”
In a chart abstraction analysis from a randomly selected subset of PDE5i-treated patients, half (110/230, 47.8% [41.3%-54.5%]) had documented right heart catheterization to confirm the presence of PH. After factoring this into their algorithm, the investigators determined that only 11.7% [8.0%-16.8%] of these patients received clearly appropriate treatment.
Over the 8-year study period, the number of patients with PH group 2 or 3 prescribed PDE5i rose more than 14-fold, the researchers said. They speculated that this figure was likely to continue to rise with the increasing use of echocardiography and detection of PH.
According to the authors, the cost of treating one PH patient for 1 year with PDE5i therapy was between $10,000 and $13,000.
The 1,711 PH patients classified as being treated inappropriately in the study translated into a cost of over $20 million, if each patient were treated for only 1 year, but many of the patients were treated for a longer period of time.
The researchers suggested that there were several reasons why clinicians might choose to deviate from the guidelines, including lacking familiarity with them or disagreeing with them.
“While guidelines do allow trials of PDE5i in treatment for groups 2 or 3 PH on a case-by-case basis after consultation with a PH expert and a confirmatory [right heart catheterization], even PH experts disagree about whether a trial of PDE5i therapy is reasonable and appropriate for patients with group 3 PH,” they wrote.
They may also overestimate the potential benefits of treatment and/or underestimate potential harm.
Clinicians may believe that guidelines developed for a general population do not apply to the patients they are treating.
“It is understandable why clinicians may offer unproven therapies like PDE5i in hopes of providing relief to very sick patients with groups 2 or 3 PH, especially if they do not believe the recommendation applies to their individual patient or they are not convinced about the potential harms of pulmonary vasodilators,” they said.
The authors expressed concern about VA clinicians’ allowing patients to take PDE5i therapy that had been initially prescribed by clinicians outside of VA hospitals. The researchers said such drugs, which potentially had been prescribed inappropriately, “were continued by VA clinicians without much apparent scrutiny.”
The chart abstraction analysis also showed that specialists prescribed the majority of potentially inappropriate PDE5i treatment, suggesting “that other interventions to prevent inappropriate use may be required.”
The researchers concluded that “[the] time has come to develop interventions to optimize prescribing for PH in order to improve the value, quality, and safety of care.”
One potential intervention suggested by the researchers was to require patients with PH to be evaluated at a PH expert center, as recommended by treatment guidelines.
The study was funded by the Department of Veterans Affairs with resources from the Edith Nourse Rogers Memorial VA Hospital. Elizabeth S. Klings, MD, one of the study’s authors, declared receiving research support from several pharmaceutical companies.
SOURCE: Wiener RS et al. Ann Am Thorac Soc. 2018 Feb 27. doi: 10.1513/AnnalsATS.201710-762OC.
FROM ANNALS OF THE AMERICAN THORACIC SOCIETY
Key clinical point: Inappropriate prescribing of phosphodiesterase-5 inhibitor (PDE5i) therapy has risen 14-fold in 8 years, at a cost of $20 million per year.
Major finding:
Study details: A retrospective analysis of veterans prescribed phosphodiesterase-5 inhibitors for pulmonary hypertension between 2005 and 2012.
Disclosures: The study was funded by the Department of Veterans Affairs with resources from the Edith Nourse Rogers Memorial Veterans Hospital. Elizabeth S. Klings, MD, one of the study’s authors, declared receiving research support from several pharmaceutical companies.
Source: Wiener RS et al. Ann Am Thorac Soc. 2018 Feb 27. doi: 10.1513/AnnalsATS.201710-762OC.
Immunotherapy regimen influences inflammatory arthritis presentation
Variations in the clinical presentation of immunotherapy-induced inflammatory arthritis is partly explained by which treatment regimen was used to treat the cancer, a single-center study suggests.
While immune checkpoint inhibitors (ICI) have revolutionized the field of oncology, their use for an ever-widening range of indications had created an increasing population of patients referred to rheumatologists for the management of immune-related adverse events (IrAEs), according to Laura C. Cappelli, MD, and her colleagues at John Hopkins University, Baltimore.
Well-established guidelines exist for managing adverse events such as colitis and pneumonitis, but there are only preliminary guidelines for evaluating and treating immunotherapy-induced inflammatory arthritis (IA). “This may stem from a lack of consistent reporting of rheumatologic IrAEs in clinical trials, the non–life threatening nature of [inflammatory arthritis], or lack of recognition of musculoskeletal symptoms by treating providers,” they wrote in Seminars in Arthritis and Rheumatism.
Clinical trials have reported ranges of arthralgia in 1%-43% of patients treated with ICIs, but no accurate estimate of the incidence of IA exists.
The researchers noted that treating patients with ICI-induced IA is complicated by a history of active or recently treated cancer and concerns over using immunosuppression in the context of ICI therapy.
They set out to evaluate the clinical presentations of 30 patients seen in their clinic with ICI-induced IA. Patients were a median of 59 years old and 12 (40%) were female. Tumor types included metastatic melanoma, non–small cell lung cancer, small cell lung cancer, colorectal cancer, Hodgkin lymphoma, cutaneous lymphoma, renal cell carcinoma, duodenal carcinoma, Merkel cell carcinoma, cutaneous basal cell carcinoma, and cutaneous squamous cell carcinoma.
Sixteen patients were treated with anti–programmed cell death protein 1 (PD-1)/programmed death ligand 1 monotherapy, and 14 were treated with combination anti–CTLA-4/PD-1 therapy.
Patients on combination therapy were significantly younger (7.5 years, P = 0.01) and were more likely to have metastatic melanoma as their underlying cancer.
Patients who received combination therapy were more likely to present first with knee IA (n = 10) and none had small joint involvement. In contrast, initial small joint involvement was more common in the monotherapy group (n = 6).
C-reactive protein levels were significantly higher in the combination therapy group (4mg/dL vs. 0.5mg/dL, P = 0.03). Only monotherapy patients were positive for anti–citrullinated peptide antibodies, rheumatoid factor, or antinuclear antibodies.
Most of the patients in the study had an additional IrAE, with colitis being the most common (n=10), followed by thyroid disease, pneumonitis, and rash. Patients on PD-1 or programmed death ligand 1 monotherapy were more likely to have IA as their first IrAE.
The research team noted that the median time to symptom onset was 5 months after ICI initiation.
Diagnosis of IA following patient-reported symptoms was an average of 5.2 months, with a significant difference in lag time to diagnosis depending on initial joint presentation. For example, patients with initial small joint involvement had a 10 month longer lag time to IA diagnosis than those with knees as the initial joint involved.
In terms of treatment, 24 patients were treated with systemic corticosteroids and 10 required additional immunosuppression. The need for corticosteroids did not differ by ICI treatment regimen, but those treated with combination therapy were more likely to require additional immunosuppression (P = 0.02).
Tumor necrosis factor inhibitors with or without methotrexate were prescribed for seven patients. All of the patients had a clinical improvement in their arthritis symptoms. Four had a complete tumor response at the time of tumor necrosis factor inhibitor initiation with none having tumor progression.
The three patients treated with methotrexate monotherapy had a complete or sustained partial tumor response to ICI therapy and their cancer did not develop during IA management follow-up.
The authors went on to look at the persistence of IA after cessation of therapy in a subset of 21 patients. They found that 18 of these patients still had IA symptoms months after stopping treatment. They suggested that the delay in diagnosis and treatment seen in their study might explain the finding.
The study provides “critical information, not just for rheumatologists as they try to recognize subgroups in ICI-induced IA and diagnose patients with this new entity, but also for oncology providers who are usually first to encounter patients with ICI-induced IA and subsequently refer patients to rheumatology,” Dr. Cappelli and colleagues wrote.
The experience so far with using immunosuppression in ICI-induced IA “has been reassuring in terms of cancer outcomes, but more studies are needed to confirm this finding,” they concluded.
SOURCE: Cappelli LC et al. Semin Arthritis Rheum. doi: 10.1016/j.semarthrit. 2018.02.011.
Variations in the clinical presentation of immunotherapy-induced inflammatory arthritis is partly explained by which treatment regimen was used to treat the cancer, a single-center study suggests.
While immune checkpoint inhibitors (ICI) have revolutionized the field of oncology, their use for an ever-widening range of indications had created an increasing population of patients referred to rheumatologists for the management of immune-related adverse events (IrAEs), according to Laura C. Cappelli, MD, and her colleagues at John Hopkins University, Baltimore.
Well-established guidelines exist for managing adverse events such as colitis and pneumonitis, but there are only preliminary guidelines for evaluating and treating immunotherapy-induced inflammatory arthritis (IA). “This may stem from a lack of consistent reporting of rheumatologic IrAEs in clinical trials, the non–life threatening nature of [inflammatory arthritis], or lack of recognition of musculoskeletal symptoms by treating providers,” they wrote in Seminars in Arthritis and Rheumatism.
Clinical trials have reported ranges of arthralgia in 1%-43% of patients treated with ICIs, but no accurate estimate of the incidence of IA exists.
The researchers noted that treating patients with ICI-induced IA is complicated by a history of active or recently treated cancer and concerns over using immunosuppression in the context of ICI therapy.
They set out to evaluate the clinical presentations of 30 patients seen in their clinic with ICI-induced IA. Patients were a median of 59 years old and 12 (40%) were female. Tumor types included metastatic melanoma, non–small cell lung cancer, small cell lung cancer, colorectal cancer, Hodgkin lymphoma, cutaneous lymphoma, renal cell carcinoma, duodenal carcinoma, Merkel cell carcinoma, cutaneous basal cell carcinoma, and cutaneous squamous cell carcinoma.
Sixteen patients were treated with anti–programmed cell death protein 1 (PD-1)/programmed death ligand 1 monotherapy, and 14 were treated with combination anti–CTLA-4/PD-1 therapy.
Patients on combination therapy were significantly younger (7.5 years, P = 0.01) and were more likely to have metastatic melanoma as their underlying cancer.
Patients who received combination therapy were more likely to present first with knee IA (n = 10) and none had small joint involvement. In contrast, initial small joint involvement was more common in the monotherapy group (n = 6).
C-reactive protein levels were significantly higher in the combination therapy group (4mg/dL vs. 0.5mg/dL, P = 0.03). Only monotherapy patients were positive for anti–citrullinated peptide antibodies, rheumatoid factor, or antinuclear antibodies.
Most of the patients in the study had an additional IrAE, with colitis being the most common (n=10), followed by thyroid disease, pneumonitis, and rash. Patients on PD-1 or programmed death ligand 1 monotherapy were more likely to have IA as their first IrAE.
The research team noted that the median time to symptom onset was 5 months after ICI initiation.
Diagnosis of IA following patient-reported symptoms was an average of 5.2 months, with a significant difference in lag time to diagnosis depending on initial joint presentation. For example, patients with initial small joint involvement had a 10 month longer lag time to IA diagnosis than those with knees as the initial joint involved.
In terms of treatment, 24 patients were treated with systemic corticosteroids and 10 required additional immunosuppression. The need for corticosteroids did not differ by ICI treatment regimen, but those treated with combination therapy were more likely to require additional immunosuppression (P = 0.02).
Tumor necrosis factor inhibitors with or without methotrexate were prescribed for seven patients. All of the patients had a clinical improvement in their arthritis symptoms. Four had a complete tumor response at the time of tumor necrosis factor inhibitor initiation with none having tumor progression.
The three patients treated with methotrexate monotherapy had a complete or sustained partial tumor response to ICI therapy and their cancer did not develop during IA management follow-up.
The authors went on to look at the persistence of IA after cessation of therapy in a subset of 21 patients. They found that 18 of these patients still had IA symptoms months after stopping treatment. They suggested that the delay in diagnosis and treatment seen in their study might explain the finding.
The study provides “critical information, not just for rheumatologists as they try to recognize subgroups in ICI-induced IA and diagnose patients with this new entity, but also for oncology providers who are usually first to encounter patients with ICI-induced IA and subsequently refer patients to rheumatology,” Dr. Cappelli and colleagues wrote.
The experience so far with using immunosuppression in ICI-induced IA “has been reassuring in terms of cancer outcomes, but more studies are needed to confirm this finding,” they concluded.
SOURCE: Cappelli LC et al. Semin Arthritis Rheum. doi: 10.1016/j.semarthrit. 2018.02.011.
Variations in the clinical presentation of immunotherapy-induced inflammatory arthritis is partly explained by which treatment regimen was used to treat the cancer, a single-center study suggests.
While immune checkpoint inhibitors (ICI) have revolutionized the field of oncology, their use for an ever-widening range of indications had created an increasing population of patients referred to rheumatologists for the management of immune-related adverse events (IrAEs), according to Laura C. Cappelli, MD, and her colleagues at John Hopkins University, Baltimore.
Well-established guidelines exist for managing adverse events such as colitis and pneumonitis, but there are only preliminary guidelines for evaluating and treating immunotherapy-induced inflammatory arthritis (IA). “This may stem from a lack of consistent reporting of rheumatologic IrAEs in clinical trials, the non–life threatening nature of [inflammatory arthritis], or lack of recognition of musculoskeletal symptoms by treating providers,” they wrote in Seminars in Arthritis and Rheumatism.
Clinical trials have reported ranges of arthralgia in 1%-43% of patients treated with ICIs, but no accurate estimate of the incidence of IA exists.
The researchers noted that treating patients with ICI-induced IA is complicated by a history of active or recently treated cancer and concerns over using immunosuppression in the context of ICI therapy.
They set out to evaluate the clinical presentations of 30 patients seen in their clinic with ICI-induced IA. Patients were a median of 59 years old and 12 (40%) were female. Tumor types included metastatic melanoma, non–small cell lung cancer, small cell lung cancer, colorectal cancer, Hodgkin lymphoma, cutaneous lymphoma, renal cell carcinoma, duodenal carcinoma, Merkel cell carcinoma, cutaneous basal cell carcinoma, and cutaneous squamous cell carcinoma.
Sixteen patients were treated with anti–programmed cell death protein 1 (PD-1)/programmed death ligand 1 monotherapy, and 14 were treated with combination anti–CTLA-4/PD-1 therapy.
Patients on combination therapy were significantly younger (7.5 years, P = 0.01) and were more likely to have metastatic melanoma as their underlying cancer.
Patients who received combination therapy were more likely to present first with knee IA (n = 10) and none had small joint involvement. In contrast, initial small joint involvement was more common in the monotherapy group (n = 6).
C-reactive protein levels were significantly higher in the combination therapy group (4mg/dL vs. 0.5mg/dL, P = 0.03). Only monotherapy patients were positive for anti–citrullinated peptide antibodies, rheumatoid factor, or antinuclear antibodies.
Most of the patients in the study had an additional IrAE, with colitis being the most common (n=10), followed by thyroid disease, pneumonitis, and rash. Patients on PD-1 or programmed death ligand 1 monotherapy were more likely to have IA as their first IrAE.
The research team noted that the median time to symptom onset was 5 months after ICI initiation.
Diagnosis of IA following patient-reported symptoms was an average of 5.2 months, with a significant difference in lag time to diagnosis depending on initial joint presentation. For example, patients with initial small joint involvement had a 10 month longer lag time to IA diagnosis than those with knees as the initial joint involved.
In terms of treatment, 24 patients were treated with systemic corticosteroids and 10 required additional immunosuppression. The need for corticosteroids did not differ by ICI treatment regimen, but those treated with combination therapy were more likely to require additional immunosuppression (P = 0.02).
Tumor necrosis factor inhibitors with or without methotrexate were prescribed for seven patients. All of the patients had a clinical improvement in their arthritis symptoms. Four had a complete tumor response at the time of tumor necrosis factor inhibitor initiation with none having tumor progression.
The three patients treated with methotrexate monotherapy had a complete or sustained partial tumor response to ICI therapy and their cancer did not develop during IA management follow-up.
The authors went on to look at the persistence of IA after cessation of therapy in a subset of 21 patients. They found that 18 of these patients still had IA symptoms months after stopping treatment. They suggested that the delay in diagnosis and treatment seen in their study might explain the finding.
The study provides “critical information, not just for rheumatologists as they try to recognize subgroups in ICI-induced IA and diagnose patients with this new entity, but also for oncology providers who are usually first to encounter patients with ICI-induced IA and subsequently refer patients to rheumatology,” Dr. Cappelli and colleagues wrote.
The experience so far with using immunosuppression in ICI-induced IA “has been reassuring in terms of cancer outcomes, but more studies are needed to confirm this finding,” they concluded.
SOURCE: Cappelli LC et al. Semin Arthritis Rheum. doi: 10.1016/j.semarthrit. 2018.02.011.
FROM SEMINARS IN ARTHRITIS AND RHEUMATISM
Key clinical point: The clinical features of patients with immunotherapy-induced inflammatory arthritis differ according to the treatment regimen used.
Major findings: Combination immune checkpoint inhibitor therapy was associated with higher C-reactive protein levels and a higher likelihood of having a large joint affected first.
Study details: A single-center, retrospective cohort study of 30 patients with rheumatologist-confirmed inflammatory arthritis after receiving immune checkpoint inhibitor therapy.
Disclosures: The study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Disease and the Jerome L. Greene Foundation.
Source: Cappelli LC et al. Semin Arthritis Rheum. doi: 10.1016/j.semarthrit. 2018.02.011.
Trial shows ‘signals’ in favor of general anesthesia during EVT for stroke
The provision of general anesthesia during endovascular therapy for acute ischemic stroke patients with large-vessel occlusions did not result in more infarct growth when compared with conscious sedation in a new randomized trial, contrary to previous findings.
Furthermore, the single-center, open-label, blinded-endpoint General or Local Anesthesia in Intra Arterial Therapy (GOLIATH) trial also reported that patients randomized to the general anesthesia (GA) group had improved functional outcomes on the modified Rankin Scale at 90 days, with a 91% greater likelihood for lower scores than with conscious sedation (CS) (odds ratio, 1.91; 95% confidence interval, 1.03-3.56).
The GOLIATH trial randomized patients to general anesthetic (n = 65) or conscious sedation (n = 63). The average age of the patients was 71.4 years and 48.4% of the cohort were women. The patients’ median National Institutes of Health Stroke Scale score was 18 (interquartile range [IQR], 14-21), and the initial infarct size was also comparable between the GA and CS groups, respectively (median [interquartile range], 10.5 [2.4-23.6] mL vs. 13.3 [5.2-31.1] mL; P = .26)
The trial’s primary endpoint results showed that although final infarct volume was smaller in the GA group, the difference in the volume of infarct growth 48-72 hours after symptom onset among patients treated under GA or CS did not reach statistical significance (median [IQR] growth, 8.2 [2.2-38.6] mL vs. 19.4 [2.4-79.0] mL; P = .10).
“Assuming a normal distribution, the mean infarct growth for CS was 57.4 mL and for GA was 34.1 mL (difference, 23.2 mL; 95% CI, –6.4 to 52.9),” the research team noted.
A higher rate of successful reperfusion in the GA arm appeared to reflect its better clinical outcomes. Successful reperfusion occurred in 76.9% of GA patients, compared with 60.3% of CS patients (P = .04).
There were no clinically meaningful differences in safety endpoints between the two arms. Four patients (6.3%) in the CS group were converted to GA.
Significantly more patients in the GA group than in the CS group experienced a decrease of greater than 20% in mean arterial pressure (MAP) (87.7% vs. 34.9%; P = .001). However, when MAP dropped below 70 mm Hg, the duration was non-significantly longer for CS patients than for GA patients (6.5 [2-13] minutes vs. 2 [1-5.5] minutes; P = .09).
A longer delay from arrival at the neurointerventional suite to groin puncture was also seen for patients in the GA group. But the median difference of 9 minutes was “acceptable in the context of the much longer overall time from stroke onset to treatment and from stroke onset to reperfusion, which was not significantly different between the competing arms,” the authors said.
The authors said that overall their findings supported GA as a viable anesthetic approach during EVT. “Contrary to numerous nonrandomized studies that have reported better outcomes with CS, the GOLIATH trial shows signals in favor of GA for multiple endpoints,” the research team wrote. “Performing EVT under GA, compared with CS, does not result in worse tissue or clinical outcomes when using a GA protocol that limits the time delay for intubation (less than 10 minutes) and blood pressure level within recommended limits (systolic blood pressure greater than 140 mm Hg and MAP greater than 70 mm Hg).”
The trial was funded by Aarhus University Hospital. One author reported research grants from Penumbra and Neuravi, and another author reported a research grant from Health Research Fund of Central Denmark Region.
SOURCE: Simonsen C et al., JAMA Neurol. 2018 Jan 16. doi: 10.1001/jamaneurol.2017.4474
The provision of general anesthesia during endovascular therapy for acute ischemic stroke patients with large-vessel occlusions did not result in more infarct growth when compared with conscious sedation in a new randomized trial, contrary to previous findings.
Furthermore, the single-center, open-label, blinded-endpoint General or Local Anesthesia in Intra Arterial Therapy (GOLIATH) trial also reported that patients randomized to the general anesthesia (GA) group had improved functional outcomes on the modified Rankin Scale at 90 days, with a 91% greater likelihood for lower scores than with conscious sedation (CS) (odds ratio, 1.91; 95% confidence interval, 1.03-3.56).
The GOLIATH trial randomized patients to general anesthetic (n = 65) or conscious sedation (n = 63). The average age of the patients was 71.4 years and 48.4% of the cohort were women. The patients’ median National Institutes of Health Stroke Scale score was 18 (interquartile range [IQR], 14-21), and the initial infarct size was also comparable between the GA and CS groups, respectively (median [interquartile range], 10.5 [2.4-23.6] mL vs. 13.3 [5.2-31.1] mL; P = .26)
The trial’s primary endpoint results showed that although final infarct volume was smaller in the GA group, the difference in the volume of infarct growth 48-72 hours after symptom onset among patients treated under GA or CS did not reach statistical significance (median [IQR] growth, 8.2 [2.2-38.6] mL vs. 19.4 [2.4-79.0] mL; P = .10).
“Assuming a normal distribution, the mean infarct growth for CS was 57.4 mL and for GA was 34.1 mL (difference, 23.2 mL; 95% CI, –6.4 to 52.9),” the research team noted.
A higher rate of successful reperfusion in the GA arm appeared to reflect its better clinical outcomes. Successful reperfusion occurred in 76.9% of GA patients, compared with 60.3% of CS patients (P = .04).
There were no clinically meaningful differences in safety endpoints between the two arms. Four patients (6.3%) in the CS group were converted to GA.
Significantly more patients in the GA group than in the CS group experienced a decrease of greater than 20% in mean arterial pressure (MAP) (87.7% vs. 34.9%; P = .001). However, when MAP dropped below 70 mm Hg, the duration was non-significantly longer for CS patients than for GA patients (6.5 [2-13] minutes vs. 2 [1-5.5] minutes; P = .09).
A longer delay from arrival at the neurointerventional suite to groin puncture was also seen for patients in the GA group. But the median difference of 9 minutes was “acceptable in the context of the much longer overall time from stroke onset to treatment and from stroke onset to reperfusion, which was not significantly different between the competing arms,” the authors said.
The authors said that overall their findings supported GA as a viable anesthetic approach during EVT. “Contrary to numerous nonrandomized studies that have reported better outcomes with CS, the GOLIATH trial shows signals in favor of GA for multiple endpoints,” the research team wrote. “Performing EVT under GA, compared with CS, does not result in worse tissue or clinical outcomes when using a GA protocol that limits the time delay for intubation (less than 10 minutes) and blood pressure level within recommended limits (systolic blood pressure greater than 140 mm Hg and MAP greater than 70 mm Hg).”
The trial was funded by Aarhus University Hospital. One author reported research grants from Penumbra and Neuravi, and another author reported a research grant from Health Research Fund of Central Denmark Region.
SOURCE: Simonsen C et al., JAMA Neurol. 2018 Jan 16. doi: 10.1001/jamaneurol.2017.4474
The provision of general anesthesia during endovascular therapy for acute ischemic stroke patients with large-vessel occlusions did not result in more infarct growth when compared with conscious sedation in a new randomized trial, contrary to previous findings.
Furthermore, the single-center, open-label, blinded-endpoint General or Local Anesthesia in Intra Arterial Therapy (GOLIATH) trial also reported that patients randomized to the general anesthesia (GA) group had improved functional outcomes on the modified Rankin Scale at 90 days, with a 91% greater likelihood for lower scores than with conscious sedation (CS) (odds ratio, 1.91; 95% confidence interval, 1.03-3.56).
The GOLIATH trial randomized patients to general anesthetic (n = 65) or conscious sedation (n = 63). The average age of the patients was 71.4 years and 48.4% of the cohort were women. The patients’ median National Institutes of Health Stroke Scale score was 18 (interquartile range [IQR], 14-21), and the initial infarct size was also comparable between the GA and CS groups, respectively (median [interquartile range], 10.5 [2.4-23.6] mL vs. 13.3 [5.2-31.1] mL; P = .26)
The trial’s primary endpoint results showed that although final infarct volume was smaller in the GA group, the difference in the volume of infarct growth 48-72 hours after symptom onset among patients treated under GA or CS did not reach statistical significance (median [IQR] growth, 8.2 [2.2-38.6] mL vs. 19.4 [2.4-79.0] mL; P = .10).
“Assuming a normal distribution, the mean infarct growth for CS was 57.4 mL and for GA was 34.1 mL (difference, 23.2 mL; 95% CI, –6.4 to 52.9),” the research team noted.
A higher rate of successful reperfusion in the GA arm appeared to reflect its better clinical outcomes. Successful reperfusion occurred in 76.9% of GA patients, compared with 60.3% of CS patients (P = .04).
There were no clinically meaningful differences in safety endpoints between the two arms. Four patients (6.3%) in the CS group were converted to GA.
Significantly more patients in the GA group than in the CS group experienced a decrease of greater than 20% in mean arterial pressure (MAP) (87.7% vs. 34.9%; P = .001). However, when MAP dropped below 70 mm Hg, the duration was non-significantly longer for CS patients than for GA patients (6.5 [2-13] minutes vs. 2 [1-5.5] minutes; P = .09).
A longer delay from arrival at the neurointerventional suite to groin puncture was also seen for patients in the GA group. But the median difference of 9 minutes was “acceptable in the context of the much longer overall time from stroke onset to treatment and from stroke onset to reperfusion, which was not significantly different between the competing arms,” the authors said.
The authors said that overall their findings supported GA as a viable anesthetic approach during EVT. “Contrary to numerous nonrandomized studies that have reported better outcomes with CS, the GOLIATH trial shows signals in favor of GA for multiple endpoints,” the research team wrote. “Performing EVT under GA, compared with CS, does not result in worse tissue or clinical outcomes when using a GA protocol that limits the time delay for intubation (less than 10 minutes) and blood pressure level within recommended limits (systolic blood pressure greater than 140 mm Hg and MAP greater than 70 mm Hg).”
The trial was funded by Aarhus University Hospital. One author reported research grants from Penumbra and Neuravi, and another author reported a research grant from Health Research Fund of Central Denmark Region.
SOURCE: Simonsen C et al., JAMA Neurol. 2018 Jan 16. doi: 10.1001/jamaneurol.2017.4474
FROM JAMA NEUROLOGY
Key clinical point: A new trial shows signals in multiple endpoints in favor of general anesthesia for acute ischemic stroke patients with large-vessel occlusions who undergo endovascular therapy.
Major finding: The difference in the volume of infarct growth 48-72 hours after symptom onset among patients treated under general anesthesia or conscious sedation did not reach statistical significance (median [IQR] growth, 8.2 [2.2-38.6] mL vs. 19.4 [2.4-79.0] mL; P = .10).
Study details: The single-center, open-label, blinded-endpoint GOLIATH trial randomized 128 acute ischemic stroke patients to general anesthesia or conscious sedation.
Disclosures: The trial was funded by Aarhus University Hospital. One author reported research grants from Penumbra and Neuravi, and another author reported a research grant from Health Research Fund of Central Denmark Region.
Source: Simonsen C et al. JAMA Neurol. 2018 Jan 16. doi: 10.1001/jamaneurol.2017.4474.
Researchers identify three distinct clinical-histologic-genetic subtypes in RA
Researchers have identified three different synovial subtypes of rheumatoid arthritis that exhibit different mechanisms of pain and correlate with specific clinical phenotypes.
The findings could be clinically meaningful and may help guide optimal treatment strategies for patients, as well as provide a better understanding of the cause of pain in patients with high tender and swollen joint counts but little tissue inflammation, according to the research team led by Dana E. Orange, MD, of the Hospital for Special Surgery and Rockefeller University in New York.
The report was published in Arthritis & Rheumatology.
The assessment of the synovium in rheumatoid arthritis (RA) has the potential to provide guidance on optimal treatment strategies, they noted, but its classification has not yet factored into current diagnosis or treatment guidelines of RA.
In total, the research team analyzed 20 histologic features on 129 synovial tissue samples.
The researchers used machine learning integration to identify three distinct molecular subtypes of RA from a consensus clustering of the 500 most variable genes expressed in a subset of 45 synovial samples, including 39 from RA patients. The subtypes were high inflammatory, low inflammatory, and a mixed phenotype.
The researchers then took the histologic features that best corresponded to each subtype to develop a histology scoring algorithm that predicted the three gene expression subtypes (using only histology features), each of which were each associated with levels of erythrocyte sedimentation rate, C-reactive protein, and autoantibodies.
The histologic features that most strongly defined the high inflammatory subtype included three plasma cell features: binucleate plasma cells, plasma cell percentage, and Russell bodies. Patients with a high inflammatory synovial subtype also exhibited higher levels of markers of systemic inflammation and autoantibodies. For example, C-reactive protein was significantly correlated with pain in the high inflammatory group.
“This suggests that pain is associated with inflammation in patients with high inflammatory subtype and that pain may be driven by distinct mechanisms in the other patients,” the study authors wrote.
The low inflammatory subgroup was characterized by high neuronal and glycoprotein gene expression. But in this group, pain scores were not associated with elevated inflammatory markers.
“It is interesting that this subtype is characterized by a paucity of inflammatory infiltrates, yet maintains high pain scores and multiple tender/swollen joints – this too is consistent with other findings of patients with established RA,” the research team noted.
The mixed subtype shared features with both the high and low subtypes, the researchers said.
“Our work suggests that RA patients with longstanding disease and poor response to anti-inflammatory treatment may warrant synovial biopsy to determine their inflammatory subtype,” the researchers concluded.
Several research institutions and the Accelerating Medicines Partnership in Rheumatoid Arthritis and Lupus Network, a public-private partnership involving several pharmaceutical companies, patient advocacy groups, and the National Institutes of Health, funded the study.
SOURCE: Orange D et al. Arthritis Rheumatol. 2018 Feb 22. doi: 10.1002/art.40428.
Researchers have identified three different synovial subtypes of rheumatoid arthritis that exhibit different mechanisms of pain and correlate with specific clinical phenotypes.
The findings could be clinically meaningful and may help guide optimal treatment strategies for patients, as well as provide a better understanding of the cause of pain in patients with high tender and swollen joint counts but little tissue inflammation, according to the research team led by Dana E. Orange, MD, of the Hospital for Special Surgery and Rockefeller University in New York.
The report was published in Arthritis & Rheumatology.
The assessment of the synovium in rheumatoid arthritis (RA) has the potential to provide guidance on optimal treatment strategies, they noted, but its classification has not yet factored into current diagnosis or treatment guidelines of RA.
In total, the research team analyzed 20 histologic features on 129 synovial tissue samples.
The researchers used machine learning integration to identify three distinct molecular subtypes of RA from a consensus clustering of the 500 most variable genes expressed in a subset of 45 synovial samples, including 39 from RA patients. The subtypes were high inflammatory, low inflammatory, and a mixed phenotype.
The researchers then took the histologic features that best corresponded to each subtype to develop a histology scoring algorithm that predicted the three gene expression subtypes (using only histology features), each of which were each associated with levels of erythrocyte sedimentation rate, C-reactive protein, and autoantibodies.
The histologic features that most strongly defined the high inflammatory subtype included three plasma cell features: binucleate plasma cells, plasma cell percentage, and Russell bodies. Patients with a high inflammatory synovial subtype also exhibited higher levels of markers of systemic inflammation and autoantibodies. For example, C-reactive protein was significantly correlated with pain in the high inflammatory group.
“This suggests that pain is associated with inflammation in patients with high inflammatory subtype and that pain may be driven by distinct mechanisms in the other patients,” the study authors wrote.
The low inflammatory subgroup was characterized by high neuronal and glycoprotein gene expression. But in this group, pain scores were not associated with elevated inflammatory markers.
“It is interesting that this subtype is characterized by a paucity of inflammatory infiltrates, yet maintains high pain scores and multiple tender/swollen joints – this too is consistent with other findings of patients with established RA,” the research team noted.
The mixed subtype shared features with both the high and low subtypes, the researchers said.
“Our work suggests that RA patients with longstanding disease and poor response to anti-inflammatory treatment may warrant synovial biopsy to determine their inflammatory subtype,” the researchers concluded.
Several research institutions and the Accelerating Medicines Partnership in Rheumatoid Arthritis and Lupus Network, a public-private partnership involving several pharmaceutical companies, patient advocacy groups, and the National Institutes of Health, funded the study.
SOURCE: Orange D et al. Arthritis Rheumatol. 2018 Feb 22. doi: 10.1002/art.40428.
Researchers have identified three different synovial subtypes of rheumatoid arthritis that exhibit different mechanisms of pain and correlate with specific clinical phenotypes.
The findings could be clinically meaningful and may help guide optimal treatment strategies for patients, as well as provide a better understanding of the cause of pain in patients with high tender and swollen joint counts but little tissue inflammation, according to the research team led by Dana E. Orange, MD, of the Hospital for Special Surgery and Rockefeller University in New York.
The report was published in Arthritis & Rheumatology.
The assessment of the synovium in rheumatoid arthritis (RA) has the potential to provide guidance on optimal treatment strategies, they noted, but its classification has not yet factored into current diagnosis or treatment guidelines of RA.
In total, the research team analyzed 20 histologic features on 129 synovial tissue samples.
The researchers used machine learning integration to identify three distinct molecular subtypes of RA from a consensus clustering of the 500 most variable genes expressed in a subset of 45 synovial samples, including 39 from RA patients. The subtypes were high inflammatory, low inflammatory, and a mixed phenotype.
The researchers then took the histologic features that best corresponded to each subtype to develop a histology scoring algorithm that predicted the three gene expression subtypes (using only histology features), each of which were each associated with levels of erythrocyte sedimentation rate, C-reactive protein, and autoantibodies.
The histologic features that most strongly defined the high inflammatory subtype included three plasma cell features: binucleate plasma cells, plasma cell percentage, and Russell bodies. Patients with a high inflammatory synovial subtype also exhibited higher levels of markers of systemic inflammation and autoantibodies. For example, C-reactive protein was significantly correlated with pain in the high inflammatory group.
“This suggests that pain is associated with inflammation in patients with high inflammatory subtype and that pain may be driven by distinct mechanisms in the other patients,” the study authors wrote.
The low inflammatory subgroup was characterized by high neuronal and glycoprotein gene expression. But in this group, pain scores were not associated with elevated inflammatory markers.
“It is interesting that this subtype is characterized by a paucity of inflammatory infiltrates, yet maintains high pain scores and multiple tender/swollen joints – this too is consistent with other findings of patients with established RA,” the research team noted.
The mixed subtype shared features with both the high and low subtypes, the researchers said.
“Our work suggests that RA patients with longstanding disease and poor response to anti-inflammatory treatment may warrant synovial biopsy to determine their inflammatory subtype,” the researchers concluded.
Several research institutions and the Accelerating Medicines Partnership in Rheumatoid Arthritis and Lupus Network, a public-private partnership involving several pharmaceutical companies, patient advocacy groups, and the National Institutes of Health, funded the study.
SOURCE: Orange D et al. Arthritis Rheumatol. 2018 Feb 22. doi: 10.1002/art.40428.
FROM ARTHRITIS & RHEUMATOLOGY
Key clinical point: Mechanisms of pain may differ in RA patients with different synovial subtypes.
Major findings:
Study details: Twenty histologic features were assessed on 129 synovial tissue samples from 123 RA patients and 6 OA patients.
Disclosures: Several research institutions and the Accelerating Medicines Partnership in Rheumatoid Arthritis and Lupus Network, a public-private partnership involving several pharmaceutical companies, patient advocacy groups, and the National Institutes of Health, funded the study.
Source: Orange D et al. Arthritis Rheumatol. 2018 Feb 22. doi: 10.1002/art.40428.
ANA assay results differ widely in established lupus patients
A new study that shows wide variation in the results of commercially-available assays used to detect antinuclear antibodies in people with established systemic lupus erythematosus has thrown into question the assays’ role in determining eligibility for trials as well as their role in clinical practice.
The study’s findings of negative results ranging from 5% to 22% of samples with three different commercially available immunofluorescence assays (IFAs), one ELISA assay, and one bead-based multiplex assay reveal that “ANA negativity can occur in established lupus not infrequently [and] the use of certain ANA assays could affect the frequency of screen failures in the trial setting as well as the eventual utilization of an agent if approved for serologically active patients,” David S. Pisetsky, MD, PhD, of Duke University, Durham, N.C., and his associates wrote in their report published in Annals of the Rheumatic Diseases.
People with systemic lupus erythematosus (SLE) have been thought to be “almost invariably” ANA positive, leaving the usual performance of testing to initial evaluation but not later unless a patient seeks care from another provider or undergoes screening to determine eligibility for entry into clinical trials of new therapeutic agents even though existing assays are not validated for this purpose. This practice first began with the development of the monoclonal antibody belimumab (Benlysta). Phase 2 trials showed that patients who were serologically positive (ANA and/or anti-DNA) were more likely to respond to the agent. Phase 3 trials that followed enrolled only serological positive patients and met their endpoints, the investigators explained.
“In view of the increasing use of ANA for determining trial eligibility, an explanation of these observations is important since it can impact both trial enrollment and eventual utilization of a product approved for autoantibody positive patients,” they wrote.
The research team assessed sera from 103 SLE patients using three different IFAs, an ELISA assay, and a bead-based multiplex assay. Results showed that the frequency of ANA positivity varied markedly depending on the assay platform and kit used. Among the IFA kits, negative results varied from 5 to 23 of 103 samples (4.9%-22.3%), although some samples had indeterminate results. Negative results occurred in 12 (11.7%) of the ELISA samples and in 14 (13.6%) of the multiplex assay samples.
Patients who consistently tested ANA positive in all assays differed from those who had discordant results among assays based on their likelihood of historical anti-double stranded DNA positivity and low levels of C3 complement.
This difference may have implications for the use of assays to determine eligibility for entry into a trial, the investigators noted. They advised that clinical trial protocols should specify which kits can be used to determine eligibility and how they characteristically perform, particularly for patients with established disease.
“Since the ANA assay used for screening is often not specified in protocols, the selection of a kit could lead to as much as a 17% change in the number of screen failures,” they speculated. “Correspondingly, for products approved for serologically active SLE, the use of certain assays could determine whether a patient meets criteria for its use.”
Future studies are needed to identify the assays that are most informative as theranostic biomarkers. Questions also remain over whether ANA positivity should be a criterion for trial entry in people with SLE of long duration, and if people with seronegative disease should be studied separately, they added.
The Lupus Industry Council supported the study. No authors had conflicts of interest to declare.
SOURCE: Pisetsky D et al. Ann Rheum Dis. 2018 Feb 9. doi: 10.1136/annrheumdis-2017-212599
A new study that shows wide variation in the results of commercially-available assays used to detect antinuclear antibodies in people with established systemic lupus erythematosus has thrown into question the assays’ role in determining eligibility for trials as well as their role in clinical practice.
The study’s findings of negative results ranging from 5% to 22% of samples with three different commercially available immunofluorescence assays (IFAs), one ELISA assay, and one bead-based multiplex assay reveal that “ANA negativity can occur in established lupus not infrequently [and] the use of certain ANA assays could affect the frequency of screen failures in the trial setting as well as the eventual utilization of an agent if approved for serologically active patients,” David S. Pisetsky, MD, PhD, of Duke University, Durham, N.C., and his associates wrote in their report published in Annals of the Rheumatic Diseases.
People with systemic lupus erythematosus (SLE) have been thought to be “almost invariably” ANA positive, leaving the usual performance of testing to initial evaluation but not later unless a patient seeks care from another provider or undergoes screening to determine eligibility for entry into clinical trials of new therapeutic agents even though existing assays are not validated for this purpose. This practice first began with the development of the monoclonal antibody belimumab (Benlysta). Phase 2 trials showed that patients who were serologically positive (ANA and/or anti-DNA) were more likely to respond to the agent. Phase 3 trials that followed enrolled only serological positive patients and met their endpoints, the investigators explained.
“In view of the increasing use of ANA for determining trial eligibility, an explanation of these observations is important since it can impact both trial enrollment and eventual utilization of a product approved for autoantibody positive patients,” they wrote.
The research team assessed sera from 103 SLE patients using three different IFAs, an ELISA assay, and a bead-based multiplex assay. Results showed that the frequency of ANA positivity varied markedly depending on the assay platform and kit used. Among the IFA kits, negative results varied from 5 to 23 of 103 samples (4.9%-22.3%), although some samples had indeterminate results. Negative results occurred in 12 (11.7%) of the ELISA samples and in 14 (13.6%) of the multiplex assay samples.
Patients who consistently tested ANA positive in all assays differed from those who had discordant results among assays based on their likelihood of historical anti-double stranded DNA positivity and low levels of C3 complement.
This difference may have implications for the use of assays to determine eligibility for entry into a trial, the investigators noted. They advised that clinical trial protocols should specify which kits can be used to determine eligibility and how they characteristically perform, particularly for patients with established disease.
“Since the ANA assay used for screening is often not specified in protocols, the selection of a kit could lead to as much as a 17% change in the number of screen failures,” they speculated. “Correspondingly, for products approved for serologically active SLE, the use of certain assays could determine whether a patient meets criteria for its use.”
Future studies are needed to identify the assays that are most informative as theranostic biomarkers. Questions also remain over whether ANA positivity should be a criterion for trial entry in people with SLE of long duration, and if people with seronegative disease should be studied separately, they added.
The Lupus Industry Council supported the study. No authors had conflicts of interest to declare.
SOURCE: Pisetsky D et al. Ann Rheum Dis. 2018 Feb 9. doi: 10.1136/annrheumdis-2017-212599
A new study that shows wide variation in the results of commercially-available assays used to detect antinuclear antibodies in people with established systemic lupus erythematosus has thrown into question the assays’ role in determining eligibility for trials as well as their role in clinical practice.
The study’s findings of negative results ranging from 5% to 22% of samples with three different commercially available immunofluorescence assays (IFAs), one ELISA assay, and one bead-based multiplex assay reveal that “ANA negativity can occur in established lupus not infrequently [and] the use of certain ANA assays could affect the frequency of screen failures in the trial setting as well as the eventual utilization of an agent if approved for serologically active patients,” David S. Pisetsky, MD, PhD, of Duke University, Durham, N.C., and his associates wrote in their report published in Annals of the Rheumatic Diseases.
People with systemic lupus erythematosus (SLE) have been thought to be “almost invariably” ANA positive, leaving the usual performance of testing to initial evaluation but not later unless a patient seeks care from another provider or undergoes screening to determine eligibility for entry into clinical trials of new therapeutic agents even though existing assays are not validated for this purpose. This practice first began with the development of the monoclonal antibody belimumab (Benlysta). Phase 2 trials showed that patients who were serologically positive (ANA and/or anti-DNA) were more likely to respond to the agent. Phase 3 trials that followed enrolled only serological positive patients and met their endpoints, the investigators explained.
“In view of the increasing use of ANA for determining trial eligibility, an explanation of these observations is important since it can impact both trial enrollment and eventual utilization of a product approved for autoantibody positive patients,” they wrote.
The research team assessed sera from 103 SLE patients using three different IFAs, an ELISA assay, and a bead-based multiplex assay. Results showed that the frequency of ANA positivity varied markedly depending on the assay platform and kit used. Among the IFA kits, negative results varied from 5 to 23 of 103 samples (4.9%-22.3%), although some samples had indeterminate results. Negative results occurred in 12 (11.7%) of the ELISA samples and in 14 (13.6%) of the multiplex assay samples.
Patients who consistently tested ANA positive in all assays differed from those who had discordant results among assays based on their likelihood of historical anti-double stranded DNA positivity and low levels of C3 complement.
This difference may have implications for the use of assays to determine eligibility for entry into a trial, the investigators noted. They advised that clinical trial protocols should specify which kits can be used to determine eligibility and how they characteristically perform, particularly for patients with established disease.
“Since the ANA assay used for screening is often not specified in protocols, the selection of a kit could lead to as much as a 17% change in the number of screen failures,” they speculated. “Correspondingly, for products approved for serologically active SLE, the use of certain assays could determine whether a patient meets criteria for its use.”
Future studies are needed to identify the assays that are most informative as theranostic biomarkers. Questions also remain over whether ANA positivity should be a criterion for trial entry in people with SLE of long duration, and if people with seronegative disease should be studied separately, they added.
The Lupus Industry Council supported the study. No authors had conflicts of interest to declare.
SOURCE: Pisetsky D et al. Ann Rheum Dis. 2018 Feb 9. doi: 10.1136/annrheumdis-2017-212599
FROM ANNALS OF THE RHEUMATIC DISEASES
Key clinical point:
Main finding: ANA negativity varied from 5% to 22% of sera samples from 103 SLE patients with established disease.
Data source: Sera from 103 SLE patients were assessed using three different commercially available immunofluorescence assays, one ELISA assay, and one bead-based multiplex assay.
Disclosures: The Lupus Industry Council supported the study. No authors had conflicts of interest to declare.
Source: Pisetsky D et al. Ann Rheum Dis. 2018 Feb 9. doi: 10.1136/annrheumdis-2017-212599.
ACR sounds more welcoming tone in new biosimilars position paper
The American College of Rheumatology has shifted from a more cautious stance toward the use of biosimilars in clinical practice to now recommend in a new position statement that health care providers incorporate biosimilars, where appropriate, into treatment regimens for their patients living with rheumatic diseases.
“Now that biosimilars have been used successfully in Europe, with rigorously acquired data supporting their broader use, and , S. Louis Bridges Jr., MD, PhD, chair of the ACR Committee on Research, wrote with seven other authors of the position statement in Arthritis & Rheumatology.
The ACR position statement addresses the issues of immunogenicity, extrapolation of indications, interchangeability, substitution, switching, and cost surrounding biosimilars.
The position statement’s authors said they expect switching and nonmedical substitution to become as common in the United States as it is in the rest of the world. They do not anticipate efficacy and safety issues for biosimilars based on available data regarding switching between reference products and biosimilars and their understanding of product drift.
“However, we encourage vigorous postmarketing surveillance of both biosimilars and their reference products as we enter the era where patients may undergo multiple switches as a result of insurance company and [pharmacy benefits manager] formulary preferences,” they said.
Immunogenicity
Concerns about immunogenicity for biosimilars approved in the United States have mostly been well addressed through studies showing similar frequencies of binding and neutralizing antidrug antibodies (ADA) in biosimilars and their reference products. Furthermore, no safety signals between biosimilars and their reference products have been observed that suggest a differential effect of ADA on efficacy, safety, or patient outcomes, the authors said. But they noted that “if immunogenicity findings are to be extrapolated from one disease to additional indications, the subjects being studied should be those most likely to develop ADA, such as subjects not receiving concomitant immunosuppressive medications.” The results of comparative immunogenicity studies carried out to date also indicate that “a patient who develops ADA to a reference drug with resultant loss of clinical response should not be switched to its biosimilar.”
Again, the authors said postmarketing pharmacovigilance using observational registry data would be critical to assessing the effect of switching on immunogenicity.
Extrapolation of indications
The extrapolation of biosimilars to reference product indications for which the biosimilar was not assessed in clinical trials continues to “be an area of uneasiness” among clinicians “who are surprised to find” that a biosimilar can be approved for inflammatory bowel disease in the absence of clinical trials in the relevant patient populations, the authors said. In geographic areas where it is not mandatory to use biosimilars, this lack of confidence in extrapolation of indications may limit their acceptance, the authors wrote, but data from studies such as NOR-SWITCH and DANBIO have provided reassuring evidence to support regulated extrapolation of indication for biosimilars.
However, since extrapolation of indications also applies to pediatric patients who often metabolize drugs faster than adults, the position paper says that “it may be important” to conduct pharmacodynamic and pharmacokinetic studies in children as well as postmarketing surveillance “since potential immunogenicity may be of particular importance in these younger patients with chronic diseases who might encounter several biological agents during their lifetime.”
Substitution, interchangeability, and switching
The “interchangeability” regulatory pathway in the United States that would allow substitution at the point of dispensing has not been finalized, but most states have enacted, or are in the process of enacting, legislation to regulate the practice, the statement says.
While substitution describes a change made by someone other than the prescriber, the authors note that switching defines the “intentional change initiated by a health care provider in partnership with the patient” for economic or medical reasons. Switching has been studied most often in open-label extension studies of biosimilar clinic trials and has shown no loss of efficacy or increase in adverse events.
Dr. Fleischmann contended that substitution, extrapolation, and interchangeability of biosimilars in clinical practice remain gray areas. For example, in a clinical trial, patients switching from a reference product to a biosimilar may show equivalency of clinical response and adverse events. “But as rheumatologists, we don’t treat groups of patients; we treat individual patients and here the results may be different,” he wrote in Arthritis & Rheumatology.
While the white paper appropriately points out that interchangeability among multiple biosimilars is a question that should be answered in postmarketing registries, Dr. Fleischmann noted that no interchangeability study has been reported, even though the FDA has issued guidance on how a study should be done.
“Although interchangeability may be safe and effective in many patients, until the results of such a study are available and properly analyzed, it is only conjecture that interchangeability is appropriate and safe,” he said.
Costs
The white paper acknowledged that the “only anticipated advantage” of a biosimilar over its reference product was lower cost, since both drugs should be therapeutically equivalent. “The degree to which the availability of biosimilars in the U.S. will drive down the cost of biologic therapy, and who will benefit from any cost reductions remains to be seen,” the authors wrote.
“To incentivize the use of biosimilars,” the authors suggested that “commercial and government insurance programs could harmonize drug prices with patients’ out-of-pocket costs and provider reimbursement. Currently, however, patients with commercial insurance are likely to have similar copayments for both biosimilars and originator biologics because of [pharmacy benefits manager]– or plan-mandated patient cost sharing. Also, patients’ out-of-pocket costs for biosimilars in the Medicare Part D (self-administered drug) program likely will be higher than for originator biologics because of a flaw that maintains, rather than reduces, biosimilar patient cost sharing in the coverage gap (also known as the “donut hole”) until 2020.”
It is not at all clear that a biosimilar would be cheaper for the individual patient, Dr. Fleischmann said. “It may be cheaper to the pharmacy benefit management firm, but this may not really help patient access to these medications. It is also not clear that nonmedical substitution will be effective in every patient nor has it been demonstrated that extrapolation is effective,” he wrote.
No disclosures were listed for the authors of the position statement. Dr. Fleischmann is a consultant for AbbVie, Amgen, Bristol-Myers Squibb, Celltrion, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, Sanofi Aventis, and UCB.
SOURCES: Bridges S et al. Arthritis Rheumatol. 2018 Feb 7. doi: 10.1002/art.40388; and Fleischmann R. Arthritis Rheumatol. 2018 Feb 7. doi: 10.1002/art.40402
The American College of Rheumatology has shifted from a more cautious stance toward the use of biosimilars in clinical practice to now recommend in a new position statement that health care providers incorporate biosimilars, where appropriate, into treatment regimens for their patients living with rheumatic diseases.
“Now that biosimilars have been used successfully in Europe, with rigorously acquired data supporting their broader use, and , S. Louis Bridges Jr., MD, PhD, chair of the ACR Committee on Research, wrote with seven other authors of the position statement in Arthritis & Rheumatology.
The ACR position statement addresses the issues of immunogenicity, extrapolation of indications, interchangeability, substitution, switching, and cost surrounding biosimilars.
The position statement’s authors said they expect switching and nonmedical substitution to become as common in the United States as it is in the rest of the world. They do not anticipate efficacy and safety issues for biosimilars based on available data regarding switching between reference products and biosimilars and their understanding of product drift.
“However, we encourage vigorous postmarketing surveillance of both biosimilars and their reference products as we enter the era where patients may undergo multiple switches as a result of insurance company and [pharmacy benefits manager] formulary preferences,” they said.
Immunogenicity
Concerns about immunogenicity for biosimilars approved in the United States have mostly been well addressed through studies showing similar frequencies of binding and neutralizing antidrug antibodies (ADA) in biosimilars and their reference products. Furthermore, no safety signals between biosimilars and their reference products have been observed that suggest a differential effect of ADA on efficacy, safety, or patient outcomes, the authors said. But they noted that “if immunogenicity findings are to be extrapolated from one disease to additional indications, the subjects being studied should be those most likely to develop ADA, such as subjects not receiving concomitant immunosuppressive medications.” The results of comparative immunogenicity studies carried out to date also indicate that “a patient who develops ADA to a reference drug with resultant loss of clinical response should not be switched to its biosimilar.”
Again, the authors said postmarketing pharmacovigilance using observational registry data would be critical to assessing the effect of switching on immunogenicity.
Extrapolation of indications
The extrapolation of biosimilars to reference product indications for which the biosimilar was not assessed in clinical trials continues to “be an area of uneasiness” among clinicians “who are surprised to find” that a biosimilar can be approved for inflammatory bowel disease in the absence of clinical trials in the relevant patient populations, the authors said. In geographic areas where it is not mandatory to use biosimilars, this lack of confidence in extrapolation of indications may limit their acceptance, the authors wrote, but data from studies such as NOR-SWITCH and DANBIO have provided reassuring evidence to support regulated extrapolation of indication for biosimilars.
However, since extrapolation of indications also applies to pediatric patients who often metabolize drugs faster than adults, the position paper says that “it may be important” to conduct pharmacodynamic and pharmacokinetic studies in children as well as postmarketing surveillance “since potential immunogenicity may be of particular importance in these younger patients with chronic diseases who might encounter several biological agents during their lifetime.”
Substitution, interchangeability, and switching
The “interchangeability” regulatory pathway in the United States that would allow substitution at the point of dispensing has not been finalized, but most states have enacted, or are in the process of enacting, legislation to regulate the practice, the statement says.
While substitution describes a change made by someone other than the prescriber, the authors note that switching defines the “intentional change initiated by a health care provider in partnership with the patient” for economic or medical reasons. Switching has been studied most often in open-label extension studies of biosimilar clinic trials and has shown no loss of efficacy or increase in adverse events.
Dr. Fleischmann contended that substitution, extrapolation, and interchangeability of biosimilars in clinical practice remain gray areas. For example, in a clinical trial, patients switching from a reference product to a biosimilar may show equivalency of clinical response and adverse events. “But as rheumatologists, we don’t treat groups of patients; we treat individual patients and here the results may be different,” he wrote in Arthritis & Rheumatology.
While the white paper appropriately points out that interchangeability among multiple biosimilars is a question that should be answered in postmarketing registries, Dr. Fleischmann noted that no interchangeability study has been reported, even though the FDA has issued guidance on how a study should be done.
“Although interchangeability may be safe and effective in many patients, until the results of such a study are available and properly analyzed, it is only conjecture that interchangeability is appropriate and safe,” he said.
Costs
The white paper acknowledged that the “only anticipated advantage” of a biosimilar over its reference product was lower cost, since both drugs should be therapeutically equivalent. “The degree to which the availability of biosimilars in the U.S. will drive down the cost of biologic therapy, and who will benefit from any cost reductions remains to be seen,” the authors wrote.
“To incentivize the use of biosimilars,” the authors suggested that “commercial and government insurance programs could harmonize drug prices with patients’ out-of-pocket costs and provider reimbursement. Currently, however, patients with commercial insurance are likely to have similar copayments for both biosimilars and originator biologics because of [pharmacy benefits manager]– or plan-mandated patient cost sharing. Also, patients’ out-of-pocket costs for biosimilars in the Medicare Part D (self-administered drug) program likely will be higher than for originator biologics because of a flaw that maintains, rather than reduces, biosimilar patient cost sharing in the coverage gap (also known as the “donut hole”) until 2020.”
It is not at all clear that a biosimilar would be cheaper for the individual patient, Dr. Fleischmann said. “It may be cheaper to the pharmacy benefit management firm, but this may not really help patient access to these medications. It is also not clear that nonmedical substitution will be effective in every patient nor has it been demonstrated that extrapolation is effective,” he wrote.
No disclosures were listed for the authors of the position statement. Dr. Fleischmann is a consultant for AbbVie, Amgen, Bristol-Myers Squibb, Celltrion, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, Sanofi Aventis, and UCB.
SOURCES: Bridges S et al. Arthritis Rheumatol. 2018 Feb 7. doi: 10.1002/art.40388; and Fleischmann R. Arthritis Rheumatol. 2018 Feb 7. doi: 10.1002/art.40402
The American College of Rheumatology has shifted from a more cautious stance toward the use of biosimilars in clinical practice to now recommend in a new position statement that health care providers incorporate biosimilars, where appropriate, into treatment regimens for their patients living with rheumatic diseases.
“Now that biosimilars have been used successfully in Europe, with rigorously acquired data supporting their broader use, and , S. Louis Bridges Jr., MD, PhD, chair of the ACR Committee on Research, wrote with seven other authors of the position statement in Arthritis & Rheumatology.
The ACR position statement addresses the issues of immunogenicity, extrapolation of indications, interchangeability, substitution, switching, and cost surrounding biosimilars.
The position statement’s authors said they expect switching and nonmedical substitution to become as common in the United States as it is in the rest of the world. They do not anticipate efficacy and safety issues for biosimilars based on available data regarding switching between reference products and biosimilars and their understanding of product drift.
“However, we encourage vigorous postmarketing surveillance of both biosimilars and their reference products as we enter the era where patients may undergo multiple switches as a result of insurance company and [pharmacy benefits manager] formulary preferences,” they said.
Immunogenicity
Concerns about immunogenicity for biosimilars approved in the United States have mostly been well addressed through studies showing similar frequencies of binding and neutralizing antidrug antibodies (ADA) in biosimilars and their reference products. Furthermore, no safety signals between biosimilars and their reference products have been observed that suggest a differential effect of ADA on efficacy, safety, or patient outcomes, the authors said. But they noted that “if immunogenicity findings are to be extrapolated from one disease to additional indications, the subjects being studied should be those most likely to develop ADA, such as subjects not receiving concomitant immunosuppressive medications.” The results of comparative immunogenicity studies carried out to date also indicate that “a patient who develops ADA to a reference drug with resultant loss of clinical response should not be switched to its biosimilar.”
Again, the authors said postmarketing pharmacovigilance using observational registry data would be critical to assessing the effect of switching on immunogenicity.
Extrapolation of indications
The extrapolation of biosimilars to reference product indications for which the biosimilar was not assessed in clinical trials continues to “be an area of uneasiness” among clinicians “who are surprised to find” that a biosimilar can be approved for inflammatory bowel disease in the absence of clinical trials in the relevant patient populations, the authors said. In geographic areas where it is not mandatory to use biosimilars, this lack of confidence in extrapolation of indications may limit their acceptance, the authors wrote, but data from studies such as NOR-SWITCH and DANBIO have provided reassuring evidence to support regulated extrapolation of indication for biosimilars.
However, since extrapolation of indications also applies to pediatric patients who often metabolize drugs faster than adults, the position paper says that “it may be important” to conduct pharmacodynamic and pharmacokinetic studies in children as well as postmarketing surveillance “since potential immunogenicity may be of particular importance in these younger patients with chronic diseases who might encounter several biological agents during their lifetime.”
Substitution, interchangeability, and switching
The “interchangeability” regulatory pathway in the United States that would allow substitution at the point of dispensing has not been finalized, but most states have enacted, or are in the process of enacting, legislation to regulate the practice, the statement says.
While substitution describes a change made by someone other than the prescriber, the authors note that switching defines the “intentional change initiated by a health care provider in partnership with the patient” for economic or medical reasons. Switching has been studied most often in open-label extension studies of biosimilar clinic trials and has shown no loss of efficacy or increase in adverse events.
Dr. Fleischmann contended that substitution, extrapolation, and interchangeability of biosimilars in clinical practice remain gray areas. For example, in a clinical trial, patients switching from a reference product to a biosimilar may show equivalency of clinical response and adverse events. “But as rheumatologists, we don’t treat groups of patients; we treat individual patients and here the results may be different,” he wrote in Arthritis & Rheumatology.
While the white paper appropriately points out that interchangeability among multiple biosimilars is a question that should be answered in postmarketing registries, Dr. Fleischmann noted that no interchangeability study has been reported, even though the FDA has issued guidance on how a study should be done.
“Although interchangeability may be safe and effective in many patients, until the results of such a study are available and properly analyzed, it is only conjecture that interchangeability is appropriate and safe,” he said.
Costs
The white paper acknowledged that the “only anticipated advantage” of a biosimilar over its reference product was lower cost, since both drugs should be therapeutically equivalent. “The degree to which the availability of biosimilars in the U.S. will drive down the cost of biologic therapy, and who will benefit from any cost reductions remains to be seen,” the authors wrote.
“To incentivize the use of biosimilars,” the authors suggested that “commercial and government insurance programs could harmonize drug prices with patients’ out-of-pocket costs and provider reimbursement. Currently, however, patients with commercial insurance are likely to have similar copayments for both biosimilars and originator biologics because of [pharmacy benefits manager]– or plan-mandated patient cost sharing. Also, patients’ out-of-pocket costs for biosimilars in the Medicare Part D (self-administered drug) program likely will be higher than for originator biologics because of a flaw that maintains, rather than reduces, biosimilar patient cost sharing in the coverage gap (also known as the “donut hole”) until 2020.”
It is not at all clear that a biosimilar would be cheaper for the individual patient, Dr. Fleischmann said. “It may be cheaper to the pharmacy benefit management firm, but this may not really help patient access to these medications. It is also not clear that nonmedical substitution will be effective in every patient nor has it been demonstrated that extrapolation is effective,” he wrote.
No disclosures were listed for the authors of the position statement. Dr. Fleischmann is a consultant for AbbVie, Amgen, Bristol-Myers Squibb, Celltrion, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, Sanofi Aventis, and UCB.
SOURCES: Bridges S et al. Arthritis Rheumatol. 2018 Feb 7. doi: 10.1002/art.40388; and Fleischmann R. Arthritis Rheumatol. 2018 Feb 7. doi: 10.1002/art.40402
FROM ARTHRITIS & RHEUMATOLOGY
Checkpoint inhibitors look safe in rheumatology patients
People with rheumatologic diseases and cancer appear to be at no higher risk of having an adverse event or disease flare if they receive checkpoint inhibitor therapy, compared with the general population, experience from the Mayo Clinic suggests.
In a brief report published in Arthritis and Rheumatology, a team from the Mayo Clinic in Rochester, Minn., reported on 16 patients with rheumatologic diseases who received cancer immunotherapy. They found that only a minority experienced a flare of their disease or another immune-related event.
The rate of severe immune-related adverse effects (IRAEs) with a single immune checkpoint inhibitor (ICI) has been reported to be less than 2% among the average population. However, less is known about patients with underlying rheumatologic disease, largely because initial trials of ICIs had excluded patients with autoimmune diseases for fear the treatment would induce a disease flare, the researchers noted.
Small studies have suggested that people with inflammatory arthritis or connective tissue diseases have higher rates of IRAEs with immunotherapy, but it is unclear how often these events represented flares of their disease or new autoimmune events, and whether the events had any predictive significance for cancer survival.
In this study, researchers performed a retrospective review of medical records and identified 16 patients with rheumatologic diseases who had received checkpoint inhibitor therapy at the Mayo Clinic between 2011 and 2016.
The most common rheumatologic diseases among the 16 patients were rheumatoid arthritis, polymyalgia rheumatica, Sjögren’s syndrome, and systemic lupus erythematosus, and the most common cancers were malignant melanoma, pulmonary malignancies, and non-Hodgkin lymphoma. Seven of the patients were receiving immunosuppressive therapy or glucocorticoids for their rheumatologic disease upon initiation of a checkpoint inhibitor.
Ten patients had received a prior disease-modifying antirheumatic drug, but only two patients were still taking this at the time of ICI initiation.
Results showed that six of the patients (38%) had an IRAE or flare of their rheumatologic disease, two were graded as mild. All of the patients responded well to glucocorticoids and discontinuation of therapy. The most common event was colitis and just one patient had a flare of rheumatologic disease.
“This is consistent with what is currently known about the management of IRAEs,” the research team wrote. “This study adds further support to the emerging notion that the rate of IRAEs is not necessarily higher in this group compared to the general population.”
The type and severity of rheumatologic disease may play an important role in both the risk of disease flare and IRAEs, a factor that they were unable to assess in the current study, the researchers wrote.
“Further large, prospective studies are needed to address the link between the type, severity, and concurrent rheumatologic disease activity on the risk of flare and IRAE. It is possible that patients with more severe or active disease are at higher risk for these complications,” they wrote.
While patients in the study did not appear to have significantly increased incidence or severity of adverse effects, the research team advised that “treatment decisions must factor in clinical judgement.”
They noted that some studies had proposed predictive biomarkers, pretreatment workup, and monitoring, but this advice was based on a small body of evidence.
“Larger, prospective studies will be necessary to validate these findings and establish evidence-based guidelines for appropriate identification and rating of the rheumatologic IRAEs as well as their treatment, such that patients can continue to receive potentially life-saving cancer treatments,” they wrote.
One of the researchers reported advisory board membership with Bristol-Myers Squibb.
SOURCE: Richter M et al. Arthritis Rheumatol. 2018 Jan 24. doi: 10.1002/art.40397.
People with rheumatologic diseases and cancer appear to be at no higher risk of having an adverse event or disease flare if they receive checkpoint inhibitor therapy, compared with the general population, experience from the Mayo Clinic suggests.
In a brief report published in Arthritis and Rheumatology, a team from the Mayo Clinic in Rochester, Minn., reported on 16 patients with rheumatologic diseases who received cancer immunotherapy. They found that only a minority experienced a flare of their disease or another immune-related event.
The rate of severe immune-related adverse effects (IRAEs) with a single immune checkpoint inhibitor (ICI) has been reported to be less than 2% among the average population. However, less is known about patients with underlying rheumatologic disease, largely because initial trials of ICIs had excluded patients with autoimmune diseases for fear the treatment would induce a disease flare, the researchers noted.
Small studies have suggested that people with inflammatory arthritis or connective tissue diseases have higher rates of IRAEs with immunotherapy, but it is unclear how often these events represented flares of their disease or new autoimmune events, and whether the events had any predictive significance for cancer survival.
In this study, researchers performed a retrospective review of medical records and identified 16 patients with rheumatologic diseases who had received checkpoint inhibitor therapy at the Mayo Clinic between 2011 and 2016.
The most common rheumatologic diseases among the 16 patients were rheumatoid arthritis, polymyalgia rheumatica, Sjögren’s syndrome, and systemic lupus erythematosus, and the most common cancers were malignant melanoma, pulmonary malignancies, and non-Hodgkin lymphoma. Seven of the patients were receiving immunosuppressive therapy or glucocorticoids for their rheumatologic disease upon initiation of a checkpoint inhibitor.
Ten patients had received a prior disease-modifying antirheumatic drug, but only two patients were still taking this at the time of ICI initiation.
Results showed that six of the patients (38%) had an IRAE or flare of their rheumatologic disease, two were graded as mild. All of the patients responded well to glucocorticoids and discontinuation of therapy. The most common event was colitis and just one patient had a flare of rheumatologic disease.
“This is consistent with what is currently known about the management of IRAEs,” the research team wrote. “This study adds further support to the emerging notion that the rate of IRAEs is not necessarily higher in this group compared to the general population.”
The type and severity of rheumatologic disease may play an important role in both the risk of disease flare and IRAEs, a factor that they were unable to assess in the current study, the researchers wrote.
“Further large, prospective studies are needed to address the link between the type, severity, and concurrent rheumatologic disease activity on the risk of flare and IRAE. It is possible that patients with more severe or active disease are at higher risk for these complications,” they wrote.
While patients in the study did not appear to have significantly increased incidence or severity of adverse effects, the research team advised that “treatment decisions must factor in clinical judgement.”
They noted that some studies had proposed predictive biomarkers, pretreatment workup, and monitoring, but this advice was based on a small body of evidence.
“Larger, prospective studies will be necessary to validate these findings and establish evidence-based guidelines for appropriate identification and rating of the rheumatologic IRAEs as well as their treatment, such that patients can continue to receive potentially life-saving cancer treatments,” they wrote.
One of the researchers reported advisory board membership with Bristol-Myers Squibb.
SOURCE: Richter M et al. Arthritis Rheumatol. 2018 Jan 24. doi: 10.1002/art.40397.
People with rheumatologic diseases and cancer appear to be at no higher risk of having an adverse event or disease flare if they receive checkpoint inhibitor therapy, compared with the general population, experience from the Mayo Clinic suggests.
In a brief report published in Arthritis and Rheumatology, a team from the Mayo Clinic in Rochester, Minn., reported on 16 patients with rheumatologic diseases who received cancer immunotherapy. They found that only a minority experienced a flare of their disease or another immune-related event.
The rate of severe immune-related adverse effects (IRAEs) with a single immune checkpoint inhibitor (ICI) has been reported to be less than 2% among the average population. However, less is known about patients with underlying rheumatologic disease, largely because initial trials of ICIs had excluded patients with autoimmune diseases for fear the treatment would induce a disease flare, the researchers noted.
Small studies have suggested that people with inflammatory arthritis or connective tissue diseases have higher rates of IRAEs with immunotherapy, but it is unclear how often these events represented flares of their disease or new autoimmune events, and whether the events had any predictive significance for cancer survival.
In this study, researchers performed a retrospective review of medical records and identified 16 patients with rheumatologic diseases who had received checkpoint inhibitor therapy at the Mayo Clinic between 2011 and 2016.
The most common rheumatologic diseases among the 16 patients were rheumatoid arthritis, polymyalgia rheumatica, Sjögren’s syndrome, and systemic lupus erythematosus, and the most common cancers were malignant melanoma, pulmonary malignancies, and non-Hodgkin lymphoma. Seven of the patients were receiving immunosuppressive therapy or glucocorticoids for their rheumatologic disease upon initiation of a checkpoint inhibitor.
Ten patients had received a prior disease-modifying antirheumatic drug, but only two patients were still taking this at the time of ICI initiation.
Results showed that six of the patients (38%) had an IRAE or flare of their rheumatologic disease, two were graded as mild. All of the patients responded well to glucocorticoids and discontinuation of therapy. The most common event was colitis and just one patient had a flare of rheumatologic disease.
“This is consistent with what is currently known about the management of IRAEs,” the research team wrote. “This study adds further support to the emerging notion that the rate of IRAEs is not necessarily higher in this group compared to the general population.”
The type and severity of rheumatologic disease may play an important role in both the risk of disease flare and IRAEs, a factor that they were unable to assess in the current study, the researchers wrote.
“Further large, prospective studies are needed to address the link between the type, severity, and concurrent rheumatologic disease activity on the risk of flare and IRAE. It is possible that patients with more severe or active disease are at higher risk for these complications,” they wrote.
While patients in the study did not appear to have significantly increased incidence or severity of adverse effects, the research team advised that “treatment decisions must factor in clinical judgement.”
They noted that some studies had proposed predictive biomarkers, pretreatment workup, and monitoring, but this advice was based on a small body of evidence.
“Larger, prospective studies will be necessary to validate these findings and establish evidence-based guidelines for appropriate identification and rating of the rheumatologic IRAEs as well as their treatment, such that patients can continue to receive potentially life-saving cancer treatments,” they wrote.
One of the researchers reported advisory board membership with Bristol-Myers Squibb.
SOURCE: Richter M et al. Arthritis Rheumatol. 2018 Jan 24. doi: 10.1002/art.40397.
FROM ARTHRITIS AND RHEUMATOLOGY
Key clinical point:
Major finding: Six of 16 patients (38%) with rheumatologic disease and cancer had an IRAE or flare of their rheumatologic disease.
Study details: A single-center, retrospective records review to identify patients with rheumatologic diseases who had received checkpoint inhibitor therapy at Mayo Clinic between 2011 and 2016.
Disclosures: One of the authors reported advisory board membership with Bristol-Myers Squibb.
Source: Richter M et al. Arthritis Rheumatol. 2018 Jan 24. doi: 10.1002/art.40397.
Ultrasound could have utility in predicting which RA patients stay in remission
Synovitis detected by ultrasound in patients with rheumatoid arthritis (RA) in clinical remission has a moderate but significant independent predictive value for the loss of remission, new research shows.
These findings, reported by Swiss investigators at multiple centers and with different sonographers and ultrasound (US) machines, adds to previous research that has shown that patients in clinical remission with US-detected residual synovitis had a tendency to flare more often and have a shorter duration of remission than did patients with sonographic remission.
“It is currently unknown whether the predictive value of US regarding flares and the duration of remission remains valid in the context of a large group of US assessors using different US machines, as encountered in a real-life setting,” wrote the research team, who conducted the research on behalf of the Swiss Sonography in Arthritis and Rheumatism group and the Swiss Clinical Quality Management in Rheumatic Diseases Foundation.
“Moreover, it remains unclear whether US should be recommended in everyday clinical practice to support therapeutic decisions and to monitor clinical remission,” they added.
In the current study, Dr. Zufferey and his associates analyzed how long 318 RA patients from the Swiss Clinical Quality Management in Rheumatic Diseases cohort remained in remission after they had their first US during remission. The investigators defined loss of remission in this study as either having a 28-joint Disease Activity Score greater than 2.6 or needing to step up treatment with disease-modifying antirheumatic drugs.
The researchers used a previously validated score developed by the Swiss Sonography in Arthritis and Rheumatism group for the definition of US-detected residual synovitis by using cutoffs for B-mode, Doppler, and combined modes that had been defined by previous studies. For example, the cutoffs for significant US-detected residual synovitis were: B-mode of 2 or more joints with synovitis grade of 2 or greater or a total B-mode score greater than 8 points (max score 66 points) and any Doppler activity inside the joint. A combined US synovitis score was defined as B-mode score greater than 8 and/or any Doppler-detected residual synovitis. Patients in clinical remission with a baseline US score above these cutoffs were considered to have significant US-detected residual synovitis (US+), compared with patients who did not have residual synovitis (US–).
The research team observed a loss of remission in 60% of 378 remission phases, with having a 28-joint Disease Activity Score greater than 2.6 deciding the loss of remission status in 66% of cases in both the US+ and the US– groups.
The time from the first US during remission to loss of remission was 2-5 months longer for US– patients than it was for US+ patients.
“After adjusting for potential confounders, [the hazard ratio] of loss of remission for all remission phases using the complete follow-up time was higher for patients with US-detected synovitis at baseline than for those without (combined US score hazard ratio, 1.4; 95% CI, 1.03-2.00 vs. HR, 1.5; 95% CI, 1.1-2.1 for left and right imputation, respectively),” the investigators wrote.
Hazard ratios for the loss of remission also showed a two- to threefold increase when US measurements were taken early in remission (that is, within 3-6 months), a finding that the authors wrote indicated “that the short-term predictive power of US-detected residual synovitis may be more significant than its long-term predictive power.”
The researchers concluded that their study showed that US could be useful in predicting how long patients were likely to remain in remission in “real-life conditions,” but said questions remained over whether it should be used at an individual level.
“According to our results, in particular regarding the moderate HR, a single US done in remission cannot be used as the unique predictor of flare,” they wrote.
Nevertheless, their results may have “some importance in promoting the widespread use of US in real-life conditions for the follow-up of RA, especially when in remission,” they said.
“The next step would be to evaluate whether previous US performed prior to reaching remission and repeated US performed while in remission, particularly after 3-6 months, could provide additional information that is useful to the clinician,” they added.
The Swiss Clinical Quality Management Foundation is supported by the Swiss Society of Rheumatology and nine pharmaceutical companies.
SOURCE: Zufferey P et al. J Rheumatol. 2018 Jan 15. doi: 10.3899/jrheum.161193
Synovitis detected by ultrasound in patients with rheumatoid arthritis (RA) in clinical remission has a moderate but significant independent predictive value for the loss of remission, new research shows.
These findings, reported by Swiss investigators at multiple centers and with different sonographers and ultrasound (US) machines, adds to previous research that has shown that patients in clinical remission with US-detected residual synovitis had a tendency to flare more often and have a shorter duration of remission than did patients with sonographic remission.
“It is currently unknown whether the predictive value of US regarding flares and the duration of remission remains valid in the context of a large group of US assessors using different US machines, as encountered in a real-life setting,” wrote the research team, who conducted the research on behalf of the Swiss Sonography in Arthritis and Rheumatism group and the Swiss Clinical Quality Management in Rheumatic Diseases Foundation.
“Moreover, it remains unclear whether US should be recommended in everyday clinical practice to support therapeutic decisions and to monitor clinical remission,” they added.
In the current study, Dr. Zufferey and his associates analyzed how long 318 RA patients from the Swiss Clinical Quality Management in Rheumatic Diseases cohort remained in remission after they had their first US during remission. The investigators defined loss of remission in this study as either having a 28-joint Disease Activity Score greater than 2.6 or needing to step up treatment with disease-modifying antirheumatic drugs.
The researchers used a previously validated score developed by the Swiss Sonography in Arthritis and Rheumatism group for the definition of US-detected residual synovitis by using cutoffs for B-mode, Doppler, and combined modes that had been defined by previous studies. For example, the cutoffs for significant US-detected residual synovitis were: B-mode of 2 or more joints with synovitis grade of 2 or greater or a total B-mode score greater than 8 points (max score 66 points) and any Doppler activity inside the joint. A combined US synovitis score was defined as B-mode score greater than 8 and/or any Doppler-detected residual synovitis. Patients in clinical remission with a baseline US score above these cutoffs were considered to have significant US-detected residual synovitis (US+), compared with patients who did not have residual synovitis (US–).
The research team observed a loss of remission in 60% of 378 remission phases, with having a 28-joint Disease Activity Score greater than 2.6 deciding the loss of remission status in 66% of cases in both the US+ and the US– groups.
The time from the first US during remission to loss of remission was 2-5 months longer for US– patients than it was for US+ patients.
“After adjusting for potential confounders, [the hazard ratio] of loss of remission for all remission phases using the complete follow-up time was higher for patients with US-detected synovitis at baseline than for those without (combined US score hazard ratio, 1.4; 95% CI, 1.03-2.00 vs. HR, 1.5; 95% CI, 1.1-2.1 for left and right imputation, respectively),” the investigators wrote.
Hazard ratios for the loss of remission also showed a two- to threefold increase when US measurements were taken early in remission (that is, within 3-6 months), a finding that the authors wrote indicated “that the short-term predictive power of US-detected residual synovitis may be more significant than its long-term predictive power.”
The researchers concluded that their study showed that US could be useful in predicting how long patients were likely to remain in remission in “real-life conditions,” but said questions remained over whether it should be used at an individual level.
“According to our results, in particular regarding the moderate HR, a single US done in remission cannot be used as the unique predictor of flare,” they wrote.
Nevertheless, their results may have “some importance in promoting the widespread use of US in real-life conditions for the follow-up of RA, especially when in remission,” they said.
“The next step would be to evaluate whether previous US performed prior to reaching remission and repeated US performed while in remission, particularly after 3-6 months, could provide additional information that is useful to the clinician,” they added.
The Swiss Clinical Quality Management Foundation is supported by the Swiss Society of Rheumatology and nine pharmaceutical companies.
SOURCE: Zufferey P et al. J Rheumatol. 2018 Jan 15. doi: 10.3899/jrheum.161193
Synovitis detected by ultrasound in patients with rheumatoid arthritis (RA) in clinical remission has a moderate but significant independent predictive value for the loss of remission, new research shows.
These findings, reported by Swiss investigators at multiple centers and with different sonographers and ultrasound (US) machines, adds to previous research that has shown that patients in clinical remission with US-detected residual synovitis had a tendency to flare more often and have a shorter duration of remission than did patients with sonographic remission.
“It is currently unknown whether the predictive value of US regarding flares and the duration of remission remains valid in the context of a large group of US assessors using different US machines, as encountered in a real-life setting,” wrote the research team, who conducted the research on behalf of the Swiss Sonography in Arthritis and Rheumatism group and the Swiss Clinical Quality Management in Rheumatic Diseases Foundation.
“Moreover, it remains unclear whether US should be recommended in everyday clinical practice to support therapeutic decisions and to monitor clinical remission,” they added.
In the current study, Dr. Zufferey and his associates analyzed how long 318 RA patients from the Swiss Clinical Quality Management in Rheumatic Diseases cohort remained in remission after they had their first US during remission. The investigators defined loss of remission in this study as either having a 28-joint Disease Activity Score greater than 2.6 or needing to step up treatment with disease-modifying antirheumatic drugs.
The researchers used a previously validated score developed by the Swiss Sonography in Arthritis and Rheumatism group for the definition of US-detected residual synovitis by using cutoffs for B-mode, Doppler, and combined modes that had been defined by previous studies. For example, the cutoffs for significant US-detected residual synovitis were: B-mode of 2 or more joints with synovitis grade of 2 or greater or a total B-mode score greater than 8 points (max score 66 points) and any Doppler activity inside the joint. A combined US synovitis score was defined as B-mode score greater than 8 and/or any Doppler-detected residual synovitis. Patients in clinical remission with a baseline US score above these cutoffs were considered to have significant US-detected residual synovitis (US+), compared with patients who did not have residual synovitis (US–).
The research team observed a loss of remission in 60% of 378 remission phases, with having a 28-joint Disease Activity Score greater than 2.6 deciding the loss of remission status in 66% of cases in both the US+ and the US– groups.
The time from the first US during remission to loss of remission was 2-5 months longer for US– patients than it was for US+ patients.
“After adjusting for potential confounders, [the hazard ratio] of loss of remission for all remission phases using the complete follow-up time was higher for patients with US-detected synovitis at baseline than for those without (combined US score hazard ratio, 1.4; 95% CI, 1.03-2.00 vs. HR, 1.5; 95% CI, 1.1-2.1 for left and right imputation, respectively),” the investigators wrote.
Hazard ratios for the loss of remission also showed a two- to threefold increase when US measurements were taken early in remission (that is, within 3-6 months), a finding that the authors wrote indicated “that the short-term predictive power of US-detected residual synovitis may be more significant than its long-term predictive power.”
The researchers concluded that their study showed that US could be useful in predicting how long patients were likely to remain in remission in “real-life conditions,” but said questions remained over whether it should be used at an individual level.
“According to our results, in particular regarding the moderate HR, a single US done in remission cannot be used as the unique predictor of flare,” they wrote.
Nevertheless, their results may have “some importance in promoting the widespread use of US in real-life conditions for the follow-up of RA, especially when in remission,” they said.
“The next step would be to evaluate whether previous US performed prior to reaching remission and repeated US performed while in remission, particularly after 3-6 months, could provide additional information that is useful to the clinician,” they added.
The Swiss Clinical Quality Management Foundation is supported by the Swiss Society of Rheumatology and nine pharmaceutical companies.
SOURCE: Zufferey P et al. J Rheumatol. 2018 Jan 15. doi: 10.3899/jrheum.161193
FROM JOURNAL OF RHEUMATOLOGY
Key clinical point: Ultrasound could be useful in predicting how long patients are likely to remain in remission in “real-life conditions.”
Major finding: Hazard ratios (HRs) for loss of remission were moderately but significantly higher for patients with ultrasound-detected synovitis at baseline than for those without (combined ultrasound score HR, 1.4; 95% CI, 1.03-2.00 vs. HR, 1.5; 95% CI, 1.1-2.1 for left and right imputation, respectively).
Study details: A multicenter cohort study of 318 RA patients from the Swiss Clinical Quality Management cohort.
Disclosures: The Swiss Clinical Quality Management Foundation is supported by the Swiss Society of Rheumatology and nine pharmaceutical companies.
Source: Zufferey P et al. J Rheumatol. 2018 Jan 15. doi: 10.3899/jrheum.161193