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Most in-hospital pneumonia deaths may not be preventable
Most in-hospital deaths from community-acquired pneumonia are not preventable with current medical therapy, according to an analysis of deaths at five U.S. hospitals with expertise in pneumonia care.
Adults who are hospitalized with community-acquired pneumonia (CAP) are at high risk for short-term mortality but it is unclear whether an improvement in care could lower this risk, noted the study authors led by Grant W. Waterer, MBBS, PhD, of Northwestern University, Chicago.
“Understanding the circumstances in which CAP patients die could facilitate improvements in the management of CAP by enabling future improvement efforts to focus on common preventable causes of death,” they wrote. Their report was published in CHEST®.
They therefore performed a secondary analysis of the Etiology of Pneumonia in the Community (EPIC) study involving adults hospitalized with CAP between January 2010 and June 2012 across five tertiary-care hospitals in the United States.
The clinical characteristics of patients who died in the hospital were compared with those of patients who survived to hospital discharge. Chronic heart failure, chronic obstructive pulmonary disease, coronary artery disease, chronic liver disease, cerebrovascular disease, cancer (excluding skin cancer), and diabetes were considered as severe chronic comorbidities based on their association with increased mortality and ICU admission in CAP severity scores.
Deaths caused by septic shock, respiratory failure, multisystem organ failure, cardiopulmonary arrest prior to stabilization of CAP, and endocarditis, were considered to be directly related to CAP.
Conversely, causes of death indirectly related to CAP included acute cardiovascular disease, stroke, acute renal failure, and secondary infections developed after hospitalization. Deaths caused by cancer, cirrhosis, and chronic neurologic conditions were considered unrelated to CAP.
Medical notes were assessed to determine whether the patient received management consistent with current recommendations; for example, antibiotics consistent with guidelines from the Infectious Diseases Society of America.
End-of-life limitations in care, such as patient/family decision not to proceed with full medical treatment, also were considered by the research team.
Results showed that among the 2,320 patients with radiographically confirmed CAP, 52 died during initial hospitalization, 33 of whom were aged 65 years or older, and 32 of whom had two or more chronic comorbidities.
Most of the in-hospital deaths occurred early in the hospitalization: 35 within the first 10 days of admission, and 5 after 30 days in hospital.
CAP was judged by an expert physician review panel to be the direct cause of death in 27 of the patients, 10 with CAP having an indirect role with major contribution, 9 with CAP having an indirect role with minor contribution, and 6 with CAP having no role in death.
Do-not-resuscitate orders were present at the time of death for 21 of the patients.
Forty-five of the patients were admitted to an ICU, with 37 dying in the ICU. The eight patients who died on the ward after transfer out of the ICU had end-of-life limitations of care in place.
The researchers noted that the number of patients dying in the ICU was greater in the United States, possibly because in Europe fewer patients are admitted to an ICU.
“This discrepancy likely reflects cultural differences between the U.S. and Europe in the role of intensive care for patients with advanced age and/or advanced comorbid conditions,” they noted.
Overall, the physician review panel identified nine patients who had a lapse in quality of in-hospital CAP care, with four of the deaths potentially linked to this lapse in care.
However, two of the patients had end-of-life limitations of care in place, which according to the authors meant that “only two patients undergoing full medical treatment without end-of-life limitations of care had an identified lapse in quality of in-hospital pneumonia care potentially contributing to in-hospital death, including one with a delay in antibiotics for over an hour in the presence of shock and one with initial antibiotics not consistent with IDSA/ATS guidelines.”
The research team concluded that most in-hospital deaths among adult patients admitted with CAP in their study would not have been preventable with higher quality in-hospital pneumonia care.
“Many of the in-hospital deaths among patients admitted with CAP occurred in older patients with severe comorbidities and end-of-life limitations in care,” they noted.
They said the influence of end-of-life limitations on care short of full palliation was an important finding, with all patients who died outside the ICU having end-of-life limitations in care.
“Current diagnostic related group (DRG) and international classification of diseases (ICD) coding systems do not have the necessary nuances to capture these limitations of care, yet they are clearly important factors in determining whether patients experience in-hospital death,” they added.
Dr. Waterer reported no conflicts. Two coauthors reported potential conflicts of interest in relation to consulting fees from several pharmaceutical companies.
SOURCE: Waterer G. et al. CHEST 2018;154(3):628-35. doi: 10.1016/j.chest.2018.05.021.
Most in-hospital deaths from community-acquired pneumonia are not preventable with current medical therapy, according to an analysis of deaths at five U.S. hospitals with expertise in pneumonia care.
Adults who are hospitalized with community-acquired pneumonia (CAP) are at high risk for short-term mortality but it is unclear whether an improvement in care could lower this risk, noted the study authors led by Grant W. Waterer, MBBS, PhD, of Northwestern University, Chicago.
“Understanding the circumstances in which CAP patients die could facilitate improvements in the management of CAP by enabling future improvement efforts to focus on common preventable causes of death,” they wrote. Their report was published in CHEST®.
They therefore performed a secondary analysis of the Etiology of Pneumonia in the Community (EPIC) study involving adults hospitalized with CAP between January 2010 and June 2012 across five tertiary-care hospitals in the United States.
The clinical characteristics of patients who died in the hospital were compared with those of patients who survived to hospital discharge. Chronic heart failure, chronic obstructive pulmonary disease, coronary artery disease, chronic liver disease, cerebrovascular disease, cancer (excluding skin cancer), and diabetes were considered as severe chronic comorbidities based on their association with increased mortality and ICU admission in CAP severity scores.
Deaths caused by septic shock, respiratory failure, multisystem organ failure, cardiopulmonary arrest prior to stabilization of CAP, and endocarditis, were considered to be directly related to CAP.
Conversely, causes of death indirectly related to CAP included acute cardiovascular disease, stroke, acute renal failure, and secondary infections developed after hospitalization. Deaths caused by cancer, cirrhosis, and chronic neurologic conditions were considered unrelated to CAP.
Medical notes were assessed to determine whether the patient received management consistent with current recommendations; for example, antibiotics consistent with guidelines from the Infectious Diseases Society of America.
End-of-life limitations in care, such as patient/family decision not to proceed with full medical treatment, also were considered by the research team.
Results showed that among the 2,320 patients with radiographically confirmed CAP, 52 died during initial hospitalization, 33 of whom were aged 65 years or older, and 32 of whom had two or more chronic comorbidities.
Most of the in-hospital deaths occurred early in the hospitalization: 35 within the first 10 days of admission, and 5 after 30 days in hospital.
CAP was judged by an expert physician review panel to be the direct cause of death in 27 of the patients, 10 with CAP having an indirect role with major contribution, 9 with CAP having an indirect role with minor contribution, and 6 with CAP having no role in death.
Do-not-resuscitate orders were present at the time of death for 21 of the patients.
Forty-five of the patients were admitted to an ICU, with 37 dying in the ICU. The eight patients who died on the ward after transfer out of the ICU had end-of-life limitations of care in place.
The researchers noted that the number of patients dying in the ICU was greater in the United States, possibly because in Europe fewer patients are admitted to an ICU.
“This discrepancy likely reflects cultural differences between the U.S. and Europe in the role of intensive care for patients with advanced age and/or advanced comorbid conditions,” they noted.
Overall, the physician review panel identified nine patients who had a lapse in quality of in-hospital CAP care, with four of the deaths potentially linked to this lapse in care.
However, two of the patients had end-of-life limitations of care in place, which according to the authors meant that “only two patients undergoing full medical treatment without end-of-life limitations of care had an identified lapse in quality of in-hospital pneumonia care potentially contributing to in-hospital death, including one with a delay in antibiotics for over an hour in the presence of shock and one with initial antibiotics not consistent with IDSA/ATS guidelines.”
The research team concluded that most in-hospital deaths among adult patients admitted with CAP in their study would not have been preventable with higher quality in-hospital pneumonia care.
“Many of the in-hospital deaths among patients admitted with CAP occurred in older patients with severe comorbidities and end-of-life limitations in care,” they noted.
They said the influence of end-of-life limitations on care short of full palliation was an important finding, with all patients who died outside the ICU having end-of-life limitations in care.
“Current diagnostic related group (DRG) and international classification of diseases (ICD) coding systems do not have the necessary nuances to capture these limitations of care, yet they are clearly important factors in determining whether patients experience in-hospital death,” they added.
Dr. Waterer reported no conflicts. Two coauthors reported potential conflicts of interest in relation to consulting fees from several pharmaceutical companies.
SOURCE: Waterer G. et al. CHEST 2018;154(3):628-35. doi: 10.1016/j.chest.2018.05.021.
Most in-hospital deaths from community-acquired pneumonia are not preventable with current medical therapy, according to an analysis of deaths at five U.S. hospitals with expertise in pneumonia care.
Adults who are hospitalized with community-acquired pneumonia (CAP) are at high risk for short-term mortality but it is unclear whether an improvement in care could lower this risk, noted the study authors led by Grant W. Waterer, MBBS, PhD, of Northwestern University, Chicago.
“Understanding the circumstances in which CAP patients die could facilitate improvements in the management of CAP by enabling future improvement efforts to focus on common preventable causes of death,” they wrote. Their report was published in CHEST®.
They therefore performed a secondary analysis of the Etiology of Pneumonia in the Community (EPIC) study involving adults hospitalized with CAP between January 2010 and June 2012 across five tertiary-care hospitals in the United States.
The clinical characteristics of patients who died in the hospital were compared with those of patients who survived to hospital discharge. Chronic heart failure, chronic obstructive pulmonary disease, coronary artery disease, chronic liver disease, cerebrovascular disease, cancer (excluding skin cancer), and diabetes were considered as severe chronic comorbidities based on their association with increased mortality and ICU admission in CAP severity scores.
Deaths caused by septic shock, respiratory failure, multisystem organ failure, cardiopulmonary arrest prior to stabilization of CAP, and endocarditis, were considered to be directly related to CAP.
Conversely, causes of death indirectly related to CAP included acute cardiovascular disease, stroke, acute renal failure, and secondary infections developed after hospitalization. Deaths caused by cancer, cirrhosis, and chronic neurologic conditions were considered unrelated to CAP.
Medical notes were assessed to determine whether the patient received management consistent with current recommendations; for example, antibiotics consistent with guidelines from the Infectious Diseases Society of America.
End-of-life limitations in care, such as patient/family decision not to proceed with full medical treatment, also were considered by the research team.
Results showed that among the 2,320 patients with radiographically confirmed CAP, 52 died during initial hospitalization, 33 of whom were aged 65 years or older, and 32 of whom had two or more chronic comorbidities.
Most of the in-hospital deaths occurred early in the hospitalization: 35 within the first 10 days of admission, and 5 after 30 days in hospital.
CAP was judged by an expert physician review panel to be the direct cause of death in 27 of the patients, 10 with CAP having an indirect role with major contribution, 9 with CAP having an indirect role with minor contribution, and 6 with CAP having no role in death.
Do-not-resuscitate orders were present at the time of death for 21 of the patients.
Forty-five of the patients were admitted to an ICU, with 37 dying in the ICU. The eight patients who died on the ward after transfer out of the ICU had end-of-life limitations of care in place.
The researchers noted that the number of patients dying in the ICU was greater in the United States, possibly because in Europe fewer patients are admitted to an ICU.
“This discrepancy likely reflects cultural differences between the U.S. and Europe in the role of intensive care for patients with advanced age and/or advanced comorbid conditions,” they noted.
Overall, the physician review panel identified nine patients who had a lapse in quality of in-hospital CAP care, with four of the deaths potentially linked to this lapse in care.
However, two of the patients had end-of-life limitations of care in place, which according to the authors meant that “only two patients undergoing full medical treatment without end-of-life limitations of care had an identified lapse in quality of in-hospital pneumonia care potentially contributing to in-hospital death, including one with a delay in antibiotics for over an hour in the presence of shock and one with initial antibiotics not consistent with IDSA/ATS guidelines.”
The research team concluded that most in-hospital deaths among adult patients admitted with CAP in their study would not have been preventable with higher quality in-hospital pneumonia care.
“Many of the in-hospital deaths among patients admitted with CAP occurred in older patients with severe comorbidities and end-of-life limitations in care,” they noted.
They said the influence of end-of-life limitations on care short of full palliation was an important finding, with all patients who died outside the ICU having end-of-life limitations in care.
“Current diagnostic related group (DRG) and international classification of diseases (ICD) coding systems do not have the necessary nuances to capture these limitations of care, yet they are clearly important factors in determining whether patients experience in-hospital death,” they added.
Dr. Waterer reported no conflicts. Two coauthors reported potential conflicts of interest in relation to consulting fees from several pharmaceutical companies.
SOURCE: Waterer G. et al. CHEST 2018;154(3):628-35. doi: 10.1016/j.chest.2018.05.021.
FROM CHEST
Key clinical point: Most in-hospital deaths from community-acquired pneumonia are not preventable with current medical therapy.
Major finding: Two out of 52 patients who died in-hospital from community-acquired pneumonia (CAP) who were undergoing full medical treatment without end-of-life limitations of care had an identified lapse in quality of in-hospital pneumonia care that potentially contributed to their death.
Study details: A secondary analysis of the prospective multicenter Etiology of Pneumonia in the Community (EPIC) study involving 2,320 adults with radiographically confirmed CAP.
Disclosures: Dr. Waterer reported no conflicts. Two coauthors reported potential conflicts of interest in relation to consulting fees from several pharmaceutical companies.
Source: Waterer G. et al. CHEST 2018;154(3):628-35.
Predictors for worse outcomes in low–disease activity RA remain tough to come by
Disease flares are common but are hard to predict in people with rheumatoid arthritis who achieve low disease activity (LDA), and these flares are “undeniably” associated with worse disease activity, quality of life, and radiographic progression, researchers report in an analysis of a prospectively observed cohort.
First author Katie Bechman, MBChB, of the academic rheumatology department at King’s College London, and her colleagues reported online in the Journal of Rheumatology that nearly one-third of patients with RA in stable LDA states, including remission, had flares during a year of follow-up in the observational prospective REMIRA study, similar to previous reports in cohort studies.
The cohort of 152 patients had 28-joint Disease Activity Scores (DAS28) less than 3.2 for at least 1 month apart, and 66% (n = 97) of the cohort fulfilled DAS28 remission criteria (DAS28 less than 2.6). The authors defined disease flare as a DAS28 increase of more than 1.2, compared with baseline, or a DAS28 increase of more than 0.6, compared with baseline, and concurrent DAS28 of 3.2 or greater. A total of 69 (35%) were taking disease-modifying antirheumatic drug monotherapy.
Nearly one-third of RA patients (30%, n = 46) with LDA states experienced a flare during 12 months of follow-up. When limiting the cohort to patients who were in remission at baseline, 25% (n = 24) had at least one flare.
Patients who had a flare experienced significantly worse clinical outcomes at 12 months than did patients in sustained remission, reflected by higher disease activity, worse functional outcomes, and higher radiographic progression scores.
For example, patients who flared had more than a threefold greater risk for erosive progression, defined as new or larger erosions over 1 year on radiographs (hazard ratio, 3.6; 95% confidence interval, 2.77-4.67; P less than .01).
Patients’ baseline values on the Health Assessment Questionnaire-Disability Index – a measure of functional activity that is reflected by difficulties in activities of daily living – proved to be a significant independent predictor of flare (HR, 1.76; 95% CI, 1.05-2.93; P = .03) in multivariate analyses.
The researchers also found that serum biomarkers were modestly correlated with DAS28 at the time of flare. DAS28 and its components significantly correlated with multibiomarker disease activity score and calprotectin at time of flare, but correlation coefficients were low at 0.52 and 0.49, respectively. Two-thirds of flares were not associated with a rise in biomarkers.
“This might be because a flare is defined by worsening of the DAS28 composite score, and an increase in [tender joint count] and [patient’s global assessment] alone may increase the DAS28 score to a sufficient level to define a flare,” the investigators suggested.
“It is possible that a flare event is not solely the result of direct synovial inflammation but may be driven by other pathways, for example chronification of pain due to central sensitization and abnormal regulatory mechanisms. This heterogeneity may partly explain why identifying predictors of flare is challenging,” they said.
“In our study, we have shown that the occurrence of a flare is hard to predict, but undeniably associated with worse clinical outcomes at 12 months,” the researchers concluded.
They suggested that it was possible that two “distinct subtypes” of flare might exist: an “inflammatory” flare that was predominantly driven by an increase in swollen joint count and erythrocyte sedimentation rate, and a “noninflammatory” flare with a disproportionately elevated tender joint count and a high patient global assessment score.
“Differentiating these two flare types may identify potential predictors. Further research is needed to determine whether distinct flares exist and to categorize the potential predictors of each,” they added.
The research was partly funded by the U.K. National Institute for Health Research Biomedical Research Centre at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London.
SOURCE: Bechman K et al. J Rheumatol. 2018 Sep 1. doi: 10.3899/jrheum.171375.
Disease flares are common but are hard to predict in people with rheumatoid arthritis who achieve low disease activity (LDA), and these flares are “undeniably” associated with worse disease activity, quality of life, and radiographic progression, researchers report in an analysis of a prospectively observed cohort.
First author Katie Bechman, MBChB, of the academic rheumatology department at King’s College London, and her colleagues reported online in the Journal of Rheumatology that nearly one-third of patients with RA in stable LDA states, including remission, had flares during a year of follow-up in the observational prospective REMIRA study, similar to previous reports in cohort studies.
The cohort of 152 patients had 28-joint Disease Activity Scores (DAS28) less than 3.2 for at least 1 month apart, and 66% (n = 97) of the cohort fulfilled DAS28 remission criteria (DAS28 less than 2.6). The authors defined disease flare as a DAS28 increase of more than 1.2, compared with baseline, or a DAS28 increase of more than 0.6, compared with baseline, and concurrent DAS28 of 3.2 or greater. A total of 69 (35%) were taking disease-modifying antirheumatic drug monotherapy.
Nearly one-third of RA patients (30%, n = 46) with LDA states experienced a flare during 12 months of follow-up. When limiting the cohort to patients who were in remission at baseline, 25% (n = 24) had at least one flare.
Patients who had a flare experienced significantly worse clinical outcomes at 12 months than did patients in sustained remission, reflected by higher disease activity, worse functional outcomes, and higher radiographic progression scores.
For example, patients who flared had more than a threefold greater risk for erosive progression, defined as new or larger erosions over 1 year on radiographs (hazard ratio, 3.6; 95% confidence interval, 2.77-4.67; P less than .01).
Patients’ baseline values on the Health Assessment Questionnaire-Disability Index – a measure of functional activity that is reflected by difficulties in activities of daily living – proved to be a significant independent predictor of flare (HR, 1.76; 95% CI, 1.05-2.93; P = .03) in multivariate analyses.
The researchers also found that serum biomarkers were modestly correlated with DAS28 at the time of flare. DAS28 and its components significantly correlated with multibiomarker disease activity score and calprotectin at time of flare, but correlation coefficients were low at 0.52 and 0.49, respectively. Two-thirds of flares were not associated with a rise in biomarkers.
“This might be because a flare is defined by worsening of the DAS28 composite score, and an increase in [tender joint count] and [patient’s global assessment] alone may increase the DAS28 score to a sufficient level to define a flare,” the investigators suggested.
“It is possible that a flare event is not solely the result of direct synovial inflammation but may be driven by other pathways, for example chronification of pain due to central sensitization and abnormal regulatory mechanisms. This heterogeneity may partly explain why identifying predictors of flare is challenging,” they said.
“In our study, we have shown that the occurrence of a flare is hard to predict, but undeniably associated with worse clinical outcomes at 12 months,” the researchers concluded.
They suggested that it was possible that two “distinct subtypes” of flare might exist: an “inflammatory” flare that was predominantly driven by an increase in swollen joint count and erythrocyte sedimentation rate, and a “noninflammatory” flare with a disproportionately elevated tender joint count and a high patient global assessment score.
“Differentiating these two flare types may identify potential predictors. Further research is needed to determine whether distinct flares exist and to categorize the potential predictors of each,” they added.
The research was partly funded by the U.K. National Institute for Health Research Biomedical Research Centre at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London.
SOURCE: Bechman K et al. J Rheumatol. 2018 Sep 1. doi: 10.3899/jrheum.171375.
Disease flares are common but are hard to predict in people with rheumatoid arthritis who achieve low disease activity (LDA), and these flares are “undeniably” associated with worse disease activity, quality of life, and radiographic progression, researchers report in an analysis of a prospectively observed cohort.
First author Katie Bechman, MBChB, of the academic rheumatology department at King’s College London, and her colleagues reported online in the Journal of Rheumatology that nearly one-third of patients with RA in stable LDA states, including remission, had flares during a year of follow-up in the observational prospective REMIRA study, similar to previous reports in cohort studies.
The cohort of 152 patients had 28-joint Disease Activity Scores (DAS28) less than 3.2 for at least 1 month apart, and 66% (n = 97) of the cohort fulfilled DAS28 remission criteria (DAS28 less than 2.6). The authors defined disease flare as a DAS28 increase of more than 1.2, compared with baseline, or a DAS28 increase of more than 0.6, compared with baseline, and concurrent DAS28 of 3.2 or greater. A total of 69 (35%) were taking disease-modifying antirheumatic drug monotherapy.
Nearly one-third of RA patients (30%, n = 46) with LDA states experienced a flare during 12 months of follow-up. When limiting the cohort to patients who were in remission at baseline, 25% (n = 24) had at least one flare.
Patients who had a flare experienced significantly worse clinical outcomes at 12 months than did patients in sustained remission, reflected by higher disease activity, worse functional outcomes, and higher radiographic progression scores.
For example, patients who flared had more than a threefold greater risk for erosive progression, defined as new or larger erosions over 1 year on radiographs (hazard ratio, 3.6; 95% confidence interval, 2.77-4.67; P less than .01).
Patients’ baseline values on the Health Assessment Questionnaire-Disability Index – a measure of functional activity that is reflected by difficulties in activities of daily living – proved to be a significant independent predictor of flare (HR, 1.76; 95% CI, 1.05-2.93; P = .03) in multivariate analyses.
The researchers also found that serum biomarkers were modestly correlated with DAS28 at the time of flare. DAS28 and its components significantly correlated with multibiomarker disease activity score and calprotectin at time of flare, but correlation coefficients were low at 0.52 and 0.49, respectively. Two-thirds of flares were not associated with a rise in biomarkers.
“This might be because a flare is defined by worsening of the DAS28 composite score, and an increase in [tender joint count] and [patient’s global assessment] alone may increase the DAS28 score to a sufficient level to define a flare,” the investigators suggested.
“It is possible that a flare event is not solely the result of direct synovial inflammation but may be driven by other pathways, for example chronification of pain due to central sensitization and abnormal regulatory mechanisms. This heterogeneity may partly explain why identifying predictors of flare is challenging,” they said.
“In our study, we have shown that the occurrence of a flare is hard to predict, but undeniably associated with worse clinical outcomes at 12 months,” the researchers concluded.
They suggested that it was possible that two “distinct subtypes” of flare might exist: an “inflammatory” flare that was predominantly driven by an increase in swollen joint count and erythrocyte sedimentation rate, and a “noninflammatory” flare with a disproportionately elevated tender joint count and a high patient global assessment score.
“Differentiating these two flare types may identify potential predictors. Further research is needed to determine whether distinct flares exist and to categorize the potential predictors of each,” they added.
The research was partly funded by the U.K. National Institute for Health Research Biomedical Research Centre at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London.
SOURCE: Bechman K et al. J Rheumatol. 2018 Sep 1. doi: 10.3899/jrheum.171375.
FROM THE JOURNAL OF RHEUMATOLOGY
Key clinical point: Flares occur frequently in RA patients with low disease activity and are associated with worse disease activity, quality of life, and radiographic progression.
Major finding:
Study details: A study of 152 RA patients taking part in the observational prospective REMIRA study who had a stable 28-joint Disease Activity Score (DAS28) less than 3.2.
Disclosures: The research was partly funded by the U.K. National Institute for Health Research Biomedical Research Centre at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London.
Source: Bechman K et al. J Rheumatol. 2018 Sep 1. doi: 10.3899/jrheum.171375.
Prognostic model has clinical utility in mCRPC
Researchers have developed what they say is a clinically useful prognostic model for overall survival in chemotherapy-naive men with metastatic castration-resistant prostate cancer (mCRPC) treated with the second-generation androgen receptor inhibitor enzalutamide.
Knowledge of prognosis gained by the model, which includes 11 variables routinely collected from patients, may help clinicians make decisions on the aggressiveness with which to pursue active therapy and could also help shape trial designs that utilize combinations with androgen receptor–directed therapies, the research team wrote in Annals of Oncology.
Led by Andrew J. Armstrong, MD, of Duke University, Durham, N.C., the researchers randomly split patients from the PREVAIL trial database (enzalutamide vs. placebo) 2:1 into training (n = 1,159) and testing (n = 550) sets.
They noted that, in the PREVAIL trial, enzalutamide significantly reduced the risk of death by 29% (hazard ratio, 0.71; P less than .001), compared with placebo.
Using the training set, the research team analyzed 23 predefined variables based on previous work demonstrating their potential importance in mCRPC outcomes. A multivariable model predicting overall survival (OS) was then developed and the HR and 95% confidence interval were established for each potentially prognostic variable.
The final validated multivariable model included 11 independent prognostic variables: albumin, alkaline phosphatase, hemoglobin, lactate dehydrogenase, neutrophil-lymphocyte ratio, number of bone metastases, presence of pain, pattern of spread, prostate specific antigen, time from diagnosis to randomization, and treatment.
The 11-variable model provided a significant separation between low-risk and high-risk patients (HR, 0.35; 95% CI, 0.27-0.46) and between low-risk (HR, 0.20; 95% CI, 0.14-0.29) and intermediate-risk (HR, 0.40; 95% CI, 0.30-0.53) versus high-risk patients.
Median OS for low-risk, intermediate-risk, and high-risk groups (testing set) defined by prognostic risk tertiles were not yet reached, 34.2 months, and 21.1 months, respectively.
“This model has potential clinical utility for individual and trial-level survival, potential outcomes prognostication, and clinical trial design of novel treatment approaches in this population,” the research team concluded.
The researchers said their model had several advantages over others because it was developed and validated in a contemporary treatment setting that reflected current practice. However, they cautioned that while the variables in their model had “strong biologic rationale” outcomes for individuals in contemporary practice may differ from those in clinical trial populations.
“External validation is recommended in a broader, nontrial population of men with mCRPC. Accordingly, the prognostic model presented in this paper and in general, should not displace the well-informed clinical judgment of health care professionals treating individual patients,” they wrote.
The research was supported by Medivation and Astellas Pharma (the codevelopers of enzalutamide).
SOURCE: Armstrong AJ et al. Ann Oncol. 2018 Sept 10. doi: 10.1093/annonc/mdy406.
Researchers have developed what they say is a clinically useful prognostic model for overall survival in chemotherapy-naive men with metastatic castration-resistant prostate cancer (mCRPC) treated with the second-generation androgen receptor inhibitor enzalutamide.
Knowledge of prognosis gained by the model, which includes 11 variables routinely collected from patients, may help clinicians make decisions on the aggressiveness with which to pursue active therapy and could also help shape trial designs that utilize combinations with androgen receptor–directed therapies, the research team wrote in Annals of Oncology.
Led by Andrew J. Armstrong, MD, of Duke University, Durham, N.C., the researchers randomly split patients from the PREVAIL trial database (enzalutamide vs. placebo) 2:1 into training (n = 1,159) and testing (n = 550) sets.
They noted that, in the PREVAIL trial, enzalutamide significantly reduced the risk of death by 29% (hazard ratio, 0.71; P less than .001), compared with placebo.
Using the training set, the research team analyzed 23 predefined variables based on previous work demonstrating their potential importance in mCRPC outcomes. A multivariable model predicting overall survival (OS) was then developed and the HR and 95% confidence interval were established for each potentially prognostic variable.
The final validated multivariable model included 11 independent prognostic variables: albumin, alkaline phosphatase, hemoglobin, lactate dehydrogenase, neutrophil-lymphocyte ratio, number of bone metastases, presence of pain, pattern of spread, prostate specific antigen, time from diagnosis to randomization, and treatment.
The 11-variable model provided a significant separation between low-risk and high-risk patients (HR, 0.35; 95% CI, 0.27-0.46) and between low-risk (HR, 0.20; 95% CI, 0.14-0.29) and intermediate-risk (HR, 0.40; 95% CI, 0.30-0.53) versus high-risk patients.
Median OS for low-risk, intermediate-risk, and high-risk groups (testing set) defined by prognostic risk tertiles were not yet reached, 34.2 months, and 21.1 months, respectively.
“This model has potential clinical utility for individual and trial-level survival, potential outcomes prognostication, and clinical trial design of novel treatment approaches in this population,” the research team concluded.
The researchers said their model had several advantages over others because it was developed and validated in a contemporary treatment setting that reflected current practice. However, they cautioned that while the variables in their model had “strong biologic rationale” outcomes for individuals in contemporary practice may differ from those in clinical trial populations.
“External validation is recommended in a broader, nontrial population of men with mCRPC. Accordingly, the prognostic model presented in this paper and in general, should not displace the well-informed clinical judgment of health care professionals treating individual patients,” they wrote.
The research was supported by Medivation and Astellas Pharma (the codevelopers of enzalutamide).
SOURCE: Armstrong AJ et al. Ann Oncol. 2018 Sept 10. doi: 10.1093/annonc/mdy406.
Researchers have developed what they say is a clinically useful prognostic model for overall survival in chemotherapy-naive men with metastatic castration-resistant prostate cancer (mCRPC) treated with the second-generation androgen receptor inhibitor enzalutamide.
Knowledge of prognosis gained by the model, which includes 11 variables routinely collected from patients, may help clinicians make decisions on the aggressiveness with which to pursue active therapy and could also help shape trial designs that utilize combinations with androgen receptor–directed therapies, the research team wrote in Annals of Oncology.
Led by Andrew J. Armstrong, MD, of Duke University, Durham, N.C., the researchers randomly split patients from the PREVAIL trial database (enzalutamide vs. placebo) 2:1 into training (n = 1,159) and testing (n = 550) sets.
They noted that, in the PREVAIL trial, enzalutamide significantly reduced the risk of death by 29% (hazard ratio, 0.71; P less than .001), compared with placebo.
Using the training set, the research team analyzed 23 predefined variables based on previous work demonstrating their potential importance in mCRPC outcomes. A multivariable model predicting overall survival (OS) was then developed and the HR and 95% confidence interval were established for each potentially prognostic variable.
The final validated multivariable model included 11 independent prognostic variables: albumin, alkaline phosphatase, hemoglobin, lactate dehydrogenase, neutrophil-lymphocyte ratio, number of bone metastases, presence of pain, pattern of spread, prostate specific antigen, time from diagnosis to randomization, and treatment.
The 11-variable model provided a significant separation between low-risk and high-risk patients (HR, 0.35; 95% CI, 0.27-0.46) and between low-risk (HR, 0.20; 95% CI, 0.14-0.29) and intermediate-risk (HR, 0.40; 95% CI, 0.30-0.53) versus high-risk patients.
Median OS for low-risk, intermediate-risk, and high-risk groups (testing set) defined by prognostic risk tertiles were not yet reached, 34.2 months, and 21.1 months, respectively.
“This model has potential clinical utility for individual and trial-level survival, potential outcomes prognostication, and clinical trial design of novel treatment approaches in this population,” the research team concluded.
The researchers said their model had several advantages over others because it was developed and validated in a contemporary treatment setting that reflected current practice. However, they cautioned that while the variables in their model had “strong biologic rationale” outcomes for individuals in contemporary practice may differ from those in clinical trial populations.
“External validation is recommended in a broader, nontrial population of men with mCRPC. Accordingly, the prognostic model presented in this paper and in general, should not displace the well-informed clinical judgment of health care professionals treating individual patients,” they wrote.
The research was supported by Medivation and Astellas Pharma (the codevelopers of enzalutamide).
SOURCE: Armstrong AJ et al. Ann Oncol. 2018 Sept 10. doi: 10.1093/annonc/mdy406.
FROM ANNALS OF ONCOLOGY
Key clinical point: A new prognosis model which includes routinely collected variables could help guide treatment decisions in patients with metastatic castration-resistant prostate cancer.
Major finding: The 11-variable model provided a significant separation between low-risk and high-risk patients (HR, 0.35; 95% confidence interval, 0.27-0.46) and between low-risk (HR, 0.20; 95% CI, 0.14-0.29) and intermediate-risk (HR, 0.40; 95% CI, 0.30-0.53) versus high-risk patients.
Study details: An analysis of data sets from the randomized, double-blind, placebo-controlled, phase 3 PREVAIL trial
Disclosures: The research was supported by Medivation and Astellas Pharma (the codevelopers of enzalutamide).
Source: Armstrong AJ et al. Ann Oncol. 2018 Sep 10. doi: 10.1093/annonc/mdy406.
Difficult-to-treat RA remains difficult to define
Active disease, failure of disease-modifying antirheumatic drug therapy, and an inability to taper glucocorticoid treatment are the main characteristics of difficult-to-treat RA, according to results of a survey of mostly European rheumatologists that also revealed a wide variation in views on the factors that contribute to the concept.
Some of the issues that survey respondents considered clinically relevant in difficult-to-treat RA are not covered by current EULAR management recommendations, Nadia M.T. Roodenrijs, of University Medical Center Utrecht, the Netherlands, and her colleagues noted in a study published online in Annals of the Rheumatic Diseases.
The investigators set out to determine what a range of rheumatologists from different countries considered to be the key characteristics of difficult-to-treat RA, which has an estimated prevalence of 5%-20%, depending on the criteria used. They also sought to identify the issues relating to work-up and management that were not covered by the current EULAR recommendations.
The online survey contained four multiple choice questions that asked about the necessity of incorporating disease activity level, fatigue, number of disease-modifying antirheumatic drugs (DMARDs) that failed, and the inability to taper glucocorticoids into the concept of difficult-to-treat RA. The survey also asked three open questions seeking additional clinically relevant views on difficult-to-treat RA.
A total of 410 respondents from 33 countries (96% European) completed the survey, which was sent to rheumatologists through the Emerging EULAR Network. Overall, half of the respondents selected “disease activity score assessing 28 joints using erythrocyte sedimentation rate [DAS28-ESR] greater than 3.2 or the presence of signs suggestive of active inflammatory disease activity with a DAS28-ESR of 3.2 or less” as characteristics of difficult-to-treat RA. About 42% of respondents included fatigue as a characteristic and 48% selected failure to two or more conventional DMARDs and two or more biological/targeted synthetic DMARDs. Furthermore, 89% of respondents identified the inability to taper glucocorticoids below 5 mg or 10 mg prednisone equivalent daily to be a characteristic of difficult-to-treat RA.
Other clinically important issues identified by the respondents as currently missing from EULAR management recommendations included interfering comorbidities, especially cardiovascular disease, infection, and malignancy; extra-articular manifestations; and polypharmacy.
“The results of this survey underscore the difficulty in establishing an unambiguous concept of difficult-to-treat RA, which is seen as a heterogeneous condition not fully covered by EULAR recommendations,” the authors wrote.
The authors noted that their findings would help fuel discussion on the issues to include in the management recommendations for difficult-to-treat RA currently under consideration by a recently established EULAR task force.
The study was not funded with a specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Some of the authors reported receiving fees from several pharmaceutical countries.
SOURCE: Roodenrijs NMT et al. Ann Rheum Dis. 2018 Sep 7. doi: 10.1136/annrheumdis-2018-213687.
Active disease, failure of disease-modifying antirheumatic drug therapy, and an inability to taper glucocorticoid treatment are the main characteristics of difficult-to-treat RA, according to results of a survey of mostly European rheumatologists that also revealed a wide variation in views on the factors that contribute to the concept.
Some of the issues that survey respondents considered clinically relevant in difficult-to-treat RA are not covered by current EULAR management recommendations, Nadia M.T. Roodenrijs, of University Medical Center Utrecht, the Netherlands, and her colleagues noted in a study published online in Annals of the Rheumatic Diseases.
The investigators set out to determine what a range of rheumatologists from different countries considered to be the key characteristics of difficult-to-treat RA, which has an estimated prevalence of 5%-20%, depending on the criteria used. They also sought to identify the issues relating to work-up and management that were not covered by the current EULAR recommendations.
The online survey contained four multiple choice questions that asked about the necessity of incorporating disease activity level, fatigue, number of disease-modifying antirheumatic drugs (DMARDs) that failed, and the inability to taper glucocorticoids into the concept of difficult-to-treat RA. The survey also asked three open questions seeking additional clinically relevant views on difficult-to-treat RA.
A total of 410 respondents from 33 countries (96% European) completed the survey, which was sent to rheumatologists through the Emerging EULAR Network. Overall, half of the respondents selected “disease activity score assessing 28 joints using erythrocyte sedimentation rate [DAS28-ESR] greater than 3.2 or the presence of signs suggestive of active inflammatory disease activity with a DAS28-ESR of 3.2 or less” as characteristics of difficult-to-treat RA. About 42% of respondents included fatigue as a characteristic and 48% selected failure to two or more conventional DMARDs and two or more biological/targeted synthetic DMARDs. Furthermore, 89% of respondents identified the inability to taper glucocorticoids below 5 mg or 10 mg prednisone equivalent daily to be a characteristic of difficult-to-treat RA.
Other clinically important issues identified by the respondents as currently missing from EULAR management recommendations included interfering comorbidities, especially cardiovascular disease, infection, and malignancy; extra-articular manifestations; and polypharmacy.
“The results of this survey underscore the difficulty in establishing an unambiguous concept of difficult-to-treat RA, which is seen as a heterogeneous condition not fully covered by EULAR recommendations,” the authors wrote.
The authors noted that their findings would help fuel discussion on the issues to include in the management recommendations for difficult-to-treat RA currently under consideration by a recently established EULAR task force.
The study was not funded with a specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Some of the authors reported receiving fees from several pharmaceutical countries.
SOURCE: Roodenrijs NMT et al. Ann Rheum Dis. 2018 Sep 7. doi: 10.1136/annrheumdis-2018-213687.
Active disease, failure of disease-modifying antirheumatic drug therapy, and an inability to taper glucocorticoid treatment are the main characteristics of difficult-to-treat RA, according to results of a survey of mostly European rheumatologists that also revealed a wide variation in views on the factors that contribute to the concept.
Some of the issues that survey respondents considered clinically relevant in difficult-to-treat RA are not covered by current EULAR management recommendations, Nadia M.T. Roodenrijs, of University Medical Center Utrecht, the Netherlands, and her colleagues noted in a study published online in Annals of the Rheumatic Diseases.
The investigators set out to determine what a range of rheumatologists from different countries considered to be the key characteristics of difficult-to-treat RA, which has an estimated prevalence of 5%-20%, depending on the criteria used. They also sought to identify the issues relating to work-up and management that were not covered by the current EULAR recommendations.
The online survey contained four multiple choice questions that asked about the necessity of incorporating disease activity level, fatigue, number of disease-modifying antirheumatic drugs (DMARDs) that failed, and the inability to taper glucocorticoids into the concept of difficult-to-treat RA. The survey also asked three open questions seeking additional clinically relevant views on difficult-to-treat RA.
A total of 410 respondents from 33 countries (96% European) completed the survey, which was sent to rheumatologists through the Emerging EULAR Network. Overall, half of the respondents selected “disease activity score assessing 28 joints using erythrocyte sedimentation rate [DAS28-ESR] greater than 3.2 or the presence of signs suggestive of active inflammatory disease activity with a DAS28-ESR of 3.2 or less” as characteristics of difficult-to-treat RA. About 42% of respondents included fatigue as a characteristic and 48% selected failure to two or more conventional DMARDs and two or more biological/targeted synthetic DMARDs. Furthermore, 89% of respondents identified the inability to taper glucocorticoids below 5 mg or 10 mg prednisone equivalent daily to be a characteristic of difficult-to-treat RA.
Other clinically important issues identified by the respondents as currently missing from EULAR management recommendations included interfering comorbidities, especially cardiovascular disease, infection, and malignancy; extra-articular manifestations; and polypharmacy.
“The results of this survey underscore the difficulty in establishing an unambiguous concept of difficult-to-treat RA, which is seen as a heterogeneous condition not fully covered by EULAR recommendations,” the authors wrote.
The authors noted that their findings would help fuel discussion on the issues to include in the management recommendations for difficult-to-treat RA currently under consideration by a recently established EULAR task force.
The study was not funded with a specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Some of the authors reported receiving fees from several pharmaceutical countries.
SOURCE: Roodenrijs NMT et al. Ann Rheum Dis. 2018 Sep 7. doi: 10.1136/annrheumdis-2018-213687.
FROM ANNALS OF THE RHEUMATIC DISEASES
Key clinical point: There is wide variation in the views of rheumatologists across Europe on the key characteristics of difficult-to-treat RA. Some issues that rheumatologists consider to be clinically relevant are not covered by current EULAR recommendations.
Major finding:
Study details: An online survey completed by 410 rheumatologists from 33 countries.
Disclosures: The study was not funded with a specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Some of the authors reported receiving fees from several pharmaceutical countries.
Source: Roodenrijs NMT et al. Ann Rheum Dis. 2018 Sep 7. doi: 10.1136/annrheumdis-2018-213687.
Updates to EULAR hand OA management recommendations reflect current evidence
Updated EULAR recommendations on the management of hand osteoarthritis include five overarching principles as well as two new recommendations that reflect new research in the field.
The task force, led by Margreet Kloppenburg, MD, PhD, of the department of rheumatology at Leiden (the Netherlands) University Medical Center, noted that a decade had passed since the first recommendations were published in 2007.
“It was timely to update the recommendations, as many new studies had emerged during this period. In light of this new evidence, many of the 2007 recommendations were modified and new recommendations were added,” wrote Dr. Kloppenburg and her colleagues. The recommendations were published online in Annals of the Rheumatic Diseases.
They noted that the recommendations were targeted to all health professionals across primary and secondary care but also aimed to inform patients about their disease to “support shared decision making.”
In line with other EULAR sets of management recommendations, the update included five overarching principles that cover treatment goals, information and education for patients, individualization of treatment, shared decision making between clinicians and patients, and the need to take into consideration a multidisciplinary and multimodal (pharmacologic and nonpharmacologic) treatment approach.
The authors noted that for a long time hand OA was a “forgotten disease” and this was reflected by the paucity of clinical trials in the area. As a direct consequence, previous recommendations were based on expert opinion rather than evidence.
However, new data allowed the task force to recommend not to treat patients with hand OA with conventional synthetic or biologic disease-modifying antirheumatic drugs (DMARDs). The recommendation achieved the strongest level of evidence and a high level of agreement from the 19-member expert panel, which included 2 patient research partners. The authors said the recommendation was based on newer studies that demonstrated a lack of efficacy of csDMARDs and bDMARDs.
The authors also advised adapting the long-term follow-up of patients with hand OA to individual needs, although they noted this was based on expert opinion alone and that in the absence of a disease-modifying treatment, the goal of follow-up differs from that of many other rheumatic diseases. Individual needs will dictate the degree of follow-up required, based on the severity of symptoms, presence of erosive disease, reevaluation of the use of pharmacologic therapy, and a patient’s wishes and expectations. They also noted that “for most patients, standard radiographic follow-up is not useful at this moment” and that “follow-up does not necessarily have to be performed by a rheumatologist.
“Follow-up will likely increase adherence to nonpharmacological therapies like exercise or orthoses, and provides an opportunity for reevaluation of treatment,” they wrote.
The recommendations advise offering education and training in ergonomic principles and exercises to patients to improve function and muscle strength, as well as considering the use of orthoses in some patients.
Treatment recommendations suggested preferring topical treatments over systemic treatments and that oral analgesics, particularly NSAIDs, should be considered for a limited duration. The authors advised that chondroitin sulfate may be used in patients for pain relief and improvement in functioning and that intra-articular glucocorticoids should not generally be used but may be considered in patients with painful interphalangeal joints. Surgery should be considered for patients with structural abnormalities when other treatment modalities have not been sufficiently effective in relieving pain.
The recommendations were funded by EULAR. Several of the authors reported receiving consultancy fees and/or honoraria as well as research funding from industry.
SOURCE: Kloppenburg M et al. Ann Rheum Dis. 2018 Aug 28. doi: 10.1136/annrheumdis-2018-213826.
EULAR has updated its 2007 guidelines for the management of hand osteoarthritis. I find the recommendations helpful, and I have no disagreements.
The authors performed a systematic literature review that was more complete than the original guidelines. In addition, the methodology in developing the guidelines was updated utilizing the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) system to guide the expert opinion. The manuscript presents recommendations that are carefully supported in the text. To understand guidelines, one really needs to read the text.
The update lists a set of research questions, similar to the 2007 recommendations.
The authors group their therapeutic recommendations according to nonpharmacologic, pharmacologic, and surgical approaches, as well as about the need for follow-up. The three nonpharmacologic recommendations include education and training, exercise and muscle strengthening, and the use of orthoses. The pharmacologic approach includes topical therapy as a first-line, oral NSAIDs and analgesics, chondroitin sulfate, and intra-articular injections. There is a negative recommendation for the use of biologics. The surgical recommendation is directed at the relief of pain. The last recommendation emphasizes the need for follow-up and individual care.
The differences between the recommendations include the removal of acetaminophen as a first-line therapy. Indeed, it seems to be barely recommended at all. In addition, there is an emphasis on topical therapy, particularly NSAIDs. The authors are equivocal on the recommendations for intra-articular therapy. Paraffin and local heat are no longer included. The recommendation against biologic therapy is new. They included agents used for rheumatoid arthritis, such as methotrexate, in this negative recommendation.
These new recommendations are an update of guidelines that are over 10 years old. They are practical and helpful. Unfortunately, more research is needed as the present day therapy is often inadequate.
Roy D. Altman, MD, is professor emeritus of medicine in the division of rheumatology and immunology at the University of California, Los Angeles. He is a consultant to Ferring, Flexion, GlaxoSmithKline, Novartis, Olatec, Pfizer, and Sorrento Therapeutics.
EULAR has updated its 2007 guidelines for the management of hand osteoarthritis. I find the recommendations helpful, and I have no disagreements.
The authors performed a systematic literature review that was more complete than the original guidelines. In addition, the methodology in developing the guidelines was updated utilizing the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) system to guide the expert opinion. The manuscript presents recommendations that are carefully supported in the text. To understand guidelines, one really needs to read the text.
The update lists a set of research questions, similar to the 2007 recommendations.
The authors group their therapeutic recommendations according to nonpharmacologic, pharmacologic, and surgical approaches, as well as about the need for follow-up. The three nonpharmacologic recommendations include education and training, exercise and muscle strengthening, and the use of orthoses. The pharmacologic approach includes topical therapy as a first-line, oral NSAIDs and analgesics, chondroitin sulfate, and intra-articular injections. There is a negative recommendation for the use of biologics. The surgical recommendation is directed at the relief of pain. The last recommendation emphasizes the need for follow-up and individual care.
The differences between the recommendations include the removal of acetaminophen as a first-line therapy. Indeed, it seems to be barely recommended at all. In addition, there is an emphasis on topical therapy, particularly NSAIDs. The authors are equivocal on the recommendations for intra-articular therapy. Paraffin and local heat are no longer included. The recommendation against biologic therapy is new. They included agents used for rheumatoid arthritis, such as methotrexate, in this negative recommendation.
These new recommendations are an update of guidelines that are over 10 years old. They are practical and helpful. Unfortunately, more research is needed as the present day therapy is often inadequate.
Roy D. Altman, MD, is professor emeritus of medicine in the division of rheumatology and immunology at the University of California, Los Angeles. He is a consultant to Ferring, Flexion, GlaxoSmithKline, Novartis, Olatec, Pfizer, and Sorrento Therapeutics.
EULAR has updated its 2007 guidelines for the management of hand osteoarthritis. I find the recommendations helpful, and I have no disagreements.
The authors performed a systematic literature review that was more complete than the original guidelines. In addition, the methodology in developing the guidelines was updated utilizing the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) system to guide the expert opinion. The manuscript presents recommendations that are carefully supported in the text. To understand guidelines, one really needs to read the text.
The update lists a set of research questions, similar to the 2007 recommendations.
The authors group their therapeutic recommendations according to nonpharmacologic, pharmacologic, and surgical approaches, as well as about the need for follow-up. The three nonpharmacologic recommendations include education and training, exercise and muscle strengthening, and the use of orthoses. The pharmacologic approach includes topical therapy as a first-line, oral NSAIDs and analgesics, chondroitin sulfate, and intra-articular injections. There is a negative recommendation for the use of biologics. The surgical recommendation is directed at the relief of pain. The last recommendation emphasizes the need for follow-up and individual care.
The differences between the recommendations include the removal of acetaminophen as a first-line therapy. Indeed, it seems to be barely recommended at all. In addition, there is an emphasis on topical therapy, particularly NSAIDs. The authors are equivocal on the recommendations for intra-articular therapy. Paraffin and local heat are no longer included. The recommendation against biologic therapy is new. They included agents used for rheumatoid arthritis, such as methotrexate, in this negative recommendation.
These new recommendations are an update of guidelines that are over 10 years old. They are practical and helpful. Unfortunately, more research is needed as the present day therapy is often inadequate.
Roy D. Altman, MD, is professor emeritus of medicine in the division of rheumatology and immunology at the University of California, Los Angeles. He is a consultant to Ferring, Flexion, GlaxoSmithKline, Novartis, Olatec, Pfizer, and Sorrento Therapeutics.
Updated EULAR recommendations on the management of hand osteoarthritis include five overarching principles as well as two new recommendations that reflect new research in the field.
The task force, led by Margreet Kloppenburg, MD, PhD, of the department of rheumatology at Leiden (the Netherlands) University Medical Center, noted that a decade had passed since the first recommendations were published in 2007.
“It was timely to update the recommendations, as many new studies had emerged during this period. In light of this new evidence, many of the 2007 recommendations were modified and new recommendations were added,” wrote Dr. Kloppenburg and her colleagues. The recommendations were published online in Annals of the Rheumatic Diseases.
They noted that the recommendations were targeted to all health professionals across primary and secondary care but also aimed to inform patients about their disease to “support shared decision making.”
In line with other EULAR sets of management recommendations, the update included five overarching principles that cover treatment goals, information and education for patients, individualization of treatment, shared decision making between clinicians and patients, and the need to take into consideration a multidisciplinary and multimodal (pharmacologic and nonpharmacologic) treatment approach.
The authors noted that for a long time hand OA was a “forgotten disease” and this was reflected by the paucity of clinical trials in the area. As a direct consequence, previous recommendations were based on expert opinion rather than evidence.
However, new data allowed the task force to recommend not to treat patients with hand OA with conventional synthetic or biologic disease-modifying antirheumatic drugs (DMARDs). The recommendation achieved the strongest level of evidence and a high level of agreement from the 19-member expert panel, which included 2 patient research partners. The authors said the recommendation was based on newer studies that demonstrated a lack of efficacy of csDMARDs and bDMARDs.
The authors also advised adapting the long-term follow-up of patients with hand OA to individual needs, although they noted this was based on expert opinion alone and that in the absence of a disease-modifying treatment, the goal of follow-up differs from that of many other rheumatic diseases. Individual needs will dictate the degree of follow-up required, based on the severity of symptoms, presence of erosive disease, reevaluation of the use of pharmacologic therapy, and a patient’s wishes and expectations. They also noted that “for most patients, standard radiographic follow-up is not useful at this moment” and that “follow-up does not necessarily have to be performed by a rheumatologist.
“Follow-up will likely increase adherence to nonpharmacological therapies like exercise or orthoses, and provides an opportunity for reevaluation of treatment,” they wrote.
The recommendations advise offering education and training in ergonomic principles and exercises to patients to improve function and muscle strength, as well as considering the use of orthoses in some patients.
Treatment recommendations suggested preferring topical treatments over systemic treatments and that oral analgesics, particularly NSAIDs, should be considered for a limited duration. The authors advised that chondroitin sulfate may be used in patients for pain relief and improvement in functioning and that intra-articular glucocorticoids should not generally be used but may be considered in patients with painful interphalangeal joints. Surgery should be considered for patients with structural abnormalities when other treatment modalities have not been sufficiently effective in relieving pain.
The recommendations were funded by EULAR. Several of the authors reported receiving consultancy fees and/or honoraria as well as research funding from industry.
SOURCE: Kloppenburg M et al. Ann Rheum Dis. 2018 Aug 28. doi: 10.1136/annrheumdis-2018-213826.
Updated EULAR recommendations on the management of hand osteoarthritis include five overarching principles as well as two new recommendations that reflect new research in the field.
The task force, led by Margreet Kloppenburg, MD, PhD, of the department of rheumatology at Leiden (the Netherlands) University Medical Center, noted that a decade had passed since the first recommendations were published in 2007.
“It was timely to update the recommendations, as many new studies had emerged during this period. In light of this new evidence, many of the 2007 recommendations were modified and new recommendations were added,” wrote Dr. Kloppenburg and her colleagues. The recommendations were published online in Annals of the Rheumatic Diseases.
They noted that the recommendations were targeted to all health professionals across primary and secondary care but also aimed to inform patients about their disease to “support shared decision making.”
In line with other EULAR sets of management recommendations, the update included five overarching principles that cover treatment goals, information and education for patients, individualization of treatment, shared decision making between clinicians and patients, and the need to take into consideration a multidisciplinary and multimodal (pharmacologic and nonpharmacologic) treatment approach.
The authors noted that for a long time hand OA was a “forgotten disease” and this was reflected by the paucity of clinical trials in the area. As a direct consequence, previous recommendations were based on expert opinion rather than evidence.
However, new data allowed the task force to recommend not to treat patients with hand OA with conventional synthetic or biologic disease-modifying antirheumatic drugs (DMARDs). The recommendation achieved the strongest level of evidence and a high level of agreement from the 19-member expert panel, which included 2 patient research partners. The authors said the recommendation was based on newer studies that demonstrated a lack of efficacy of csDMARDs and bDMARDs.
The authors also advised adapting the long-term follow-up of patients with hand OA to individual needs, although they noted this was based on expert opinion alone and that in the absence of a disease-modifying treatment, the goal of follow-up differs from that of many other rheumatic diseases. Individual needs will dictate the degree of follow-up required, based on the severity of symptoms, presence of erosive disease, reevaluation of the use of pharmacologic therapy, and a patient’s wishes and expectations. They also noted that “for most patients, standard radiographic follow-up is not useful at this moment” and that “follow-up does not necessarily have to be performed by a rheumatologist.
“Follow-up will likely increase adherence to nonpharmacological therapies like exercise or orthoses, and provides an opportunity for reevaluation of treatment,” they wrote.
The recommendations advise offering education and training in ergonomic principles and exercises to patients to improve function and muscle strength, as well as considering the use of orthoses in some patients.
Treatment recommendations suggested preferring topical treatments over systemic treatments and that oral analgesics, particularly NSAIDs, should be considered for a limited duration. The authors advised that chondroitin sulfate may be used in patients for pain relief and improvement in functioning and that intra-articular glucocorticoids should not generally be used but may be considered in patients with painful interphalangeal joints. Surgery should be considered for patients with structural abnormalities when other treatment modalities have not been sufficiently effective in relieving pain.
The recommendations were funded by EULAR. Several of the authors reported receiving consultancy fees and/or honoraria as well as research funding from industry.
SOURCE: Kloppenburg M et al. Ann Rheum Dis. 2018 Aug 28. doi: 10.1136/annrheumdis-2018-213826.
FROM ANNALS OF THE RHEUMATIC DISEASES
Childhood-onset SLE has major impact in adult life
The majority of adults with childhood-onset systemic lupus erythematosus in a longitudinal Dutch study developed significant damage at a young age, remain on corticosteroids in adulthood, and have an impaired health-related quality of life.
The findings in the study, dubbed Childhood-Onset SLE in the Netherlands (CHILL-NL), highlighted the need for preventive screening measures to be put in place before the age of 30 to facilitate a better outcome for patients, who still face high morbidity from childhood-onset systemic lupus erythematosus (cSLE) despite improved survival. Such information is helpful to “answer questions from children and parents regarding the future course of the disease,” wrote Noortje Groot, PhD, of the department of pediatric rheumatology at Erasmus Medical Center–Sophia Children’s Hospital in Rotterdam, the Netherlands, and her colleagues. The report is in Arthritis & Rheumatology.
The current study included all adult SLE patients treated in any Dutch public hospital during the period of November 2013 to April 2016 who were diagnosed with the autoimmune disease prior to their 18th birthday.
All 111 patients involved in the study were seen for a 1.5-hour visit at Erasmus University Medical Center or a local hospital of their choice. During the appointment, a medical history was taken, a physical examination was performed, and the patients completed questionnaires on health-related quality of life (HRQOL).
The average age of patients at the study visit was 33 years, 91% were female, and 72% were white. Median disease duration was 20 years and disease activity was low (median SLE Disease Activity Index 2000 [SLEDAI-2k] = 4). Low complement (32%), skin rashes (14%), and proteinuria (13%) were the most common SLEDAI items reported.
Overall, 68% of the cohort (n = 76) were taking hydroxychloroquine (HCQ), 29% of whom (n = 22) were taking it as monotherapy.
Furthermore, 68% of patients at the study visit were taking corticosteroids and/or non-HCQ disease-modifying antirheumatic drugs (DMARDs), and just over half (51%) of patients (n = 56) were taking corticosteroids either alone or with a non-HCQ DMARD.
“This [finding] is worrying as corticosteroids are associated with the development of damage. Patients are certainly eager to limit corticosteroid use, as almost all patients in the CHILL-NL cohort reported to have negative experiences with prednisone regarding their physical appearance and or mental well-being,” the study authors wrote.
Results also showed that 62% of the patients had damage, predominantly in the musculoskeletal, neuropsychiatric, and renal systems.
Most organ systems became involved within the first 2 years of diagnosis, but after 5 years of disease the nature of disease manifestations tended to shift to damage such as myocardial infarctions.
Notably, after 10-20 years, when cSLE patients were in their early 20s and 30s, significant damage had occurred in more than half of the patients, the authors noted.
“This shift to damage has also been observed in adult-onset SLE patients and urges for preventative screening measures of such (cardiovascular) damage and healthy lifestyle advice (healthy diet, regular exercise, abstinence from smoking),” they wrote.
Multivariate logistic regression showed that damage accrual was associated with disease duration (odds ratio, 1.15; P less than .001), antiphospholipid‐antibody positivity (OR, 3.56; P = .026), and hypertension (OR, 3.21; P = .043). On the other hand, current HCQ monotherapy was associated with an SLICC-Damage Index score of 0 (OR, 0.16; P = .009).
The HRQOL of the cohort, assessed via the Short Form–36, was also impaired compared with the general population, the researchers discovered. For example, the presence of damage reduced HRQOL in one domain, and high disease activity, defined as SLEDAI-2k of 8 or more, strongly reduced HRQOL in four of eight domains. Changes in physical appearance lowered HRQOL in seven of eight domains.
“HRQOL of adults with cSLE is impaired and affected by other factors than disease activity or damage alone. By identifying and addressing these factors, like physical appearance and potentially coping styles, HRQOL may be improved,” they advised.
The study was supported financially by the Dutch Arthritis Foundation and the Dutch national patient association for lupus, antiphospholipid syndrome, scleroderma, and mixed connective tissue diseases.
SOURCE: Groot N et al. Arthritis Rheumatol. 2018 Aug 27. doi: 10.1002/art.40697
The majority of adults with childhood-onset systemic lupus erythematosus in a longitudinal Dutch study developed significant damage at a young age, remain on corticosteroids in adulthood, and have an impaired health-related quality of life.
The findings in the study, dubbed Childhood-Onset SLE in the Netherlands (CHILL-NL), highlighted the need for preventive screening measures to be put in place before the age of 30 to facilitate a better outcome for patients, who still face high morbidity from childhood-onset systemic lupus erythematosus (cSLE) despite improved survival. Such information is helpful to “answer questions from children and parents regarding the future course of the disease,” wrote Noortje Groot, PhD, of the department of pediatric rheumatology at Erasmus Medical Center–Sophia Children’s Hospital in Rotterdam, the Netherlands, and her colleagues. The report is in Arthritis & Rheumatology.
The current study included all adult SLE patients treated in any Dutch public hospital during the period of November 2013 to April 2016 who were diagnosed with the autoimmune disease prior to their 18th birthday.
All 111 patients involved in the study were seen for a 1.5-hour visit at Erasmus University Medical Center or a local hospital of their choice. During the appointment, a medical history was taken, a physical examination was performed, and the patients completed questionnaires on health-related quality of life (HRQOL).
The average age of patients at the study visit was 33 years, 91% were female, and 72% were white. Median disease duration was 20 years and disease activity was low (median SLE Disease Activity Index 2000 [SLEDAI-2k] = 4). Low complement (32%), skin rashes (14%), and proteinuria (13%) were the most common SLEDAI items reported.
Overall, 68% of the cohort (n = 76) were taking hydroxychloroquine (HCQ), 29% of whom (n = 22) were taking it as monotherapy.
Furthermore, 68% of patients at the study visit were taking corticosteroids and/or non-HCQ disease-modifying antirheumatic drugs (DMARDs), and just over half (51%) of patients (n = 56) were taking corticosteroids either alone or with a non-HCQ DMARD.
“This [finding] is worrying as corticosteroids are associated with the development of damage. Patients are certainly eager to limit corticosteroid use, as almost all patients in the CHILL-NL cohort reported to have negative experiences with prednisone regarding their physical appearance and or mental well-being,” the study authors wrote.
Results also showed that 62% of the patients had damage, predominantly in the musculoskeletal, neuropsychiatric, and renal systems.
Most organ systems became involved within the first 2 years of diagnosis, but after 5 years of disease the nature of disease manifestations tended to shift to damage such as myocardial infarctions.
Notably, after 10-20 years, when cSLE patients were in their early 20s and 30s, significant damage had occurred in more than half of the patients, the authors noted.
“This shift to damage has also been observed in adult-onset SLE patients and urges for preventative screening measures of such (cardiovascular) damage and healthy lifestyle advice (healthy diet, regular exercise, abstinence from smoking),” they wrote.
Multivariate logistic regression showed that damage accrual was associated with disease duration (odds ratio, 1.15; P less than .001), antiphospholipid‐antibody positivity (OR, 3.56; P = .026), and hypertension (OR, 3.21; P = .043). On the other hand, current HCQ monotherapy was associated with an SLICC-Damage Index score of 0 (OR, 0.16; P = .009).
The HRQOL of the cohort, assessed via the Short Form–36, was also impaired compared with the general population, the researchers discovered. For example, the presence of damage reduced HRQOL in one domain, and high disease activity, defined as SLEDAI-2k of 8 or more, strongly reduced HRQOL in four of eight domains. Changes in physical appearance lowered HRQOL in seven of eight domains.
“HRQOL of adults with cSLE is impaired and affected by other factors than disease activity or damage alone. By identifying and addressing these factors, like physical appearance and potentially coping styles, HRQOL may be improved,” they advised.
The study was supported financially by the Dutch Arthritis Foundation and the Dutch national patient association for lupus, antiphospholipid syndrome, scleroderma, and mixed connective tissue diseases.
SOURCE: Groot N et al. Arthritis Rheumatol. 2018 Aug 27. doi: 10.1002/art.40697
The majority of adults with childhood-onset systemic lupus erythematosus in a longitudinal Dutch study developed significant damage at a young age, remain on corticosteroids in adulthood, and have an impaired health-related quality of life.
The findings in the study, dubbed Childhood-Onset SLE in the Netherlands (CHILL-NL), highlighted the need for preventive screening measures to be put in place before the age of 30 to facilitate a better outcome for patients, who still face high morbidity from childhood-onset systemic lupus erythematosus (cSLE) despite improved survival. Such information is helpful to “answer questions from children and parents regarding the future course of the disease,” wrote Noortje Groot, PhD, of the department of pediatric rheumatology at Erasmus Medical Center–Sophia Children’s Hospital in Rotterdam, the Netherlands, and her colleagues. The report is in Arthritis & Rheumatology.
The current study included all adult SLE patients treated in any Dutch public hospital during the period of November 2013 to April 2016 who were diagnosed with the autoimmune disease prior to their 18th birthday.
All 111 patients involved in the study were seen for a 1.5-hour visit at Erasmus University Medical Center or a local hospital of their choice. During the appointment, a medical history was taken, a physical examination was performed, and the patients completed questionnaires on health-related quality of life (HRQOL).
The average age of patients at the study visit was 33 years, 91% were female, and 72% were white. Median disease duration was 20 years and disease activity was low (median SLE Disease Activity Index 2000 [SLEDAI-2k] = 4). Low complement (32%), skin rashes (14%), and proteinuria (13%) were the most common SLEDAI items reported.
Overall, 68% of the cohort (n = 76) were taking hydroxychloroquine (HCQ), 29% of whom (n = 22) were taking it as monotherapy.
Furthermore, 68% of patients at the study visit were taking corticosteroids and/or non-HCQ disease-modifying antirheumatic drugs (DMARDs), and just over half (51%) of patients (n = 56) were taking corticosteroids either alone or with a non-HCQ DMARD.
“This [finding] is worrying as corticosteroids are associated with the development of damage. Patients are certainly eager to limit corticosteroid use, as almost all patients in the CHILL-NL cohort reported to have negative experiences with prednisone regarding their physical appearance and or mental well-being,” the study authors wrote.
Results also showed that 62% of the patients had damage, predominantly in the musculoskeletal, neuropsychiatric, and renal systems.
Most organ systems became involved within the first 2 years of diagnosis, but after 5 years of disease the nature of disease manifestations tended to shift to damage such as myocardial infarctions.
Notably, after 10-20 years, when cSLE patients were in their early 20s and 30s, significant damage had occurred in more than half of the patients, the authors noted.
“This shift to damage has also been observed in adult-onset SLE patients and urges for preventative screening measures of such (cardiovascular) damage and healthy lifestyle advice (healthy diet, regular exercise, abstinence from smoking),” they wrote.
Multivariate logistic regression showed that damage accrual was associated with disease duration (odds ratio, 1.15; P less than .001), antiphospholipid‐antibody positivity (OR, 3.56; P = .026), and hypertension (OR, 3.21; P = .043). On the other hand, current HCQ monotherapy was associated with an SLICC-Damage Index score of 0 (OR, 0.16; P = .009).
The HRQOL of the cohort, assessed via the Short Form–36, was also impaired compared with the general population, the researchers discovered. For example, the presence of damage reduced HRQOL in one domain, and high disease activity, defined as SLEDAI-2k of 8 or more, strongly reduced HRQOL in four of eight domains. Changes in physical appearance lowered HRQOL in seven of eight domains.
“HRQOL of adults with cSLE is impaired and affected by other factors than disease activity or damage alone. By identifying and addressing these factors, like physical appearance and potentially coping styles, HRQOL may be improved,” they advised.
The study was supported financially by the Dutch Arthritis Foundation and the Dutch national patient association for lupus, antiphospholipid syndrome, scleroderma, and mixed connective tissue diseases.
SOURCE: Groot N et al. Arthritis Rheumatol. 2018 Aug 27. doi: 10.1002/art.40697
FROM ARTHRITIS & RHEUMATOLOGY
Key clinical point:
Major finding: Among 111 patients, 62% had damage, predominantly in the musculoskeletal, neuropsychiatric, and renal systems.
Study details: Adult SLE patients diagnosed prior to their 18th birthday who were treated during November 2013 to April 2016 in any Dutch public hospital.
Disclosures: The study was supported financially by the Dutch Arthritis Foundation and the Dutch national patient association for lupus, antiphospholipid syndrome, scleroderma, and mixed connective tissue diseases.
Source: Groot N et al. Arthritis Rheumatol. 2018 Aug 27. doi: 10.1002/art.40697.
Eosinophils could be a marker for nonceliac gluten or wheat sensitivity
. 
NCGWS could be considered an inflammatory condition of the entire intestinal track and the eosinophil infiltration “may represent a key candidate player” in its pathogenesis, wrote the authors, led by Antonio Carroccio, MD, of Giovanni Paolo II Hospital, Sciacca, and DiBiMIS University of Palermo, Italy. The report is in Clinical Gastroenterology and Hepatology.
The research team noted that duodenal histology, a lack of villous atrophy, and evaluation of intraepithelial infiltration of the duodenal mucosa were the usual steps involved in the diagnostic work-up of NCGWS.
Many people with NCGWS had symptoms that overlapped with irritable bowel syndrome but no studies had evaluated histologic features of duodenal and rectal biopsies from these patients.
“Alterations of the mucosal immune system are believed to play a role in IBS and some patients may indeed have inflammation of the colonic mucosa. Consequently, it would be logical to study the colon of NCGWS patients for possible inflammation in this site,” they wrote.
The current study involved 78 consecutive adult patients attending two tertiary referral centers in Italy. The average age of the patients was 36.4 years and they were diagnosed with NCGWS through a double-blind wheat challenge. A non-NCGWS control group of 55 patients had either celiac disease (n = 16) or self-reported NCGWS but with negative results from the wheat challenge (n = 39).
Both duodenal and rectal biopsies were performed in both groups of patients after they had consumed a wheat-containing diet (a minimum of 100 g) for at least 4 weeks.
The researchers then analyzed intraepithelial CD3+T cells, lamina propria CD45+ cells, CD4+ and CD8+ T cells, mast cells, and eosinophils as well as the presence and size of lymphoid nodules.
Histologic evaluation of the duodenal mucosa showed that none of the NCGWS patients or non-NCGWS controls had a villus/crypt ratio less than 3, whereas all the controls with celiac disease (CD) had villous atrophy.
Mucosal inflammation both in the duodenum and the rectal mucosa was common in patients with NCGWS. For example, intraepithelial CD3+ lymphocytes progressively increased from the non-NCGWS controls (14.3 ± 4.2) to NCGWS patients (19.6 ± 10.7; P less than .03) and CD controls (47.7 ± 23.3; P less than .001 vs. NCGWS patients).
Lamina propria CD45+ cells, which the authors said represented the “total immunocyte” infiltration were significantly higher in NCGWS patients than in the non-NCGWS controls at both sites.
In patients with NCGWS, the mean eosinophil infiltration was more than 2.5-fold the upper normal limit in the rectum and nearly twice the upper normal limit in the duodenum (P less than .0001).
Eosinophil numbers in the duodenal mucosa were also higher in the NCGWS patients with dyspepsia than in the NCGWS patients without upper digestive tract symptoms.
For example, in 33 patients who reported upper digestive tract symptoms, the number of lamina propria eosinophils was significantly higher than in the remaining NCGWS patients who did not report symptoms (8.6 ± 2.6 vs. 6.8 ± 3.6; P less than .01).
“Functional dyspepsia is frequently associated with IBS [irritable bowel syndrome], suggesting that these two diseases have a shared pathogenesis,” the researchers speculated.
The researchers suggested that in the absence of endoscopic findings, eosinophil infiltration of the rectal mucosa could be a marker of NCGWS, noting that it could not be considered a specific marker as eosinophils were found in the colon and rectal mucosa in several clinical conditions, such as inflammatory bowel diseases and celiac disease.
“However, these clinical conditions have clinical, endoscopic, serologic, and histologic aspects markedly different from NCGWS. ... We would suggest that in clinical practice, subjects showing an IBS clinical presentation and mucosa eosinophil infiltration should be recommended to commence an elimination diet with a subsequent wheat challenge,” they said.
The authors said another noteworthy finding from their study was that about 95% of patients had lymphoid follicles that were significantly larger than those of the control group. Although this can be considered a “normal” finding in rectal mucosa, they said in their experience the presence of large follicles was associated with non-IgE mediated food allergy.
“It can be hypothesized that not only eosinophils could play a pathogenetic role in NCGWS, and that a complex immunologic response involving both innate and acquired immunity may be responsible for this disease,” they said.
A study limitation was selection bias stemming from the fact that the cohort included patients referred to tertiary centers, they noted. “Our results must not be extended to all self-treated or diagnosed NCGWS patients,” they cautioned.
SOURCE: Clin Gastroenterol Hepatol. 2018 Aug 20. doi: 10.1016/j.cgh.2018.08.043.
.
NCGWS could be considered an inflammatory condition of the entire intestinal track and the eosinophil infiltration “may represent a key candidate player” in its pathogenesis, wrote the authors, led by Antonio Carroccio, MD, of Giovanni Paolo II Hospital, Sciacca, and DiBiMIS University of Palermo, Italy. The report is in Clinical Gastroenterology and Hepatology.
The research team noted that duodenal histology, a lack of villous atrophy, and evaluation of intraepithelial infiltration of the duodenal mucosa were the usual steps involved in the diagnostic work-up of NCGWS.
Many people with NCGWS had symptoms that overlapped with irritable bowel syndrome but no studies had evaluated histologic features of duodenal and rectal biopsies from these patients.
“Alterations of the mucosal immune system are believed to play a role in IBS and some patients may indeed have inflammation of the colonic mucosa. Consequently, it would be logical to study the colon of NCGWS patients for possible inflammation in this site,” they wrote.
The current study involved 78 consecutive adult patients attending two tertiary referral centers in Italy. The average age of the patients was 36.4 years and they were diagnosed with NCGWS through a double-blind wheat challenge. A non-NCGWS control group of 55 patients had either celiac disease (n = 16) or self-reported NCGWS but with negative results from the wheat challenge (n = 39).
Both duodenal and rectal biopsies were performed in both groups of patients after they had consumed a wheat-containing diet (a minimum of 100 g) for at least 4 weeks.
The researchers then analyzed intraepithelial CD3+T cells, lamina propria CD45+ cells, CD4+ and CD8+ T cells, mast cells, and eosinophils as well as the presence and size of lymphoid nodules.
Histologic evaluation of the duodenal mucosa showed that none of the NCGWS patients or non-NCGWS controls had a villus/crypt ratio less than 3, whereas all the controls with celiac disease (CD) had villous atrophy.
Mucosal inflammation both in the duodenum and the rectal mucosa was common in patients with NCGWS. For example, intraepithelial CD3+ lymphocytes progressively increased from the non-NCGWS controls (14.3 ± 4.2) to NCGWS patients (19.6 ± 10.7; P less than .03) and CD controls (47.7 ± 23.3; P less than .001 vs. NCGWS patients).
Lamina propria CD45+ cells, which the authors said represented the “total immunocyte” infiltration were significantly higher in NCGWS patients than in the non-NCGWS controls at both sites.
In patients with NCGWS, the mean eosinophil infiltration was more than 2.5-fold the upper normal limit in the rectum and nearly twice the upper normal limit in the duodenum (P less than .0001).
Eosinophil numbers in the duodenal mucosa were also higher in the NCGWS patients with dyspepsia than in the NCGWS patients without upper digestive tract symptoms.
For example, in 33 patients who reported upper digestive tract symptoms, the number of lamina propria eosinophils was significantly higher than in the remaining NCGWS patients who did not report symptoms (8.6 ± 2.6 vs. 6.8 ± 3.6; P less than .01).
“Functional dyspepsia is frequently associated with IBS [irritable bowel syndrome], suggesting that these two diseases have a shared pathogenesis,” the researchers speculated.
The researchers suggested that in the absence of endoscopic findings, eosinophil infiltration of the rectal mucosa could be a marker of NCGWS, noting that it could not be considered a specific marker as eosinophils were found in the colon and rectal mucosa in several clinical conditions, such as inflammatory bowel diseases and celiac disease.
“However, these clinical conditions have clinical, endoscopic, serologic, and histologic aspects markedly different from NCGWS. ... We would suggest that in clinical practice, subjects showing an IBS clinical presentation and mucosa eosinophil infiltration should be recommended to commence an elimination diet with a subsequent wheat challenge,” they said.
The authors said another noteworthy finding from their study was that about 95% of patients had lymphoid follicles that were significantly larger than those of the control group. Although this can be considered a “normal” finding in rectal mucosa, they said in their experience the presence of large follicles was associated with non-IgE mediated food allergy.
“It can be hypothesized that not only eosinophils could play a pathogenetic role in NCGWS, and that a complex immunologic response involving both innate and acquired immunity may be responsible for this disease,” they said.
A study limitation was selection bias stemming from the fact that the cohort included patients referred to tertiary centers, they noted. “Our results must not be extended to all self-treated or diagnosed NCGWS patients,” they cautioned.
SOURCE: Clin Gastroenterol Hepatol. 2018 Aug 20. doi: 10.1016/j.cgh.2018.08.043.
.
NCGWS could be considered an inflammatory condition of the entire intestinal track and the eosinophil infiltration “may represent a key candidate player” in its pathogenesis, wrote the authors, led by Antonio Carroccio, MD, of Giovanni Paolo II Hospital, Sciacca, and DiBiMIS University of Palermo, Italy. The report is in Clinical Gastroenterology and Hepatology.
The research team noted that duodenal histology, a lack of villous atrophy, and evaluation of intraepithelial infiltration of the duodenal mucosa were the usual steps involved in the diagnostic work-up of NCGWS.
Many people with NCGWS had symptoms that overlapped with irritable bowel syndrome but no studies had evaluated histologic features of duodenal and rectal biopsies from these patients.
“Alterations of the mucosal immune system are believed to play a role in IBS and some patients may indeed have inflammation of the colonic mucosa. Consequently, it would be logical to study the colon of NCGWS patients for possible inflammation in this site,” they wrote.
The current study involved 78 consecutive adult patients attending two tertiary referral centers in Italy. The average age of the patients was 36.4 years and they were diagnosed with NCGWS through a double-blind wheat challenge. A non-NCGWS control group of 55 patients had either celiac disease (n = 16) or self-reported NCGWS but with negative results from the wheat challenge (n = 39).
Both duodenal and rectal biopsies were performed in both groups of patients after they had consumed a wheat-containing diet (a minimum of 100 g) for at least 4 weeks.
The researchers then analyzed intraepithelial CD3+T cells, lamina propria CD45+ cells, CD4+ and CD8+ T cells, mast cells, and eosinophils as well as the presence and size of lymphoid nodules.
Histologic evaluation of the duodenal mucosa showed that none of the NCGWS patients or non-NCGWS controls had a villus/crypt ratio less than 3, whereas all the controls with celiac disease (CD) had villous atrophy.
Mucosal inflammation both in the duodenum and the rectal mucosa was common in patients with NCGWS. For example, intraepithelial CD3+ lymphocytes progressively increased from the non-NCGWS controls (14.3 ± 4.2) to NCGWS patients (19.6 ± 10.7; P less than .03) and CD controls (47.7 ± 23.3; P less than .001 vs. NCGWS patients).
Lamina propria CD45+ cells, which the authors said represented the “total immunocyte” infiltration were significantly higher in NCGWS patients than in the non-NCGWS controls at both sites.
In patients with NCGWS, the mean eosinophil infiltration was more than 2.5-fold the upper normal limit in the rectum and nearly twice the upper normal limit in the duodenum (P less than .0001).
Eosinophil numbers in the duodenal mucosa were also higher in the NCGWS patients with dyspepsia than in the NCGWS patients without upper digestive tract symptoms.
For example, in 33 patients who reported upper digestive tract symptoms, the number of lamina propria eosinophils was significantly higher than in the remaining NCGWS patients who did not report symptoms (8.6 ± 2.6 vs. 6.8 ± 3.6; P less than .01).
“Functional dyspepsia is frequently associated with IBS [irritable bowel syndrome], suggesting that these two diseases have a shared pathogenesis,” the researchers speculated.
The researchers suggested that in the absence of endoscopic findings, eosinophil infiltration of the rectal mucosa could be a marker of NCGWS, noting that it could not be considered a specific marker as eosinophils were found in the colon and rectal mucosa in several clinical conditions, such as inflammatory bowel diseases and celiac disease.
“However, these clinical conditions have clinical, endoscopic, serologic, and histologic aspects markedly different from NCGWS. ... We would suggest that in clinical practice, subjects showing an IBS clinical presentation and mucosa eosinophil infiltration should be recommended to commence an elimination diet with a subsequent wheat challenge,” they said.
The authors said another noteworthy finding from their study was that about 95% of patients had lymphoid follicles that were significantly larger than those of the control group. Although this can be considered a “normal” finding in rectal mucosa, they said in their experience the presence of large follicles was associated with non-IgE mediated food allergy.
“It can be hypothesized that not only eosinophils could play a pathogenetic role in NCGWS, and that a complex immunologic response involving both innate and acquired immunity may be responsible for this disease,” they said.
A study limitation was selection bias stemming from the fact that the cohort included patients referred to tertiary centers, they noted. “Our results must not be extended to all self-treated or diagnosed NCGWS patients,” they cautioned.
SOURCE: Clin Gastroenterol Hepatol. 2018 Aug 20. doi: 10.1016/j.cgh.2018.08.043.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: The evaluation of patients for nonceliac gluten or wheat sensitivity should include histologic analysis of rectal biopsies.
Major finding: Mucosal inflammation in the duodenum and in the rectal mucosa was common in patients with NCGWS. In these patients the mean eosinophil infiltration was more than 2.5-fold the upper normal limit in the rectum and nearly twice the upper normal limit in the duodenum (P less than .0001).
Study details: A prospective study of 78 patients with NCGWS and 55 controls with either celiac disease or self-reported NCGWS but negative wheat challenge results.
Disclosures: The Italian Foundation for Celiac Disease funded the study. The authors declared no conflicts of interest.
Source: Clin Gastroenterol Hepatol. 2018 Aug 20. doi: 10.1016/j.cgh.2018.08.043.
Study supports effects of smoking, drinking on SLE risk in black women
Black women who smoke cigarettes are at increased risk of systemic lupus erythematosus (SLE), while those who drink alcohol in moderation have a decreased risk, data from the prospective Black Women’s Health Study suggests.
The current findings among black women, who are the demographic group at the highest risk of SLE in the U.S. population, are consistent with the previously reported positive association of cigarette smoking with risk of SLE and inverse association of alcohol consumption with SLE,” lead researchers Yvette Cozier, DSc, and Medha Barbhaiya, MD, and their colleagues wrote in a study published in Arthritis Care & Research.
“The role of environmental factors in the pathogenesis of SLE is of great interest, as genetic factors do not explain a major portion of the incidence. Cigarette smoking has been associated with SLE risk in several, but not all, past studies,” wrote Dr. Cozier of the Slone Epidemiology Center at Boston University and Dr. Barbhaiya of the Hospital for Special Surgery, New York, and their coauthors.
Their analysis of data from the Black Women’s Health Study, a prospective study following 59,000 black women in the United States since 1995, identified 127 new cases of SLE between 1995 and 2015 that were confirmed by medical records.
At baseline, 8,851 women (16%) were current smokers, and 10,447 (18%) were past smokers. A total of 14,001 (25%) were current drinkers, and 10,255 (18%) were past drinkers.
The researchers reported that, compared with never smokers, women who had ever smoked had a 45% higher risk for SLE than did never smokers (hazard ratio, 1.45; 95% confidence interval, 0.97-2.18), but the finding was not statistically significant.
The risk of SLE was greater among current smokers (52% higher risk) than among past smokers (41% higher risk), and greater for 20 or more pack-years of smoking (60% higher risk) than for less than 20 pack-years of smoking (37% higher risk), although the authors noted that none of these differences were statistically significant.
Current and past alcohol consumption were associated with nonsignificant reductions in risk for SLE, 29% and 21%, respectively. However, “moderate” current alcohol consumption, measured as four or more drinks per week, was associated with a 57% reduction in risk for SLE (HR, 0.43; 95% CI, 0.19-0.96).
The researchers said that the associations between cigarette smoking and alcohol intake with SLE risk were biologically plausible and may lead to insights into SLE pathogenesis. For example, exposure to toxic components from cigarette smoke was associated with increased oxidative stress and stimulation of autoantibody production, and such exposure can directly damage endogenous proteins and DNA. Alcohol suppresses the synthesis of proinflammatory cytokines and may inhibit DNA synthesis.
The small number of lupus cases in the Black Women’s Health Study cohort limited the statistical power of the analysis. Smoking and alcohol use were also relatively uncommon among women in the Black Women’s Health Study cohort, the investigators said.
“Future studies are needed to confirm these findings and establish the biologic mechanisms by which cigarette smoking and alcohol consumption influence the risk of SLE in this population and others,“ they wrote.
The study was supported by individual investigators’ grant awards from the National Cancer Institute, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Rheumatology Research Foundation, and the Lupus Foundation of America. The authors declared no relevant conflicts of interest.
SOURCE: Cozier Y et al. Arthritis Care Res. 2018 Aug 9. doi: 10.1002/acr.23703.
Black women who smoke cigarettes are at increased risk of systemic lupus erythematosus (SLE), while those who drink alcohol in moderation have a decreased risk, data from the prospective Black Women’s Health Study suggests.
The current findings among black women, who are the demographic group at the highest risk of SLE in the U.S. population, are consistent with the previously reported positive association of cigarette smoking with risk of SLE and inverse association of alcohol consumption with SLE,” lead researchers Yvette Cozier, DSc, and Medha Barbhaiya, MD, and their colleagues wrote in a study published in Arthritis Care & Research.
“The role of environmental factors in the pathogenesis of SLE is of great interest, as genetic factors do not explain a major portion of the incidence. Cigarette smoking has been associated with SLE risk in several, but not all, past studies,” wrote Dr. Cozier of the Slone Epidemiology Center at Boston University and Dr. Barbhaiya of the Hospital for Special Surgery, New York, and their coauthors.
Their analysis of data from the Black Women’s Health Study, a prospective study following 59,000 black women in the United States since 1995, identified 127 new cases of SLE between 1995 and 2015 that were confirmed by medical records.
At baseline, 8,851 women (16%) were current smokers, and 10,447 (18%) were past smokers. A total of 14,001 (25%) were current drinkers, and 10,255 (18%) were past drinkers.
The researchers reported that, compared with never smokers, women who had ever smoked had a 45% higher risk for SLE than did never smokers (hazard ratio, 1.45; 95% confidence interval, 0.97-2.18), but the finding was not statistically significant.
The risk of SLE was greater among current smokers (52% higher risk) than among past smokers (41% higher risk), and greater for 20 or more pack-years of smoking (60% higher risk) than for less than 20 pack-years of smoking (37% higher risk), although the authors noted that none of these differences were statistically significant.
Current and past alcohol consumption were associated with nonsignificant reductions in risk for SLE, 29% and 21%, respectively. However, “moderate” current alcohol consumption, measured as four or more drinks per week, was associated with a 57% reduction in risk for SLE (HR, 0.43; 95% CI, 0.19-0.96).
The researchers said that the associations between cigarette smoking and alcohol intake with SLE risk were biologically plausible and may lead to insights into SLE pathogenesis. For example, exposure to toxic components from cigarette smoke was associated with increased oxidative stress and stimulation of autoantibody production, and such exposure can directly damage endogenous proteins and DNA. Alcohol suppresses the synthesis of proinflammatory cytokines and may inhibit DNA synthesis.
The small number of lupus cases in the Black Women’s Health Study cohort limited the statistical power of the analysis. Smoking and alcohol use were also relatively uncommon among women in the Black Women’s Health Study cohort, the investigators said.
“Future studies are needed to confirm these findings and establish the biologic mechanisms by which cigarette smoking and alcohol consumption influence the risk of SLE in this population and others,“ they wrote.
The study was supported by individual investigators’ grant awards from the National Cancer Institute, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Rheumatology Research Foundation, and the Lupus Foundation of America. The authors declared no relevant conflicts of interest.
SOURCE: Cozier Y et al. Arthritis Care Res. 2018 Aug 9. doi: 10.1002/acr.23703.
Black women who smoke cigarettes are at increased risk of systemic lupus erythematosus (SLE), while those who drink alcohol in moderation have a decreased risk, data from the prospective Black Women’s Health Study suggests.
The current findings among black women, who are the demographic group at the highest risk of SLE in the U.S. population, are consistent with the previously reported positive association of cigarette smoking with risk of SLE and inverse association of alcohol consumption with SLE,” lead researchers Yvette Cozier, DSc, and Medha Barbhaiya, MD, and their colleagues wrote in a study published in Arthritis Care & Research.
“The role of environmental factors in the pathogenesis of SLE is of great interest, as genetic factors do not explain a major portion of the incidence. Cigarette smoking has been associated with SLE risk in several, but not all, past studies,” wrote Dr. Cozier of the Slone Epidemiology Center at Boston University and Dr. Barbhaiya of the Hospital for Special Surgery, New York, and their coauthors.
Their analysis of data from the Black Women’s Health Study, a prospective study following 59,000 black women in the United States since 1995, identified 127 new cases of SLE between 1995 and 2015 that were confirmed by medical records.
At baseline, 8,851 women (16%) were current smokers, and 10,447 (18%) were past smokers. A total of 14,001 (25%) were current drinkers, and 10,255 (18%) were past drinkers.
The researchers reported that, compared with never smokers, women who had ever smoked had a 45% higher risk for SLE than did never smokers (hazard ratio, 1.45; 95% confidence interval, 0.97-2.18), but the finding was not statistically significant.
The risk of SLE was greater among current smokers (52% higher risk) than among past smokers (41% higher risk), and greater for 20 or more pack-years of smoking (60% higher risk) than for less than 20 pack-years of smoking (37% higher risk), although the authors noted that none of these differences were statistically significant.
Current and past alcohol consumption were associated with nonsignificant reductions in risk for SLE, 29% and 21%, respectively. However, “moderate” current alcohol consumption, measured as four or more drinks per week, was associated with a 57% reduction in risk for SLE (HR, 0.43; 95% CI, 0.19-0.96).
The researchers said that the associations between cigarette smoking and alcohol intake with SLE risk were biologically plausible and may lead to insights into SLE pathogenesis. For example, exposure to toxic components from cigarette smoke was associated with increased oxidative stress and stimulation of autoantibody production, and such exposure can directly damage endogenous proteins and DNA. Alcohol suppresses the synthesis of proinflammatory cytokines and may inhibit DNA synthesis.
The small number of lupus cases in the Black Women’s Health Study cohort limited the statistical power of the analysis. Smoking and alcohol use were also relatively uncommon among women in the Black Women’s Health Study cohort, the investigators said.
“Future studies are needed to confirm these findings and establish the biologic mechanisms by which cigarette smoking and alcohol consumption influence the risk of SLE in this population and others,“ they wrote.
The study was supported by individual investigators’ grant awards from the National Cancer Institute, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Rheumatology Research Foundation, and the Lupus Foundation of America. The authors declared no relevant conflicts of interest.
SOURCE: Cozier Y et al. Arthritis Care Res. 2018 Aug 9. doi: 10.1002/acr.23703.
FROM ARTHRITIS CARE & RESEARCH
Key clinical point:
Major finding: There was an estimated 45% increase in risk of SLE for ever smoking relative to never smoking, but the finding was of borderline statistical significance. Moderate current alcohol consumption, measured as four or more drinks per week, was associated with a 57% reduction in SLE risk.
Study details: Analysis of data from 59,000 women enrolled in the prospective Black Women’s Health Study between 1995 and 2015.
Disclosures: The study was supported by individual investigators’ grant awards from the National Cancer Institute, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Rheumatology Research Foundation, and the Lupus Foundation of America. The authors declared no relevant conflicts of interest.
Source: Cozier Y et al. Arthritis Care Res. 2018 Aug 9. doi: 10.1002/acr.23703.
Real-world bleeding risk with ibrutinib
The Bruton tyrosine kinase inhibitor ibrutinib has been linked to a 20-fold increased risk of major bleeding in blood cancer patients taking concomitant antiplatelet and anticoagulation therapy in a clinical setting.
Caution should be used when weighing the risks and benefits of ibrutinib for patients already taking antiplatelet or anticoagulation therapy, or both, wrote Joseph Mock, MD, of the University of Virginia Health System in Charlottesville, and his colleagues.
Their report was published in Clinical Lymphoma, Myeloma & Leukemia.
Ibrutinib had been associated with an increased risk of bleeding, albeit low, in the clinical trial setting, but the authors suggested this rate could be higher in everyday clinical practice.
“Much of the information [from clinical trials] on the bleeding risk with ibrutinib, included pooled analyses, was from patients exclusively treated in clinical trials with specific exclusion criteria,” the researchers wrote. “These criteria have generally excluded patients with significant comorbidities. However, these patients are seen in clinical practice.”
The researchers conducted a review of patients treated within the University of Virginia Health System between January 2012 and May 2016.
The team identified 70 patients, with an average age of 72, who were taking ibrutinib for chronic lymphocytic leukemia (64%), mantle cell lymphoma (27%), diffuse large B-cell lymphoma (4%), lymphoblastic lymphoma (3%), and Waldenström’s macroglobulinemia (1%).
Bleeding of any grade occurred in 56% of patients, mostly grade 1-2 bruising and epistaxis.
However, major bleeding, defined as grade 3 or higher, occurred in 19% of patients (n=13). Seven of these patients were taking combined antiplatelet and anticoagulant therapy, 4 were taking antiplatelet agents alone, 1 was taking an anticoagulant agent alone, and 1 was taking only ibrutinib.
Univariate analysis showed that the factors associated with an increased risk of major bleeding were antiplatelet or anticoagulant medication, the combination of the 2 medications, interacting medications, anemia (hemoglobin less than 12 g/dL), and an elevated international normalized ratio (INR, > 1.5).
In a multivariate analysis, only the following factors were associated with an increased risk of major bleeding:
- Concomitant antiplatelet and anticoagulant use—hazard ratio=20.0 (95% CI, 2.1-200.0; P=0.0005) vs no antiplatelet/anticoagulant therapy
- Elevated INR—hazard ratio=4.6 (95% CI, 1.1-19.6; P=0.0409).
The researchers said the risk of major bleeding in patients taking both antiplatelet and anticoagulant therapy was “unacceptably high” and “medications other than ibrutinib should be considered” in this patient population.
Overall, the team said their findings confirm “the increasingly recognized risk of major bleeding complications with ibrutinib compared with what was originally reported in the clinical trial setting.”
They noted that this study was limited by the relatively small population size. Their finding that platelet count was not associated with bleeding risk was also “counterintuitive.”
The Bruton tyrosine kinase inhibitor ibrutinib has been linked to a 20-fold increased risk of major bleeding in blood cancer patients taking concomitant antiplatelet and anticoagulation therapy in a clinical setting.
Caution should be used when weighing the risks and benefits of ibrutinib for patients already taking antiplatelet or anticoagulation therapy, or both, wrote Joseph Mock, MD, of the University of Virginia Health System in Charlottesville, and his colleagues.
Their report was published in Clinical Lymphoma, Myeloma & Leukemia.
Ibrutinib had been associated with an increased risk of bleeding, albeit low, in the clinical trial setting, but the authors suggested this rate could be higher in everyday clinical practice.
“Much of the information [from clinical trials] on the bleeding risk with ibrutinib, included pooled analyses, was from patients exclusively treated in clinical trials with specific exclusion criteria,” the researchers wrote. “These criteria have generally excluded patients with significant comorbidities. However, these patients are seen in clinical practice.”
The researchers conducted a review of patients treated within the University of Virginia Health System between January 2012 and May 2016.
The team identified 70 patients, with an average age of 72, who were taking ibrutinib for chronic lymphocytic leukemia (64%), mantle cell lymphoma (27%), diffuse large B-cell lymphoma (4%), lymphoblastic lymphoma (3%), and Waldenström’s macroglobulinemia (1%).
Bleeding of any grade occurred in 56% of patients, mostly grade 1-2 bruising and epistaxis.
However, major bleeding, defined as grade 3 or higher, occurred in 19% of patients (n=13). Seven of these patients were taking combined antiplatelet and anticoagulant therapy, 4 were taking antiplatelet agents alone, 1 was taking an anticoagulant agent alone, and 1 was taking only ibrutinib.
Univariate analysis showed that the factors associated with an increased risk of major bleeding were antiplatelet or anticoagulant medication, the combination of the 2 medications, interacting medications, anemia (hemoglobin less than 12 g/dL), and an elevated international normalized ratio (INR, > 1.5).
In a multivariate analysis, only the following factors were associated with an increased risk of major bleeding:
- Concomitant antiplatelet and anticoagulant use—hazard ratio=20.0 (95% CI, 2.1-200.0; P=0.0005) vs no antiplatelet/anticoagulant therapy
- Elevated INR—hazard ratio=4.6 (95% CI, 1.1-19.6; P=0.0409).
The researchers said the risk of major bleeding in patients taking both antiplatelet and anticoagulant therapy was “unacceptably high” and “medications other than ibrutinib should be considered” in this patient population.
Overall, the team said their findings confirm “the increasingly recognized risk of major bleeding complications with ibrutinib compared with what was originally reported in the clinical trial setting.”
They noted that this study was limited by the relatively small population size. Their finding that platelet count was not associated with bleeding risk was also “counterintuitive.”
The Bruton tyrosine kinase inhibitor ibrutinib has been linked to a 20-fold increased risk of major bleeding in blood cancer patients taking concomitant antiplatelet and anticoagulation therapy in a clinical setting.
Caution should be used when weighing the risks and benefits of ibrutinib for patients already taking antiplatelet or anticoagulation therapy, or both, wrote Joseph Mock, MD, of the University of Virginia Health System in Charlottesville, and his colleagues.
Their report was published in Clinical Lymphoma, Myeloma & Leukemia.
Ibrutinib had been associated with an increased risk of bleeding, albeit low, in the clinical trial setting, but the authors suggested this rate could be higher in everyday clinical practice.
“Much of the information [from clinical trials] on the bleeding risk with ibrutinib, included pooled analyses, was from patients exclusively treated in clinical trials with specific exclusion criteria,” the researchers wrote. “These criteria have generally excluded patients with significant comorbidities. However, these patients are seen in clinical practice.”
The researchers conducted a review of patients treated within the University of Virginia Health System between January 2012 and May 2016.
The team identified 70 patients, with an average age of 72, who were taking ibrutinib for chronic lymphocytic leukemia (64%), mantle cell lymphoma (27%), diffuse large B-cell lymphoma (4%), lymphoblastic lymphoma (3%), and Waldenström’s macroglobulinemia (1%).
Bleeding of any grade occurred in 56% of patients, mostly grade 1-2 bruising and epistaxis.
However, major bleeding, defined as grade 3 or higher, occurred in 19% of patients (n=13). Seven of these patients were taking combined antiplatelet and anticoagulant therapy, 4 were taking antiplatelet agents alone, 1 was taking an anticoagulant agent alone, and 1 was taking only ibrutinib.
Univariate analysis showed that the factors associated with an increased risk of major bleeding were antiplatelet or anticoagulant medication, the combination of the 2 medications, interacting medications, anemia (hemoglobin less than 12 g/dL), and an elevated international normalized ratio (INR, > 1.5).
In a multivariate analysis, only the following factors were associated with an increased risk of major bleeding:
- Concomitant antiplatelet and anticoagulant use—hazard ratio=20.0 (95% CI, 2.1-200.0; P=0.0005) vs no antiplatelet/anticoagulant therapy
- Elevated INR—hazard ratio=4.6 (95% CI, 1.1-19.6; P=0.0409).
The researchers said the risk of major bleeding in patients taking both antiplatelet and anticoagulant therapy was “unacceptably high” and “medications other than ibrutinib should be considered” in this patient population.
Overall, the team said their findings confirm “the increasingly recognized risk of major bleeding complications with ibrutinib compared with what was originally reported in the clinical trial setting.”
They noted that this study was limited by the relatively small population size. Their finding that platelet count was not associated with bleeding risk was also “counterintuitive.”
Prolonged antimalarial therapy linked to elevated cardiac biomarkers, cardiomyopathy
People with systemic lupus erythematosus (SLE) taking antimalarials, particularly for prolonged periods, could be at risk for cardiomyopathy, and measuring specific myocardial biomarkers could help identify patients at particularly high risk, researchers have suggested.
Writing in the Journal of Rheumatology, the research team led by Konstantinos Tselios, MD, PhD, of the University of Toronto Lupus Clinic at the Centre for Prognosis Studies in the Rheumatic Diseases, noted that antimalarial-induced cardiomyopathy (AMIC) had been reported in 47 patients to date, 19 of whom had SLE, with duration and cumulative use of antimalarials thought to be the cause.
The authors suggested that AMIC could be underrecognized because antimalarials were currently recommended for all patients with SLE (without known contraindications) for prolonged periods. It was speculated that the mechanism by which AMIC occurred involved the deposition of antimalarials in the myocardial fibers and that this could lead to chronic, subclinical tissue necrosis, a process which, if not reversed, could lead to heart failure.
“Heart-specific biomarkers, such as cardiac troponin (for the assessment of myocardial necrosis) and brain natriuretic peptide (BNP; for the assessment of volume and/or pressure overload), may be of value in identifying subclinical heart damage,” the research team suggested.
The current study involved 151 consecutive patients with SLE who had no prior cardiac disease and were attending the University of Toronto Lupus Clinic from March to May 2016.
During the course of the disease, 28 of the patients had been taking chloroquine, and 137 had been taking hydroxychloroquine (14 patients had been treated with both drugs at different time periods). In the study, normal range was less than 26 ng/mL for high-sensitivity cardiac troponin I (cTnI) and less than 100 pg/mL for BNP.
Overall, 16 patients (10.6%) had abnormal BNP, of whom 9 (6%) also had abnormal cTnI. Prolonged antimalarial use (greater than 5.6 yrs) was associated with increased risk for these elevated biomarkers, regardless of age and SLE disease duration.
“Because duration of AM [antimalarial] treatment is the critical predictor of AMIC, the majority of patients with SLE should be considered at risk because most of them receive long-term maintenance therapy,” the researchers wrote.
They said that elevations of the biomarkers implicated possible active myocardial necrosis (elevated cTnI) and/or increased intracardiac ventricular pressure (elevated BNP).
“In this context, AM deposition in the myocardium, leading over time to overt cardiomyopathy, may be an important contributing factor. Indeed, 6 out of 16 of these patients were ultimately diagnosed with definite or possible AMIC, while 3 of them were completely asymptomatic, and their investigation was initiated because of the abnormal biomarkers,” they wrote.
The researchers also found that persistent creatine phosphokinase (CPK) elevation was also an important predictor for elevated cardiac biomarkers.
“We showed that chronic AM use is associated with a more than threefold increased risk for elevated CPK (after excluding patients with active myositis and statin therapy). ... It is not known whether elevated CPK may predict patients at risk for development of AMIC or whether certain patients are predisposed to AM-related muscle damage,” they said.
“Prolonged AM therapy and persistent CPK elevation conferred an increased risk for abnormal BNP and cTnI, which might predict AMIC,” they concluded.
Nevertheless, the authors acknowledged that expensive and invasive investigation was unjustified in asymptomatic individuals. They therefore suggested that identifying heart-specific biomarkers for the detection of subclinical heart damage could allow patients to be stratified according to their risk.
“Cardiac biomarkers could become a screening test for patients with SLE using AM for longer than 5.6 years and/or who have persistently elevated CPK levels. Further research is needed to delineate the differential toxicity of CQ [chloroquine] and HCQ [hydroxychloroquine],” they suggested.
The University of Toronto Lupus Research Program is supported by the University Health Network, Lou and Marissa Rocca, and the Lupus Foundation of Ontario. Dr. Tselios is financially supported by Lupus Ontario.
SOURCE: Tselios K et al. J Rheumatol. 2018. doi: 10.3899/jrheum.171436.
People with systemic lupus erythematosus (SLE) taking antimalarials, particularly for prolonged periods, could be at risk for cardiomyopathy, and measuring specific myocardial biomarkers could help identify patients at particularly high risk, researchers have suggested.
Writing in the Journal of Rheumatology, the research team led by Konstantinos Tselios, MD, PhD, of the University of Toronto Lupus Clinic at the Centre for Prognosis Studies in the Rheumatic Diseases, noted that antimalarial-induced cardiomyopathy (AMIC) had been reported in 47 patients to date, 19 of whom had SLE, with duration and cumulative use of antimalarials thought to be the cause.
The authors suggested that AMIC could be underrecognized because antimalarials were currently recommended for all patients with SLE (without known contraindications) for prolonged periods. It was speculated that the mechanism by which AMIC occurred involved the deposition of antimalarials in the myocardial fibers and that this could lead to chronic, subclinical tissue necrosis, a process which, if not reversed, could lead to heart failure.
“Heart-specific biomarkers, such as cardiac troponin (for the assessment of myocardial necrosis) and brain natriuretic peptide (BNP; for the assessment of volume and/or pressure overload), may be of value in identifying subclinical heart damage,” the research team suggested.
The current study involved 151 consecutive patients with SLE who had no prior cardiac disease and were attending the University of Toronto Lupus Clinic from March to May 2016.
During the course of the disease, 28 of the patients had been taking chloroquine, and 137 had been taking hydroxychloroquine (14 patients had been treated with both drugs at different time periods). In the study, normal range was less than 26 ng/mL for high-sensitivity cardiac troponin I (cTnI) and less than 100 pg/mL for BNP.
Overall, 16 patients (10.6%) had abnormal BNP, of whom 9 (6%) also had abnormal cTnI. Prolonged antimalarial use (greater than 5.6 yrs) was associated with increased risk for these elevated biomarkers, regardless of age and SLE disease duration.
“Because duration of AM [antimalarial] treatment is the critical predictor of AMIC, the majority of patients with SLE should be considered at risk because most of them receive long-term maintenance therapy,” the researchers wrote.
They said that elevations of the biomarkers implicated possible active myocardial necrosis (elevated cTnI) and/or increased intracardiac ventricular pressure (elevated BNP).
“In this context, AM deposition in the myocardium, leading over time to overt cardiomyopathy, may be an important contributing factor. Indeed, 6 out of 16 of these patients were ultimately diagnosed with definite or possible AMIC, while 3 of them were completely asymptomatic, and their investigation was initiated because of the abnormal biomarkers,” they wrote.
The researchers also found that persistent creatine phosphokinase (CPK) elevation was also an important predictor for elevated cardiac biomarkers.
“We showed that chronic AM use is associated with a more than threefold increased risk for elevated CPK (after excluding patients with active myositis and statin therapy). ... It is not known whether elevated CPK may predict patients at risk for development of AMIC or whether certain patients are predisposed to AM-related muscle damage,” they said.
“Prolonged AM therapy and persistent CPK elevation conferred an increased risk for abnormal BNP and cTnI, which might predict AMIC,” they concluded.
Nevertheless, the authors acknowledged that expensive and invasive investigation was unjustified in asymptomatic individuals. They therefore suggested that identifying heart-specific biomarkers for the detection of subclinical heart damage could allow patients to be stratified according to their risk.
“Cardiac biomarkers could become a screening test for patients with SLE using AM for longer than 5.6 years and/or who have persistently elevated CPK levels. Further research is needed to delineate the differential toxicity of CQ [chloroquine] and HCQ [hydroxychloroquine],” they suggested.
The University of Toronto Lupus Research Program is supported by the University Health Network, Lou and Marissa Rocca, and the Lupus Foundation of Ontario. Dr. Tselios is financially supported by Lupus Ontario.
SOURCE: Tselios K et al. J Rheumatol. 2018. doi: 10.3899/jrheum.171436.
People with systemic lupus erythematosus (SLE) taking antimalarials, particularly for prolonged periods, could be at risk for cardiomyopathy, and measuring specific myocardial biomarkers could help identify patients at particularly high risk, researchers have suggested.
Writing in the Journal of Rheumatology, the research team led by Konstantinos Tselios, MD, PhD, of the University of Toronto Lupus Clinic at the Centre for Prognosis Studies in the Rheumatic Diseases, noted that antimalarial-induced cardiomyopathy (AMIC) had been reported in 47 patients to date, 19 of whom had SLE, with duration and cumulative use of antimalarials thought to be the cause.
The authors suggested that AMIC could be underrecognized because antimalarials were currently recommended for all patients with SLE (without known contraindications) for prolonged periods. It was speculated that the mechanism by which AMIC occurred involved the deposition of antimalarials in the myocardial fibers and that this could lead to chronic, subclinical tissue necrosis, a process which, if not reversed, could lead to heart failure.
“Heart-specific biomarkers, such as cardiac troponin (for the assessment of myocardial necrosis) and brain natriuretic peptide (BNP; for the assessment of volume and/or pressure overload), may be of value in identifying subclinical heart damage,” the research team suggested.
The current study involved 151 consecutive patients with SLE who had no prior cardiac disease and were attending the University of Toronto Lupus Clinic from March to May 2016.
During the course of the disease, 28 of the patients had been taking chloroquine, and 137 had been taking hydroxychloroquine (14 patients had been treated with both drugs at different time periods). In the study, normal range was less than 26 ng/mL for high-sensitivity cardiac troponin I (cTnI) and less than 100 pg/mL for BNP.
Overall, 16 patients (10.6%) had abnormal BNP, of whom 9 (6%) also had abnormal cTnI. Prolonged antimalarial use (greater than 5.6 yrs) was associated with increased risk for these elevated biomarkers, regardless of age and SLE disease duration.
“Because duration of AM [antimalarial] treatment is the critical predictor of AMIC, the majority of patients with SLE should be considered at risk because most of them receive long-term maintenance therapy,” the researchers wrote.
They said that elevations of the biomarkers implicated possible active myocardial necrosis (elevated cTnI) and/or increased intracardiac ventricular pressure (elevated BNP).
“In this context, AM deposition in the myocardium, leading over time to overt cardiomyopathy, may be an important contributing factor. Indeed, 6 out of 16 of these patients were ultimately diagnosed with definite or possible AMIC, while 3 of them were completely asymptomatic, and their investigation was initiated because of the abnormal biomarkers,” they wrote.
The researchers also found that persistent creatine phosphokinase (CPK) elevation was also an important predictor for elevated cardiac biomarkers.
“We showed that chronic AM use is associated with a more than threefold increased risk for elevated CPK (after excluding patients with active myositis and statin therapy). ... It is not known whether elevated CPK may predict patients at risk for development of AMIC or whether certain patients are predisposed to AM-related muscle damage,” they said.
“Prolonged AM therapy and persistent CPK elevation conferred an increased risk for abnormal BNP and cTnI, which might predict AMIC,” they concluded.
Nevertheless, the authors acknowledged that expensive and invasive investigation was unjustified in asymptomatic individuals. They therefore suggested that identifying heart-specific biomarkers for the detection of subclinical heart damage could allow patients to be stratified according to their risk.
“Cardiac biomarkers could become a screening test for patients with SLE using AM for longer than 5.6 years and/or who have persistently elevated CPK levels. Further research is needed to delineate the differential toxicity of CQ [chloroquine] and HCQ [hydroxychloroquine],” they suggested.
The University of Toronto Lupus Research Program is supported by the University Health Network, Lou and Marissa Rocca, and the Lupus Foundation of Ontario. Dr. Tselios is financially supported by Lupus Ontario.
SOURCE: Tselios K et al. J Rheumatol. 2018. doi: 10.3899/jrheum.171436.
FROM JOURNAL OF RHEUMATOLOGY
Key clinical point: Patients with SLE who receive prolonged antimalarial treatment (greater than 5.6 years) are at increased risk for elevated cardiac biomarkers (BNP/cTnI), particularly when persistently elevated creatine phosphokinase is present. These biomarkers could be used to predict antimalarial-induced cardiomyopathy.
Major finding: Of a cohort of 151 patients with SLE, 10% had elevated myocardial biomarkers in the absence of prior cardiac disease or pulmonary arterial hypertension. One-third of the patients were diagnosed with antimalarial-induced cardiomyopathy.
Study details: The study enrolled 151 consecutive patients attending the University of Toronto Lupus Clinic from March to May 2016.
Disclosures: The University of Toronto Lupus Research Program is supported by the University Health Network, Lou and Marissa Rocca, and the Lupus Foundation of Ontario. Dr. Tselios is financially supported by Lupus Ontario.
Source: Tselios K et al. J Rheumatol. 2018. doi: 10.3899/jrheum.171436.