Nicola Garrett

The Bruton tyrosine kinase inhibitor ibrutinib has been linked to an almost 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 Paul R. Kunk, MD, of University of Virginia, Charlottesville, and his colleagues. Their report is 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 that 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. These criteria have generally excluded patients with significant comorbidities. However, these patients are seen in clinical practice,” the researchers wrote.

They conducted a review of patients attending their center and associated regional clinics between January 2012 and May 2016. They identified 70 patients, average age 72, who were taking ibrutinib for chronic lymphocytic leukemia (64%) and mantle cell lymphoma (27%), diffuse large B-cell lymphoma (4%), lymphoblastic lymphoma (3%), and Waldenström macroglobulinemia (1%).

The analysis showed that bleeding of any grade occurred in 56% of patients, mostly grade 1-2 bruising and epistaxis. However, major bleeding, defined as grade 3, occurred in 13 patients (19%), a figure that the authors noted was greater than the rate of around 7% reported by clinical trials.

Of these patients, seven were taking combined antiplatelet and anticoagulant therapy, four were taking antiplatelets alone, one was taking an anticoagulant agent alone, and one was taking only ibrutinib.

Univariate analysis showed that the factors associated with an increased risk of major bleeding included antiplatelet or anticoagulant medication, the combination of the two medications or interacting medications, anemia (hemoglobin less than 12 g/dL) and an elevated international normalized ratio (greater than 1.5).

However, in a multivariate analysis, only combined antiplatelet and anticoagulant use (hazard ratio, 20.0; 95% confidence interval, 2.1-200.0; P less than .01) and an elevated INR (HR, 4.6; 95% CI, 1.1-19.6; P less than .01) remained statistically significant.

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, they said their findings confirmed “the increasingly recognized risk of major bleeding complications with ibrutinib compared with what was originally reported in the clinical trial setting.

“As ibrutinib increases in use, it is paramount to increase awareness of the known adverse events. This is especially important given the association of ibrutinib use with atrial fibrillation,” they wrote.

They noted that their trial was limited by the relatively small population size. Their finding that platelet count was not associated with bleeding risk was also “counterintuitive,” they noted.

SOURCE: Kunk PR et al. Clin Lymphoma Myeloma Leuk. 2018 Jul 15. doi: 10.1016/j.clml.2018.07.287.

The Bruton tyrosine kinase inhibitor ibrutinib has been linked to an almost 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 Paul R. Kunk, MD, of University of Virginia, Charlottesville, and his colleagues. Their report is 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 that 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. These criteria have generally excluded patients with significant comorbidities. However, these patients are seen in clinical practice,” the researchers wrote.

They conducted a review of patients attending their center and associated regional clinics between January 2012 and May 2016. They identified 70 patients, average age 72, who were taking ibrutinib for chronic lymphocytic leukemia (64%) and mantle cell lymphoma (27%), diffuse large B-cell lymphoma (4%), lymphoblastic lymphoma (3%), and Waldenström macroglobulinemia (1%).

The analysis showed that bleeding of any grade occurred in 56% of patients, mostly grade 1-2 bruising and epistaxis. However, major bleeding, defined as grade 3, occurred in 13 patients (19%), a figure that the authors noted was greater than the rate of around 7% reported by clinical trials.

Of these patients, seven were taking combined antiplatelet and anticoagulant therapy, four were taking antiplatelets alone, one was taking an anticoagulant agent alone, and one was taking only ibrutinib.

Univariate analysis showed that the factors associated with an increased risk of major bleeding included antiplatelet or anticoagulant medication, the combination of the two medications or interacting medications, anemia (hemoglobin less than 12 g/dL) and an elevated international normalized ratio (greater than 1.5).

However, in a multivariate analysis, only combined antiplatelet and anticoagulant use (hazard ratio, 20.0; 95% confidence interval, 2.1-200.0; P less than .01) and an elevated INR (HR, 4.6; 95% CI, 1.1-19.6; P less than .01) remained statistically significant.

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, they said their findings confirmed “the increasingly recognized risk of major bleeding complications with ibrutinib compared with what was originally reported in the clinical trial setting.

“As ibrutinib increases in use, it is paramount to increase awareness of the known adverse events. This is especially important given the association of ibrutinib use with atrial fibrillation,” they wrote.

They noted that their trial was limited by the relatively small population size. Their finding that platelet count was not associated with bleeding risk was also “counterintuitive,” they noted.

SOURCE: Kunk PR et al. Clin Lymphoma Myeloma Leuk. 2018 Jul 15. doi: 10.1016/j.clml.2018.07.287.

The Bruton tyrosine kinase inhibitor ibrutinib has been linked to an almost 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 Paul R. Kunk, MD, of University of Virginia, Charlottesville, and his colleagues. Their report is 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 that 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. These criteria have generally excluded patients with significant comorbidities. However, these patients are seen in clinical practice,” the researchers wrote.

They conducted a review of patients attending their center and associated regional clinics between January 2012 and May 2016. They identified 70 patients, average age 72, who were taking ibrutinib for chronic lymphocytic leukemia (64%) and mantle cell lymphoma (27%), diffuse large B-cell lymphoma (4%), lymphoblastic lymphoma (3%), and Waldenström macroglobulinemia (1%).

The analysis showed that bleeding of any grade occurred in 56% of patients, mostly grade 1-2 bruising and epistaxis. However, major bleeding, defined as grade 3, occurred in 13 patients (19%), a figure that the authors noted was greater than the rate of around 7% reported by clinical trials.

Of these patients, seven were taking combined antiplatelet and anticoagulant therapy, four were taking antiplatelets alone, one was taking an anticoagulant agent alone, and one was taking only ibrutinib.

Univariate analysis showed that the factors associated with an increased risk of major bleeding included antiplatelet or anticoagulant medication, the combination of the two medications or interacting medications, anemia (hemoglobin less than 12 g/dL) and an elevated international normalized ratio (greater than 1.5).

However, in a multivariate analysis, only combined antiplatelet and anticoagulant use (hazard ratio, 20.0; 95% confidence interval, 2.1-200.0; P less than .01) and an elevated INR (HR, 4.6; 95% CI, 1.1-19.6; P less than .01) remained statistically significant.

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, they said their findings confirmed “the increasingly recognized risk of major bleeding complications with ibrutinib compared with what was originally reported in the clinical trial setting.

“As ibrutinib increases in use, it is paramount to increase awareness of the known adverse events. This is especially important given the association of ibrutinib use with atrial fibrillation,” they wrote.

They noted that their trial was limited by the relatively small population size. Their finding that platelet count was not associated with bleeding risk was also “counterintuitive,” they noted.

SOURCE: Kunk PR et al. Clin Lymphoma Myeloma Leuk. 2018 Jul 15. doi: 10.1016/j.clml.2018.07.287.

Combining the vascular endothelial growth factor (VEGF) receptor–targeting tyrosine kinase inhibitor apatinib with oral etoposide in people with platinum resistant or refractory ovarian cancer has shown promising efficacy and manageable toxicity in a Phase 2 study.

Angiogenesis was a “hallmark” process in cancer, and antiangiogenic therapy, including anti-VEGF antibodies and multireceptor tyrosine kinase inhibitors, has been shown to be an attractive therapeutic strategy for ovarian cancer.

“Increasing evidence suggests that the combination of antiangiogenic therapy and single-agent chemotherapy improves the outcome of platinum-resistant ovarian cancer,” Chun-Yan Lan, MD, of the Collaborative Innovation Center for Cancer Medicine at Sun Yat-sen University Cancer Center in Guangzhou, China, and colleagues wrote in Lancet Oncology.

The investigators chose apatinib because it has shown encouraging antitumor activities and tolerable toxicities in several malignant tumors and was available in mainland China, they said.

The single-arm prospective study enrolled 35 women aged 18-70 years with heavily pretreated ovarian cancer that was refractory to platinum (defined as progression during the initial platinum-based treatment) or resistant to platinum (defined as progression within 6 months after the last platinum treatment).

Women were treated with apatinib at an initial dose of 500 mg once daily on a continuous basis and with oral etoposide at a dose of 50 mg once daily on days 1-14 of a 21-day cycle. Oral etoposide was administered for a maximum of six cycles. Dose modifications, including dose interruptions, were allowed in order to manage adverse events.

Treatment was continued until disease progression, patient withdrawal, or unacceptable toxic effects. The primary endpoint of the study was the proportion of patients achieving an objective response according to Response Evaluation Criteria in Solid Tumors (RECIST). The study authors analyzed efficacy data using three populations: intention-to-treat, per-protocol, and safety populations.

Results showed that 19 of 35 patients achieved an objective response (54%; 95% confidence interval, 36.6%-71.2%) in an intention-to-treat analysis. In the per-protocol population, 19 of 31 patients (61%; 95% CI, 42.2%-78.2%) achieved an objective response.

Median progression-free survival was 8.1 months (interquartile range, 4.3-14.6; 95% CI, 2.8-13.4), and the median duration of response was 7.4 months (IQR, 4.0-13.0; 95% CI, 2.3-12.0).

The most common grade 3 or 4 adverse events reported were neutropenia (n = 17), fatigue (n = 11), anemia n = 10), and mucositis (n = 8). Serious adverse events were reported in two patients who were admitted to the hospital.

Dose reductions were required in 82% (n = 28) of 34 patients on apatinib and 77% (n = 26) for etoposide. The authors said they would suggest future studies use a lower starting dose of apatinib and give etoposide for 10 days rather than 14.

“Our study showed that the combination therapy of apatinib with oral etoposide shows promising efficacy and manageable toxicities in patients with platinum-resistant or platinum-refractory recurrent ovarian cancer and further study in phase 3 trials is warranted,” the study authors concluded.

They said that a strength of their study was that both apatinib and oral etoposide were able to be given orally without the need for hospital admission or an infusion pump, factors that could improve adherence and cost effectiveness for patients.

However, they noted that one limitation was that it was a single-arm study with no control group, which meant the selection bias could not be ruled out.

Source: Lan CY et al. Lancet Oncol. 2018 Aug 3. doi: 10.1016/ S1470-2045(18)30349-8.

Combining the vascular endothelial growth factor (VEGF) receptor–targeting tyrosine kinase inhibitor apatinib with oral etoposide in people with platinum resistant or refractory ovarian cancer has shown promising efficacy and manageable toxicity in a Phase 2 study.

Angiogenesis was a “hallmark” process in cancer, and antiangiogenic therapy, including anti-VEGF antibodies and multireceptor tyrosine kinase inhibitors, has been shown to be an attractive therapeutic strategy for ovarian cancer.

“Increasing evidence suggests that the combination of antiangiogenic therapy and single-agent chemotherapy improves the outcome of platinum-resistant ovarian cancer,” Chun-Yan Lan, MD, of the Collaborative Innovation Center for Cancer Medicine at Sun Yat-sen University Cancer Center in Guangzhou, China, and colleagues wrote in Lancet Oncology.

The investigators chose apatinib because it has shown encouraging antitumor activities and tolerable toxicities in several malignant tumors and was available in mainland China, they said.

The single-arm prospective study enrolled 35 women aged 18-70 years with heavily pretreated ovarian cancer that was refractory to platinum (defined as progression during the initial platinum-based treatment) or resistant to platinum (defined as progression within 6 months after the last platinum treatment).

Women were treated with apatinib at an initial dose of 500 mg once daily on a continuous basis and with oral etoposide at a dose of 50 mg once daily on days 1-14 of a 21-day cycle. Oral etoposide was administered for a maximum of six cycles. Dose modifications, including dose interruptions, were allowed in order to manage adverse events.

Treatment was continued until disease progression, patient withdrawal, or unacceptable toxic effects. The primary endpoint of the study was the proportion of patients achieving an objective response according to Response Evaluation Criteria in Solid Tumors (RECIST). The study authors analyzed efficacy data using three populations: intention-to-treat, per-protocol, and safety populations.

Results showed that 19 of 35 patients achieved an objective response (54%; 95% confidence interval, 36.6%-71.2%) in an intention-to-treat analysis. In the per-protocol population, 19 of 31 patients (61%; 95% CI, 42.2%-78.2%) achieved an objective response.

Median progression-free survival was 8.1 months (interquartile range, 4.3-14.6; 95% CI, 2.8-13.4), and the median duration of response was 7.4 months (IQR, 4.0-13.0; 95% CI, 2.3-12.0).

The most common grade 3 or 4 adverse events reported were neutropenia (n = 17), fatigue (n = 11), anemia n = 10), and mucositis (n = 8). Serious adverse events were reported in two patients who were admitted to the hospital.

Dose reductions were required in 82% (n = 28) of 34 patients on apatinib and 77% (n = 26) for etoposide. The authors said they would suggest future studies use a lower starting dose of apatinib and give etoposide for 10 days rather than 14.

“Our study showed that the combination therapy of apatinib with oral etoposide shows promising efficacy and manageable toxicities in patients with platinum-resistant or platinum-refractory recurrent ovarian cancer and further study in phase 3 trials is warranted,” the study authors concluded.

They said that a strength of their study was that both apatinib and oral etoposide were able to be given orally without the need for hospital admission or an infusion pump, factors that could improve adherence and cost effectiveness for patients.

However, they noted that one limitation was that it was a single-arm study with no control group, which meant the selection bias could not be ruled out.

Source: Lan CY et al. Lancet Oncol. 2018 Aug 3. doi: 10.1016/ S1470-2045(18)30349-8.

Combining the vascular endothelial growth factor (VEGF) receptor–targeting tyrosine kinase inhibitor apatinib with oral etoposide in people with platinum resistant or refractory ovarian cancer has shown promising efficacy and manageable toxicity in a Phase 2 study.

Angiogenesis was a “hallmark” process in cancer, and antiangiogenic therapy, including anti-VEGF antibodies and multireceptor tyrosine kinase inhibitors, has been shown to be an attractive therapeutic strategy for ovarian cancer.

“Increasing evidence suggests that the combination of antiangiogenic therapy and single-agent chemotherapy improves the outcome of platinum-resistant ovarian cancer,” Chun-Yan Lan, MD, of the Collaborative Innovation Center for Cancer Medicine at Sun Yat-sen University Cancer Center in Guangzhou, China, and colleagues wrote in Lancet Oncology.

The investigators chose apatinib because it has shown encouraging antitumor activities and tolerable toxicities in several malignant tumors and was available in mainland China, they said.

The single-arm prospective study enrolled 35 women aged 18-70 years with heavily pretreated ovarian cancer that was refractory to platinum (defined as progression during the initial platinum-based treatment) or resistant to platinum (defined as progression within 6 months after the last platinum treatment).

Women were treated with apatinib at an initial dose of 500 mg once daily on a continuous basis and with oral etoposide at a dose of 50 mg once daily on days 1-14 of a 21-day cycle. Oral etoposide was administered for a maximum of six cycles. Dose modifications, including dose interruptions, were allowed in order to manage adverse events.

Treatment was continued until disease progression, patient withdrawal, or unacceptable toxic effects. The primary endpoint of the study was the proportion of patients achieving an objective response according to Response Evaluation Criteria in Solid Tumors (RECIST). The study authors analyzed efficacy data using three populations: intention-to-treat, per-protocol, and safety populations.

Results showed that 19 of 35 patients achieved an objective response (54%; 95% confidence interval, 36.6%-71.2%) in an intention-to-treat analysis. In the per-protocol population, 19 of 31 patients (61%; 95% CI, 42.2%-78.2%) achieved an objective response.

Median progression-free survival was 8.1 months (interquartile range, 4.3-14.6; 95% CI, 2.8-13.4), and the median duration of response was 7.4 months (IQR, 4.0-13.0; 95% CI, 2.3-12.0).

The most common grade 3 or 4 adverse events reported were neutropenia (n = 17), fatigue (n = 11), anemia n = 10), and mucositis (n = 8). Serious adverse events were reported in two patients who were admitted to the hospital.

Dose reductions were required in 82% (n = 28) of 34 patients on apatinib and 77% (n = 26) for etoposide. The authors said they would suggest future studies use a lower starting dose of apatinib and give etoposide for 10 days rather than 14.

“Our study showed that the combination therapy of apatinib with oral etoposide shows promising efficacy and manageable toxicities in patients with platinum-resistant or platinum-refractory recurrent ovarian cancer and further study in phase 3 trials is warranted,” the study authors concluded.

They said that a strength of their study was that both apatinib and oral etoposide were able to be given orally without the need for hospital admission or an infusion pump, factors that could improve adherence and cost effectiveness for patients.

However, they noted that one limitation was that it was a single-arm study with no control group, which meant the selection bias could not be ruled out.

Source: Lan CY et al. Lancet Oncol. 2018 Aug 3. doi: 10.1016/ S1470-2045(18)30349-8.

Established criteria for identifying inflammatory back pain in people with ankylosing spondylitis do not perform well in identifying axial involvement in people with psoriatic arthritis and neither does clinical judgment, a study shows.

feellife/Thinkstock

Radiology data from these patients showed that 27 with baseline x-rays fulfilled the New York radiographic criteria for AS, and 45 had radiographic sacroiliitis not satisfying NY criteria (excluding grade 1) and/or syndesmophytes. Nine out of 31 patients with no axial disease on x-ray had evidence of axial disease on MRI. Eighteen out of 54 patients had axial involvement without back pain.

Results showed that agreement (kappa coefficient) between rheumatologist judgment of IBP and IBP criteria in patients with back pain was moderate and was highest for the Calin criteria (0.70; 95% confidence interval, 0.56-0.85), followed by the ASAS criteria (0.61; 95% CI, 0.46-0.76) and the Rudwaleit criteria (0.59; 95% CI, 0.44-0.74).

When x-ray or MRI change was considered “gold standard” for axial involvement for all patients, the specificity was high for rheumatologist judgment of IBP as well as Calin, Rudwaleit, and ASAS criteria, but their sensitivity was low, the researchers reported.

When the investigators compared positive likelihood ratios (LRs) for the presence of back pain, the Rudwaleit criteria (2.17) performed the best in ruling in axial disease, whereas the LRs were 1.75 for Calin and 1.86 for ASAS criteria. Rheumatologist-reported back pain (0.68) performed the best for ruling out axial disease when comparing negative LRs.

“The low positive LRs of the Calin, Rudwaleit, and ASAS criteria as well as that of rheumatologist report of back pain or judgment of IBP for [axial] PsA defined as any axial radiological change found in our study suggests that none of these criteria performed well in detecting axial disease in patients with PsA,” the study authors wrote.

The authors also conducted an exploratory analysis within patients with PsA with back involvement (defined by x-rays or MRI) and compared those with back pain (n = 36) or without (n = 18). The back pain group had a significantly higher Bath Ankylosing Spondylitis Disease Activity Index score (5.72 vs. 4.27), a finding that the authors said they expected because it is a patient-reported measure.

The back pain group also had a lower prevalence of human leukocyte antigen-B*38 (2.78 vs. 27.78), a finding that the authors said was interesting but would need to be replicated in future studies.

The prevalence of HLA-B*27, HLA-B*08, and HLA-C*06 was similar between patients with and without back pain, indicating “that the two groups are largely similar and hence, for the purpose of defining axial disease in PsA, symptoms (back pain) may not be important.”

“The findings of this study suggest that rheumatologist-judged IBP or the criteria for IBP developed for AS may not perform well when ascertaining axial involvement in PsA,” the study authors concluded.

“Moreover, patients with axial radiological changes without back pain were similar to those with back pain. ... In order to stratify patients with poorer prognosis, rheumatologists should consider conducting axial imaging in all patients with PsA regardless of the presence or the nature of back pain,” they added.

The study was funded by the University of Toronto Psoriatic Arthritis Program, which is supported by the Krembil Foundation.

SOURCE: Yap KS et al. Ann Rheum Dis. 2018 Aug 4. doi: 10.1136/annrheumdis-2018-213334.

Established criteria for identifying inflammatory back pain in people with ankylosing spondylitis do not perform well in identifying axial involvement in people with psoriatic arthritis and neither does clinical judgment, a study shows.

feellife/Thinkstock

Radiology data from these patients showed that 27 with baseline x-rays fulfilled the New York radiographic criteria for AS, and 45 had radiographic sacroiliitis not satisfying NY criteria (excluding grade 1) and/or syndesmophytes. Nine out of 31 patients with no axial disease on x-ray had evidence of axial disease on MRI. Eighteen out of 54 patients had axial involvement without back pain.

Results showed that agreement (kappa coefficient) between rheumatologist judgment of IBP and IBP criteria in patients with back pain was moderate and was highest for the Calin criteria (0.70; 95% confidence interval, 0.56-0.85), followed by the ASAS criteria (0.61; 95% CI, 0.46-0.76) and the Rudwaleit criteria (0.59; 95% CI, 0.44-0.74).

When x-ray or MRI change was considered “gold standard” for axial involvement for all patients, the specificity was high for rheumatologist judgment of IBP as well as Calin, Rudwaleit, and ASAS criteria, but their sensitivity was low, the researchers reported.

When the investigators compared positive likelihood ratios (LRs) for the presence of back pain, the Rudwaleit criteria (2.17) performed the best in ruling in axial disease, whereas the LRs were 1.75 for Calin and 1.86 for ASAS criteria. Rheumatologist-reported back pain (0.68) performed the best for ruling out axial disease when comparing negative LRs.

“The low positive LRs of the Calin, Rudwaleit, and ASAS criteria as well as that of rheumatologist report of back pain or judgment of IBP for [axial] PsA defined as any axial radiological change found in our study suggests that none of these criteria performed well in detecting axial disease in patients with PsA,” the study authors wrote.

The authors also conducted an exploratory analysis within patients with PsA with back involvement (defined by x-rays or MRI) and compared those with back pain (n = 36) or without (n = 18). The back pain group had a significantly higher Bath Ankylosing Spondylitis Disease Activity Index score (5.72 vs. 4.27), a finding that the authors said they expected because it is a patient-reported measure.

The back pain group also had a lower prevalence of human leukocyte antigen-B*38 (2.78 vs. 27.78), a finding that the authors said was interesting but would need to be replicated in future studies.

The prevalence of HLA-B*27, HLA-B*08, and HLA-C*06 was similar between patients with and without back pain, indicating “that the two groups are largely similar and hence, for the purpose of defining axial disease in PsA, symptoms (back pain) may not be important.”

“The findings of this study suggest that rheumatologist-judged IBP or the criteria for IBP developed for AS may not perform well when ascertaining axial involvement in PsA,” the study authors concluded.

“Moreover, patients with axial radiological changes without back pain were similar to those with back pain. ... In order to stratify patients with poorer prognosis, rheumatologists should consider conducting axial imaging in all patients with PsA regardless of the presence or the nature of back pain,” they added.

The study was funded by the University of Toronto Psoriatic Arthritis Program, which is supported by the Krembil Foundation.

SOURCE: Yap KS et al. Ann Rheum Dis. 2018 Aug 4. doi: 10.1136/annrheumdis-2018-213334.

Established criteria for identifying inflammatory back pain in people with ankylosing spondylitis do not perform well in identifying axial involvement in people with psoriatic arthritis and neither does clinical judgment, a study shows.

feellife/Thinkstock

Radiology data from these patients showed that 27 with baseline x-rays fulfilled the New York radiographic criteria for AS, and 45 had radiographic sacroiliitis not satisfying NY criteria (excluding grade 1) and/or syndesmophytes. Nine out of 31 patients with no axial disease on x-ray had evidence of axial disease on MRI. Eighteen out of 54 patients had axial involvement without back pain.

Results showed that agreement (kappa coefficient) between rheumatologist judgment of IBP and IBP criteria in patients with back pain was moderate and was highest for the Calin criteria (0.70; 95% confidence interval, 0.56-0.85), followed by the ASAS criteria (0.61; 95% CI, 0.46-0.76) and the Rudwaleit criteria (0.59; 95% CI, 0.44-0.74).

When x-ray or MRI change was considered “gold standard” for axial involvement for all patients, the specificity was high for rheumatologist judgment of IBP as well as Calin, Rudwaleit, and ASAS criteria, but their sensitivity was low, the researchers reported.

When the investigators compared positive likelihood ratios (LRs) for the presence of back pain, the Rudwaleit criteria (2.17) performed the best in ruling in axial disease, whereas the LRs were 1.75 for Calin and 1.86 for ASAS criteria. Rheumatologist-reported back pain (0.68) performed the best for ruling out axial disease when comparing negative LRs.

“The low positive LRs of the Calin, Rudwaleit, and ASAS criteria as well as that of rheumatologist report of back pain or judgment of IBP for [axial] PsA defined as any axial radiological change found in our study suggests that none of these criteria performed well in detecting axial disease in patients with PsA,” the study authors wrote.

The authors also conducted an exploratory analysis within patients with PsA with back involvement (defined by x-rays or MRI) and compared those with back pain (n = 36) or without (n = 18). The back pain group had a significantly higher Bath Ankylosing Spondylitis Disease Activity Index score (5.72 vs. 4.27), a finding that the authors said they expected because it is a patient-reported measure.

The back pain group also had a lower prevalence of human leukocyte antigen-B*38 (2.78 vs. 27.78), a finding that the authors said was interesting but would need to be replicated in future studies.

The prevalence of HLA-B*27, HLA-B*08, and HLA-C*06 was similar between patients with and without back pain, indicating “that the two groups are largely similar and hence, for the purpose of defining axial disease in PsA, symptoms (back pain) may not be important.”

“The findings of this study suggest that rheumatologist-judged IBP or the criteria for IBP developed for AS may not perform well when ascertaining axial involvement in PsA,” the study authors concluded.

“Moreover, patients with axial radiological changes without back pain were similar to those with back pain. ... In order to stratify patients with poorer prognosis, rheumatologists should consider conducting axial imaging in all patients with PsA regardless of the presence or the nature of back pain,” they added.

The study was funded by the University of Toronto Psoriatic Arthritis Program, which is supported by the Krembil Foundation.

SOURCE: Yap KS et al. Ann Rheum Dis. 2018 Aug 4. doi: 10.1136/annrheumdis-2018-213334.

There is broad acceptance for the use of guideline-endorsed neuroimaging studies as the standard of care in evaluating early-life epilepsy across U.S pediatric centers, an observational study shows.

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Furthermore, the study authors reported, the use of neuroimaging is supported by their data, which showed that a brain MRI obtained up to 1 year after an early-life epilepsy (ELE) diagnosis provides a high diagnostic yield, regardless of clinical factors – including seizure type or development.

“Neuroimaging, and MRI in particular, frequently identifies an etiology for ELE, enhancing the ability of neurologists to provide a precise diagnosis, offer anticipatory guidance, and consider the full array of available therapies,” wrote Jason Coryell, MD, a child neurologist, and his colleagues Aug. 8 in Pediatrics.

Early childhood epilepsy occurs in 1-2 out of every 1,000 children under age 3, Dr. Coryell and his colleagues said. Consensus guidelines recommend MRI for the evaluation of ELE, but no data evaluate whether it is being used in clinical practice, said Dr. Coryell of the Oregon Health & Science University, Portland, and his colleagues. The research team, therefore, set out to identify the yield and findings of neuroimaging in incident cases of epilepsy in 775 children with newly diagnosed ELE (diagnosed before age 3 years) seen at 17 U.S. pediatric epilepsy centers between 2012 and 2015.

They found that the use of neuroimaging was high, with 725 children (93.5%) having had a neuroimaging study. Of those, 714 had an MRI as recommended in current guidelines (87% with seizure protocols), and 11 had computed tomography or ultrasound only.

According to Dr. Coryell and his colleagues, the high use of MRI in the cohort likely could be attributed to three factors: neuroimaging is recommended in guidelines, the improved accessibility of imaging, and increased physician familiarity with the role of MRI in epilepsy.

Overall, 40% of the children (n = 290) had etiologically relevant abnormalities, a rate that the authors noted was higher than previous estimates. These included an acquired injury in 97 (13.4%), malformations of cortical development in 56 (7.7%), and other diffuse disorders of brain development in 51 (7.0%).

Neuroimaging was abnormal in 61% (160 of 262) of children with abnormal development at diagnosis, compared with 24% (113 of 463) with typical development.

Structural abnormalities also were high and most common in children with focal seizure semiology (40%), spasms (47%), or unclear semiology (42%).

In children without spasms or focal semiology with typical development, 16% (29 of 185 children) had imaging abnormalities. Pathogenic genetic variants were identified in 44% (53 of 121) of children with abnormal neuroimaging in whom genetic testing was performed.

The research team concluded that their data supported the universal adoption of imaging guidelines for ELE, because the yield was substantially high – even in the lowest-risk group.

“In our cohort 1 in 6 children presenting with typical development and without either focal seizures or spasms still had abnormal neuroimaging,” Dr. Coryell and his coauthors wrote. “This supports the continued adherence to guidelines.”

They advised that next steps include standardization of ELE MRI protocol. “Although there has been widespread adoption of epilepsy protocols, these have been geared toward identification of hippocampal abnormalities in older children and adults rather than toward the young, myelinating brain,” the researchers added.

The team noted several limitations. One limitation cited is the study’s identification of patients by using tertiary centers that might provide care for children who are more severely affected than those in the general population.

The Pediatric Epilepsy Research Foundation in Dallas funded the research. Dr. Coryell and his colleagues said they have no financial disclosures. Several of the researchers declared potential conflicts of interest relating to consulting fees.

SOURCE: Coryell J et al. Pediatrics. 2018 Aug 8. doi: 10.1542/peds.2018.0672.

There is broad acceptance for the use of guideline-endorsed neuroimaging studies as the standard of care in evaluating early-life epilepsy across U.S pediatric centers, an observational study shows.

Zerbor/Thinkstock

Furthermore, the study authors reported, the use of neuroimaging is supported by their data, which showed that a brain MRI obtained up to 1 year after an early-life epilepsy (ELE) diagnosis provides a high diagnostic yield, regardless of clinical factors – including seizure type or development.

“Neuroimaging, and MRI in particular, frequently identifies an etiology for ELE, enhancing the ability of neurologists to provide a precise diagnosis, offer anticipatory guidance, and consider the full array of available therapies,” wrote Jason Coryell, MD, a child neurologist, and his colleagues Aug. 8 in Pediatrics.

Early childhood epilepsy occurs in 1-2 out of every 1,000 children under age 3, Dr. Coryell and his colleagues said. Consensus guidelines recommend MRI for the evaluation of ELE, but no data evaluate whether it is being used in clinical practice, said Dr. Coryell of the Oregon Health & Science University, Portland, and his colleagues. The research team, therefore, set out to identify the yield and findings of neuroimaging in incident cases of epilepsy in 775 children with newly diagnosed ELE (diagnosed before age 3 years) seen at 17 U.S. pediatric epilepsy centers between 2012 and 2015.

They found that the use of neuroimaging was high, with 725 children (93.5%) having had a neuroimaging study. Of those, 714 had an MRI as recommended in current guidelines (87% with seizure protocols), and 11 had computed tomography or ultrasound only.

According to Dr. Coryell and his colleagues, the high use of MRI in the cohort likely could be attributed to three factors: neuroimaging is recommended in guidelines, the improved accessibility of imaging, and increased physician familiarity with the role of MRI in epilepsy.

Overall, 40% of the children (n = 290) had etiologically relevant abnormalities, a rate that the authors noted was higher than previous estimates. These included an acquired injury in 97 (13.4%), malformations of cortical development in 56 (7.7%), and other diffuse disorders of brain development in 51 (7.0%).

Neuroimaging was abnormal in 61% (160 of 262) of children with abnormal development at diagnosis, compared with 24% (113 of 463) with typical development.

Structural abnormalities also were high and most common in children with focal seizure semiology (40%), spasms (47%), or unclear semiology (42%).

In children without spasms or focal semiology with typical development, 16% (29 of 185 children) had imaging abnormalities. Pathogenic genetic variants were identified in 44% (53 of 121) of children with abnormal neuroimaging in whom genetic testing was performed.

The research team concluded that their data supported the universal adoption of imaging guidelines for ELE, because the yield was substantially high – even in the lowest-risk group.

“In our cohort 1 in 6 children presenting with typical development and without either focal seizures or spasms still had abnormal neuroimaging,” Dr. Coryell and his coauthors wrote. “This supports the continued adherence to guidelines.”

They advised that next steps include standardization of ELE MRI protocol. “Although there has been widespread adoption of epilepsy protocols, these have been geared toward identification of hippocampal abnormalities in older children and adults rather than toward the young, myelinating brain,” the researchers added.

The team noted several limitations. One limitation cited is the study’s identification of patients by using tertiary centers that might provide care for children who are more severely affected than those in the general population.

The Pediatric Epilepsy Research Foundation in Dallas funded the research. Dr. Coryell and his colleagues said they have no financial disclosures. Several of the researchers declared potential conflicts of interest relating to consulting fees.

SOURCE: Coryell J et al. Pediatrics. 2018 Aug 8. doi: 10.1542/peds.2018.0672.

There is broad acceptance for the use of guideline-endorsed neuroimaging studies as the standard of care in evaluating early-life epilepsy across U.S pediatric centers, an observational study shows.

Zerbor/Thinkstock

Furthermore, the study authors reported, the use of neuroimaging is supported by their data, which showed that a brain MRI obtained up to 1 year after an early-life epilepsy (ELE) diagnosis provides a high diagnostic yield, regardless of clinical factors – including seizure type or development.

“Neuroimaging, and MRI in particular, frequently identifies an etiology for ELE, enhancing the ability of neurologists to provide a precise diagnosis, offer anticipatory guidance, and consider the full array of available therapies,” wrote Jason Coryell, MD, a child neurologist, and his colleagues Aug. 8 in Pediatrics.

Early childhood epilepsy occurs in 1-2 out of every 1,000 children under age 3, Dr. Coryell and his colleagues said. Consensus guidelines recommend MRI for the evaluation of ELE, but no data evaluate whether it is being used in clinical practice, said Dr. Coryell of the Oregon Health & Science University, Portland, and his colleagues. The research team, therefore, set out to identify the yield and findings of neuroimaging in incident cases of epilepsy in 775 children with newly diagnosed ELE (diagnosed before age 3 years) seen at 17 U.S. pediatric epilepsy centers between 2012 and 2015.

They found that the use of neuroimaging was high, with 725 children (93.5%) having had a neuroimaging study. Of those, 714 had an MRI as recommended in current guidelines (87% with seizure protocols), and 11 had computed tomography or ultrasound only.

According to Dr. Coryell and his colleagues, the high use of MRI in the cohort likely could be attributed to three factors: neuroimaging is recommended in guidelines, the improved accessibility of imaging, and increased physician familiarity with the role of MRI in epilepsy.

Overall, 40% of the children (n = 290) had etiologically relevant abnormalities, a rate that the authors noted was higher than previous estimates. These included an acquired injury in 97 (13.4%), malformations of cortical development in 56 (7.7%), and other diffuse disorders of brain development in 51 (7.0%).

Neuroimaging was abnormal in 61% (160 of 262) of children with abnormal development at diagnosis, compared with 24% (113 of 463) with typical development.

Structural abnormalities also were high and most common in children with focal seizure semiology (40%), spasms (47%), or unclear semiology (42%).

In children without spasms or focal semiology with typical development, 16% (29 of 185 children) had imaging abnormalities. Pathogenic genetic variants were identified in 44% (53 of 121) of children with abnormal neuroimaging in whom genetic testing was performed.

The research team concluded that their data supported the universal adoption of imaging guidelines for ELE, because the yield was substantially high – even in the lowest-risk group.

“In our cohort 1 in 6 children presenting with typical development and without either focal seizures or spasms still had abnormal neuroimaging,” Dr. Coryell and his coauthors wrote. “This supports the continued adherence to guidelines.”

They advised that next steps include standardization of ELE MRI protocol. “Although there has been widespread adoption of epilepsy protocols, these have been geared toward identification of hippocampal abnormalities in older children and adults rather than toward the young, myelinating brain,” the researchers added.

The team noted several limitations. One limitation cited is the study’s identification of patients by using tertiary centers that might provide care for children who are more severely affected than those in the general population.

The Pediatric Epilepsy Research Foundation in Dallas funded the research. Dr. Coryell and his colleagues said they have no financial disclosures. Several of the researchers declared potential conflicts of interest relating to consulting fees.

SOURCE: Coryell J et al. Pediatrics. 2018 Aug 8. doi: 10.1542/peds.2018.0672.

Systemic lupus erythematosus (SLE) patients who achieve prolonged low disease activity have damage accrual over 10 years similar to patients in sustained clinical remission, Canadian researchers report.

The findings endorse the endpoint used to define low disease activity in the study – Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) of 2 or less – as a meaningful treat-to-target outcome in SLE and also help to fill in missing information about the long-term longitudinal status of patients with recent-onset disease who enter either low disease activity or clinical remission status, first author Konstantinos Tselios, MD, PhD, and coauthors at the Centre for Prognosis Studies in the Rheumatic Diseases at the University Health Network’s Toronto Lupus Clinic, wrote in Arthritis Care & Research.

The concept of low disease activity (LDA) has emerged because it is rare for SLE patients to achieve sustained complete remission, the authors said. Existing studies on the outcomes of LDA and clinical remission have demonstrated comparable outcomes between the two in terms of damage accrual after 2 years, but they enrolled patients with prevalent disease, many of whom were in late stages.

“Given that disease duration has a significant impact on disease activity, the prevalence and characteristics of complete remission and LDA might have been affected,” they wrote.

The investigators therefore conducted the current study to assess damage accrual, medications used, flare rate, and mortality in inception patients who sustained complete remission and LDA status for 10 years.

The study involved 267 patients attending the University of Toronto Lupus Clinic who had at least 10 years of follow-up and no time interval between clinic visits exceeding 18 months. All patients fulfilled the revised American College of Rheumatology criteria for SLE classification or had three criteria and a supportive biopsy. The patients all had either LDA or clinical remission (SLEDAI-2K = 0, excluding serology) within the first 5 years since enrollment and maintained that status for 10 consecutive years, regardless of therapy.

A total of 10.1% of patients (n = 27) achieved prolonged clinical remission. Clinical manifestations at baseline included mucocutaneous disease in 70.4%, arthritis in 59.3%, cytopenias in 55.6%, nephritis in 25.9%, and central nervous involvement in 25.9%. Nephritis was class II in three patients, class III in one, and class IV in three.

For the 18% of patients (n = 48) who achieved sustained LDA, clinical manifestations included mucocutaneous disease in 81.3%, cytopenias in 66.7%, arthritis in 60.4%, serositis in 29.2%, nephritis in 22.9%, and central nervous system disease in 8.3%. The nephritis was class II in two patients, class III in four, class IV in two, and class VI in one. Patients in both groups were similar at baseline, but mean prednisone dose was higher in the remission group and more patients in the LDA group were taking antimalarials.

Time to remission and time to LDA were 1.2 years in both groups. After 10 years of follow-up, the mean SLEDAI was 1.2 in the remission group and 1.6 in the LDA group (P = .31) and 3.7 among patients not achieving either goal (n = 192; P less than .001).

Moreover, serology (complement C3/C4 and anti-double stranded DNA positivity) and antiextractable nuclear antigen antibody profile were similar in both groups.

No differences in flare rate or mortality emerged. Disease flares were observed in 25.9% of the remission group and 31.2% of the LDA group (P = .63) and flare rates were 0.038/patient-year and 0.065/patient-year, respectively (P = .23). Mortality after 10 years was 11.1% in the remission group and 10.4% in the LDA group (P = .93).

“Maintenance of this state could be an acceptable target for the long-term management of SLE. The concept of LDA is relatively new in SLE. Since complete remission has not been strictly defined yet and is rare, a more realistic target, such as LDA, may be of value in daily clinical practice as well as in clinical trials,” the investigators wrote.

The authors noted that the study was limited by the relatively low number of patients.

The University of Toronto Lupus Research Program is supported by the University Health Network, Lou & Marissa Rocca, and the Lupus Foundation of Ontario. The authors declared no potential conflicts of interests.

SOURCE: Tselios K et al. Arthritis Care Res. 2018 Jul 28. doi: 10.1002/acr.23720

Systemic lupus erythematosus (SLE) patients who achieve prolonged low disease activity have damage accrual over 10 years similar to patients in sustained clinical remission, Canadian researchers report.

The findings endorse the endpoint used to define low disease activity in the study – Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) of 2 or less – as a meaningful treat-to-target outcome in SLE and also help to fill in missing information about the long-term longitudinal status of patients with recent-onset disease who enter either low disease activity or clinical remission status, first author Konstantinos Tselios, MD, PhD, and coauthors at the Centre for Prognosis Studies in the Rheumatic Diseases at the University Health Network’s Toronto Lupus Clinic, wrote in Arthritis Care & Research.

The concept of low disease activity (LDA) has emerged because it is rare for SLE patients to achieve sustained complete remission, the authors said. Existing studies on the outcomes of LDA and clinical remission have demonstrated comparable outcomes between the two in terms of damage accrual after 2 years, but they enrolled patients with prevalent disease, many of whom were in late stages.

“Given that disease duration has a significant impact on disease activity, the prevalence and characteristics of complete remission and LDA might have been affected,” they wrote.

The investigators therefore conducted the current study to assess damage accrual, medications used, flare rate, and mortality in inception patients who sustained complete remission and LDA status for 10 years.

The study involved 267 patients attending the University of Toronto Lupus Clinic who had at least 10 years of follow-up and no time interval between clinic visits exceeding 18 months. All patients fulfilled the revised American College of Rheumatology criteria for SLE classification or had three criteria and a supportive biopsy. The patients all had either LDA or clinical remission (SLEDAI-2K = 0, excluding serology) within the first 5 years since enrollment and maintained that status for 10 consecutive years, regardless of therapy.

A total of 10.1% of patients (n = 27) achieved prolonged clinical remission. Clinical manifestations at baseline included mucocutaneous disease in 70.4%, arthritis in 59.3%, cytopenias in 55.6%, nephritis in 25.9%, and central nervous involvement in 25.9%. Nephritis was class II in three patients, class III in one, and class IV in three.

For the 18% of patients (n = 48) who achieved sustained LDA, clinical manifestations included mucocutaneous disease in 81.3%, cytopenias in 66.7%, arthritis in 60.4%, serositis in 29.2%, nephritis in 22.9%, and central nervous system disease in 8.3%. The nephritis was class II in two patients, class III in four, class IV in two, and class VI in one. Patients in both groups were similar at baseline, but mean prednisone dose was higher in the remission group and more patients in the LDA group were taking antimalarials.

Time to remission and time to LDA were 1.2 years in both groups. After 10 years of follow-up, the mean SLEDAI was 1.2 in the remission group and 1.6 in the LDA group (P = .31) and 3.7 among patients not achieving either goal (n = 192; P less than .001).

Moreover, serology (complement C3/C4 and anti-double stranded DNA positivity) and antiextractable nuclear antigen antibody profile were similar in both groups.

No differences in flare rate or mortality emerged. Disease flares were observed in 25.9% of the remission group and 31.2% of the LDA group (P = .63) and flare rates were 0.038/patient-year and 0.065/patient-year, respectively (P = .23). Mortality after 10 years was 11.1% in the remission group and 10.4% in the LDA group (P = .93).

“Maintenance of this state could be an acceptable target for the long-term management of SLE. The concept of LDA is relatively new in SLE. Since complete remission has not been strictly defined yet and is rare, a more realistic target, such as LDA, may be of value in daily clinical practice as well as in clinical trials,” the investigators wrote.

The authors noted that the study was limited by the relatively low number of patients.

The University of Toronto Lupus Research Program is supported by the University Health Network, Lou & Marissa Rocca, and the Lupus Foundation of Ontario. The authors declared no potential conflicts of interests.

SOURCE: Tselios K et al. Arthritis Care Res. 2018 Jul 28. doi: 10.1002/acr.23720

Systemic lupus erythematosus (SLE) patients who achieve prolonged low disease activity have damage accrual over 10 years similar to patients in sustained clinical remission, Canadian researchers report.

The findings endorse the endpoint used to define low disease activity in the study – Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) of 2 or less – as a meaningful treat-to-target outcome in SLE and also help to fill in missing information about the long-term longitudinal status of patients with recent-onset disease who enter either low disease activity or clinical remission status, first author Konstantinos Tselios, MD, PhD, and coauthors at the Centre for Prognosis Studies in the Rheumatic Diseases at the University Health Network’s Toronto Lupus Clinic, wrote in Arthritis Care & Research.

The concept of low disease activity (LDA) has emerged because it is rare for SLE patients to achieve sustained complete remission, the authors said. Existing studies on the outcomes of LDA and clinical remission have demonstrated comparable outcomes between the two in terms of damage accrual after 2 years, but they enrolled patients with prevalent disease, many of whom were in late stages.

“Given that disease duration has a significant impact on disease activity, the prevalence and characteristics of complete remission and LDA might have been affected,” they wrote.

The investigators therefore conducted the current study to assess damage accrual, medications used, flare rate, and mortality in inception patients who sustained complete remission and LDA status for 10 years.

The study involved 267 patients attending the University of Toronto Lupus Clinic who had at least 10 years of follow-up and no time interval between clinic visits exceeding 18 months. All patients fulfilled the revised American College of Rheumatology criteria for SLE classification or had three criteria and a supportive biopsy. The patients all had either LDA or clinical remission (SLEDAI-2K = 0, excluding serology) within the first 5 years since enrollment and maintained that status for 10 consecutive years, regardless of therapy.

A total of 10.1% of patients (n = 27) achieved prolonged clinical remission. Clinical manifestations at baseline included mucocutaneous disease in 70.4%, arthritis in 59.3%, cytopenias in 55.6%, nephritis in 25.9%, and central nervous involvement in 25.9%. Nephritis was class II in three patients, class III in one, and class IV in three.

For the 18% of patients (n = 48) who achieved sustained LDA, clinical manifestations included mucocutaneous disease in 81.3%, cytopenias in 66.7%, arthritis in 60.4%, serositis in 29.2%, nephritis in 22.9%, and central nervous system disease in 8.3%. The nephritis was class II in two patients, class III in four, class IV in two, and class VI in one. Patients in both groups were similar at baseline, but mean prednisone dose was higher in the remission group and more patients in the LDA group were taking antimalarials.

Time to remission and time to LDA were 1.2 years in both groups. After 10 years of follow-up, the mean SLEDAI was 1.2 in the remission group and 1.6 in the LDA group (P = .31) and 3.7 among patients not achieving either goal (n = 192; P less than .001).

Moreover, serology (complement C3/C4 and anti-double stranded DNA positivity) and antiextractable nuclear antigen antibody profile were similar in both groups.

No differences in flare rate or mortality emerged. Disease flares were observed in 25.9% of the remission group and 31.2% of the LDA group (P = .63) and flare rates were 0.038/patient-year and 0.065/patient-year, respectively (P = .23). Mortality after 10 years was 11.1% in the remission group and 10.4% in the LDA group (P = .93).

“Maintenance of this state could be an acceptable target for the long-term management of SLE. The concept of LDA is relatively new in SLE. Since complete remission has not been strictly defined yet and is rare, a more realistic target, such as LDA, may be of value in daily clinical practice as well as in clinical trials,” the investigators wrote.

The authors noted that the study was limited by the relatively low number of patients.

The University of Toronto Lupus Research Program is supported by the University Health Network, Lou & Marissa Rocca, and the Lupus Foundation of Ontario. The authors declared no potential conflicts of interests.

SOURCE: Tselios K et al. Arthritis Care Res. 2018 Jul 28. doi: 10.1002/acr.23720

An increase in functional connectivity in certain regions of the brains of people with depression could explain the link between the disease and poor sleep quality – and could have implications for the treatment of both conditions, the first research of its kind suggests.

Wei Cheng, PhD, of the Institute of Science and Technology for Brain-Inspired Intelligence at the Fudan University in Shanghai, China, and colleagues noted that many people with depression report poor sleep quality and sleep disturbance.

“Understanding the neural connectivity that underlies both conditions and mediates the association between them is likely to lead to better-directed treatments for depression and associated sleep problems,” they wrote in JAMA Psychiatry.

In the current study, the research team used data from 1,017 participants of the Human Connectome Project drawn from the general population in the United States (who were not selected for symptoms of depression). Subjects, whose ages ranged from 22 to 35 years, had completed the Adult Self-Report of Depressive Problems portion of the Achenbach Adult Self-Report for Ages 18-59 – a survey of self-reported sleep quality and resting-state functional MRI.

“Resting-state functional connectivity between brain areas, which reflects correlations of activity, is a fundamental tool in augmenting understanding of the brain regions with altered connectivity and function in mental disorders,” the study authors noted.

The researchers then cross-validated the sleep findings using a sample of 8,718 participants from with the United Kingdom Biobank data set.

In total, the research team identified 162 functional connectivity links involving areas associated with sleep, with 39 of these areas also associated with Depressive Problems Scores (P less than .001).

Overall, the brain areas with increased functional connectivity associated with the Pittsburgh Sleep Quality Index score and Depressive Problems scores included the lateral orbitofrontal cortex, dorsolateral prefrontal cortex, anterior and posterior cingulate cortices, insula, parahippocampal gyrus, hippocampus, amygdala, temporal cortex, and precuneus.

A mediation analysis conducted by the authors aimed at assessing the underlying mechanisms showed that “these functional connectivities underlie the association of depressive problems score with poor sleep quality (P less than .001).”

They observed “much smaller” associations in the reverse direction – in that the associations of sleep quality with depressive problems mediated by these links were less significant.

“These findings provide a neural basis for understanding how depression is associated with poor sleep quality, and this in turn has implications for treatment because of the brain areas identified,” the research team concluded.

Dr. Cheng and colleagues cited several limitations. One is that the Depressive Problems scores used were not reflective of a formal diagnosis. Nevertheless, they said, the current findings provided “strong support” for the role of the lateral orbitofrontal cortex in depression, particularly as the investigators observed relatively high correlations with functional connectivities in this area of the brains of 92 participants who had been diagnosed with a major depressive episode over their lifetime.

“The understanding that we developed in this study is consistent with areas of the brain involved in short-term memory (the dorsolateral prefrontal cortex), the self (precuneus), and negative emotion (the lateral orbitofrontal cortex) being highly connected in depression which results in increased ruminating thoughts that are at least part of the mechanism that impairs sleep quality,” they added.

The study was supported by several entities, including the Shanghai Science & Technology Innovation Plan and the National Natural Science Foundation of China. No conflicts of interest were reported.

SOURCE: Cheng W et al. JAMA Psychiatry. 2018 Jul 25. doi: 10.1001/jamapsychiatry.2018.1941.

An increase in functional connectivity in certain regions of the brains of people with depression could explain the link between the disease and poor sleep quality – and could have implications for the treatment of both conditions, the first research of its kind suggests.

Wei Cheng, PhD, of the Institute of Science and Technology for Brain-Inspired Intelligence at the Fudan University in Shanghai, China, and colleagues noted that many people with depression report poor sleep quality and sleep disturbance.

“Understanding the neural connectivity that underlies both conditions and mediates the association between them is likely to lead to better-directed treatments for depression and associated sleep problems,” they wrote in JAMA Psychiatry.

In the current study, the research team used data from 1,017 participants of the Human Connectome Project drawn from the general population in the United States (who were not selected for symptoms of depression). Subjects, whose ages ranged from 22 to 35 years, had completed the Adult Self-Report of Depressive Problems portion of the Achenbach Adult Self-Report for Ages 18-59 – a survey of self-reported sleep quality and resting-state functional MRI.

“Resting-state functional connectivity between brain areas, which reflects correlations of activity, is a fundamental tool in augmenting understanding of the brain regions with altered connectivity and function in mental disorders,” the study authors noted.

The researchers then cross-validated the sleep findings using a sample of 8,718 participants from with the United Kingdom Biobank data set.

In total, the research team identified 162 functional connectivity links involving areas associated with sleep, with 39 of these areas also associated with Depressive Problems Scores (P less than .001).

Overall, the brain areas with increased functional connectivity associated with the Pittsburgh Sleep Quality Index score and Depressive Problems scores included the lateral orbitofrontal cortex, dorsolateral prefrontal cortex, anterior and posterior cingulate cortices, insula, parahippocampal gyrus, hippocampus, amygdala, temporal cortex, and precuneus.

A mediation analysis conducted by the authors aimed at assessing the underlying mechanisms showed that “these functional connectivities underlie the association of depressive problems score with poor sleep quality (P less than .001).”

They observed “much smaller” associations in the reverse direction – in that the associations of sleep quality with depressive problems mediated by these links were less significant.

“These findings provide a neural basis for understanding how depression is associated with poor sleep quality, and this in turn has implications for treatment because of the brain areas identified,” the research team concluded.

Dr. Cheng and colleagues cited several limitations. One is that the Depressive Problems scores used were not reflective of a formal diagnosis. Nevertheless, they said, the current findings provided “strong support” for the role of the lateral orbitofrontal cortex in depression, particularly as the investigators observed relatively high correlations with functional connectivities in this area of the brains of 92 participants who had been diagnosed with a major depressive episode over their lifetime.

“The understanding that we developed in this study is consistent with areas of the brain involved in short-term memory (the dorsolateral prefrontal cortex), the self (precuneus), and negative emotion (the lateral orbitofrontal cortex) being highly connected in depression which results in increased ruminating thoughts that are at least part of the mechanism that impairs sleep quality,” they added.

The study was supported by several entities, including the Shanghai Science & Technology Innovation Plan and the National Natural Science Foundation of China. No conflicts of interest were reported.

SOURCE: Cheng W et al. JAMA Psychiatry. 2018 Jul 25. doi: 10.1001/jamapsychiatry.2018.1941.

An increase in functional connectivity in certain regions of the brains of people with depression could explain the link between the disease and poor sleep quality – and could have implications for the treatment of both conditions, the first research of its kind suggests.

Wei Cheng, PhD, of the Institute of Science and Technology for Brain-Inspired Intelligence at the Fudan University in Shanghai, China, and colleagues noted that many people with depression report poor sleep quality and sleep disturbance.

“Understanding the neural connectivity that underlies both conditions and mediates the association between them is likely to lead to better-directed treatments for depression and associated sleep problems,” they wrote in JAMA Psychiatry.

In the current study, the research team used data from 1,017 participants of the Human Connectome Project drawn from the general population in the United States (who were not selected for symptoms of depression). Subjects, whose ages ranged from 22 to 35 years, had completed the Adult Self-Report of Depressive Problems portion of the Achenbach Adult Self-Report for Ages 18-59 – a survey of self-reported sleep quality and resting-state functional MRI.

“Resting-state functional connectivity between brain areas, which reflects correlations of activity, is a fundamental tool in augmenting understanding of the brain regions with altered connectivity and function in mental disorders,” the study authors noted.

The researchers then cross-validated the sleep findings using a sample of 8,718 participants from with the United Kingdom Biobank data set.

In total, the research team identified 162 functional connectivity links involving areas associated with sleep, with 39 of these areas also associated with Depressive Problems Scores (P less than .001).

Overall, the brain areas with increased functional connectivity associated with the Pittsburgh Sleep Quality Index score and Depressive Problems scores included the lateral orbitofrontal cortex, dorsolateral prefrontal cortex, anterior and posterior cingulate cortices, insula, parahippocampal gyrus, hippocampus, amygdala, temporal cortex, and precuneus.

A mediation analysis conducted by the authors aimed at assessing the underlying mechanisms showed that “these functional connectivities underlie the association of depressive problems score with poor sleep quality (P less than .001).”

They observed “much smaller” associations in the reverse direction – in that the associations of sleep quality with depressive problems mediated by these links were less significant.

“These findings provide a neural basis for understanding how depression is associated with poor sleep quality, and this in turn has implications for treatment because of the brain areas identified,” the research team concluded.

Dr. Cheng and colleagues cited several limitations. One is that the Depressive Problems scores used were not reflective of a formal diagnosis. Nevertheless, they said, the current findings provided “strong support” for the role of the lateral orbitofrontal cortex in depression, particularly as the investigators observed relatively high correlations with functional connectivities in this area of the brains of 92 participants who had been diagnosed with a major depressive episode over their lifetime.

“The understanding that we developed in this study is consistent with areas of the brain involved in short-term memory (the dorsolateral prefrontal cortex), the self (precuneus), and negative emotion (the lateral orbitofrontal cortex) being highly connected in depression which results in increased ruminating thoughts that are at least part of the mechanism that impairs sleep quality,” they added.

The study was supported by several entities, including the Shanghai Science & Technology Innovation Plan and the National Natural Science Foundation of China. No conflicts of interest were reported.

SOURCE: Cheng W et al. JAMA Psychiatry. 2018 Jul 25. doi: 10.1001/jamapsychiatry.2018.1941.

The liver enzyme autotaxin may be a useful noninvasive marker of disease progression in people with primary biliary cholangitis (PBC), new research has suggested.

Satoru Joshita, MD, from the gastroenterology and hepatology department at Shinshu University in Matsumoto, Japan, and colleagues noted that the liver-specific autoimmune disease PBC is characterized by the destruction of bile ducts, leading to cirrhosis and liver failure, and is more often seen in women.

Symptoms at diagnosis, a lack of response to gold standard treatment with ursodeoxycholic acid, and more advanced histologic phase are linked to worse patient outcomes, the research team explained in Scientific Reports.

While liver biopsy could give vital information on the severity of disease, it is an invasive procedure that is limited by sampling error and interobserver disparity. “As advanced histological stage is associated with a worse prognosis in PBC patients, it is important for clinicians to know clinical stage noninvasively when deciding appropriate therapies,” they wrote.

Noninvasive measures of liver fibrosis and PBC progression are available, such as Wisteria floribunda agglutinin–positive Mac-2 binding protein, hyaluronic acid, and type IV collagen 7S, but the authors said their “diagnostic abilities remain under scrutiny” because of their “moderate” accuracy.

Previous research had described autotaxin (ATX), a secreted enzyme metabolized by liver sinusoidal endothelial cells, as a prognostic factor for overall survival in cirrhosis patients, which suggested “an important role of ATX in the progression of liver disease,” the researchers noted.

They therefore set out to assess its utility as a marker of primary biliary cholangitis disease progression by measuring the serum ATX values of 128 treatment-naive, histologically assessed PBC patients, 108 of whom were female and 20 were male. Their ATX levels were then compared with 80 healthy controls.

Results showed that the ATX levels of patients with PBC were significantly higher than those of controls (median, 0.97 mg/L vs. 0.76 mg/L, respectively; P less than .0001).

Autotaxin results were validated by biopsy-proven histologic assessment: Patients with PBC that was classified as Nakanuma’s stage I, II, III, and IV had median ATX concentrations of 0.70, 0.80, 0.87, 1.03, and 1.70 mg/L, respectively, which demonstrated significant increases in concentration of ATX with disease stage (r = 0.53; P less than .0001). The researchers confirmed this finding using Scheuer’s classification of the disease (r = 0.43; P less than .0001).

The researchers noted that their findings were also “well correlated with other established noninvasive fibrosis markers, indicating ATX to be a reliable clinical surrogate marker to predict disease progression in patients with PBC.”

For example, autotaxin levels correlated with W. floribunda agglutinin–positive Mac-2 binding protein (r = 0.51; P less than .0001) and the fibrosis index based on four factors index (r = 0.51; P less than .0001).

Interestingly, the researchers found a sex difference in ATX levels: Not only were ATX values in female patients significantly higher than those in female controls (median, 1.00 mg/L vs. 0.82 mg/L, respectively; P less than .001) but they also were higher than those of male patients (median, 0.78 mg/L; P = .005).

According to the authors, these findings highlighted a need for sex-specific benchmarks, as well as more research to clarify why the sex disparity existed.

A further longitudinal study conducted by the authors involving 29 patients seen at their clinic showed that ATX levels increased slowly but significantly over an 18-year period, with a median increase rate of 0.03 mg/L per year (P less than .00001).

Patients who died from their disease had a significantly higher autotaxin increase rate than did survivors (0.05 mg/L per year vs. 0.02 mg/L per year, respectively; P less than .01).

Based on their findings, the researchers concluded that serum ATX levels “represent an accurate, noninvasive biomarker for estimating disease progression in patients with PBC.”

However, they said a longer longitudinal study of patients with PBC looking at ATX levels and clinical features, as well as long-term prognosis and complicating hepatocellular carcinoma, was warranted.

Two coauthors are employees of TOSOH corporation and Inova Diagnostics. The remaining authors had no conflicts to declare related to this study.

SOURCE: Joshita S et al. Scientific Reports. 2018 May 25. doi: 10.1038/s41598-018-26531-0.

The liver enzyme autotaxin may be a useful noninvasive marker of disease progression in people with primary biliary cholangitis (PBC), new research has suggested.

Satoru Joshita, MD, from the gastroenterology and hepatology department at Shinshu University in Matsumoto, Japan, and colleagues noted that the liver-specific autoimmune disease PBC is characterized by the destruction of bile ducts, leading to cirrhosis and liver failure, and is more often seen in women.

Symptoms at diagnosis, a lack of response to gold standard treatment with ursodeoxycholic acid, and more advanced histologic phase are linked to worse patient outcomes, the research team explained in Scientific Reports.

While liver biopsy could give vital information on the severity of disease, it is an invasive procedure that is limited by sampling error and interobserver disparity. “As advanced histological stage is associated with a worse prognosis in PBC patients, it is important for clinicians to know clinical stage noninvasively when deciding appropriate therapies,” they wrote.

Noninvasive measures of liver fibrosis and PBC progression are available, such as Wisteria floribunda agglutinin–positive Mac-2 binding protein, hyaluronic acid, and type IV collagen 7S, but the authors said their “diagnostic abilities remain under scrutiny” because of their “moderate” accuracy.

Previous research had described autotaxin (ATX), a secreted enzyme metabolized by liver sinusoidal endothelial cells, as a prognostic factor for overall survival in cirrhosis patients, which suggested “an important role of ATX in the progression of liver disease,” the researchers noted.

They therefore set out to assess its utility as a marker of primary biliary cholangitis disease progression by measuring the serum ATX values of 128 treatment-naive, histologically assessed PBC patients, 108 of whom were female and 20 were male. Their ATX levels were then compared with 80 healthy controls.

Results showed that the ATX levels of patients with PBC were significantly higher than those of controls (median, 0.97 mg/L vs. 0.76 mg/L, respectively; P less than .0001).

Autotaxin results were validated by biopsy-proven histologic assessment: Patients with PBC that was classified as Nakanuma’s stage I, II, III, and IV had median ATX concentrations of 0.70, 0.80, 0.87, 1.03, and 1.70 mg/L, respectively, which demonstrated significant increases in concentration of ATX with disease stage (r = 0.53; P less than .0001). The researchers confirmed this finding using Scheuer’s classification of the disease (r = 0.43; P less than .0001).

The researchers noted that their findings were also “well correlated with other established noninvasive fibrosis markers, indicating ATX to be a reliable clinical surrogate marker to predict disease progression in patients with PBC.”

For example, autotaxin levels correlated with W. floribunda agglutinin–positive Mac-2 binding protein (r = 0.51; P less than .0001) and the fibrosis index based on four factors index (r = 0.51; P less than .0001).

Interestingly, the researchers found a sex difference in ATX levels: Not only were ATX values in female patients significantly higher than those in female controls (median, 1.00 mg/L vs. 0.82 mg/L, respectively; P less than .001) but they also were higher than those of male patients (median, 0.78 mg/L; P = .005).

According to the authors, these findings highlighted a need for sex-specific benchmarks, as well as more research to clarify why the sex disparity existed.

A further longitudinal study conducted by the authors involving 29 patients seen at their clinic showed that ATX levels increased slowly but significantly over an 18-year period, with a median increase rate of 0.03 mg/L per year (P less than .00001).

Patients who died from their disease had a significantly higher autotaxin increase rate than did survivors (0.05 mg/L per year vs. 0.02 mg/L per year, respectively; P less than .01).

Based on their findings, the researchers concluded that serum ATX levels “represent an accurate, noninvasive biomarker for estimating disease progression in patients with PBC.”

However, they said a longer longitudinal study of patients with PBC looking at ATX levels and clinical features, as well as long-term prognosis and complicating hepatocellular carcinoma, was warranted.

Two coauthors are employees of TOSOH corporation and Inova Diagnostics. The remaining authors had no conflicts to declare related to this study.

SOURCE: Joshita S et al. Scientific Reports. 2018 May 25. doi: 10.1038/s41598-018-26531-0.

The liver enzyme autotaxin may be a useful noninvasive marker of disease progression in people with primary biliary cholangitis (PBC), new research has suggested.

Satoru Joshita, MD, from the gastroenterology and hepatology department at Shinshu University in Matsumoto, Japan, and colleagues noted that the liver-specific autoimmune disease PBC is characterized by the destruction of bile ducts, leading to cirrhosis and liver failure, and is more often seen in women.

Symptoms at diagnosis, a lack of response to gold standard treatment with ursodeoxycholic acid, and more advanced histologic phase are linked to worse patient outcomes, the research team explained in Scientific Reports.

While liver biopsy could give vital information on the severity of disease, it is an invasive procedure that is limited by sampling error and interobserver disparity. “As advanced histological stage is associated with a worse prognosis in PBC patients, it is important for clinicians to know clinical stage noninvasively when deciding appropriate therapies,” they wrote.

Noninvasive measures of liver fibrosis and PBC progression are available, such as Wisteria floribunda agglutinin–positive Mac-2 binding protein, hyaluronic acid, and type IV collagen 7S, but the authors said their “diagnostic abilities remain under scrutiny” because of their “moderate” accuracy.

Previous research had described autotaxin (ATX), a secreted enzyme metabolized by liver sinusoidal endothelial cells, as a prognostic factor for overall survival in cirrhosis patients, which suggested “an important role of ATX in the progression of liver disease,” the researchers noted.

They therefore set out to assess its utility as a marker of primary biliary cholangitis disease progression by measuring the serum ATX values of 128 treatment-naive, histologically assessed PBC patients, 108 of whom were female and 20 were male. Their ATX levels were then compared with 80 healthy controls.

Results showed that the ATX levels of patients with PBC were significantly higher than those of controls (median, 0.97 mg/L vs. 0.76 mg/L, respectively; P less than .0001).

Autotaxin results were validated by biopsy-proven histologic assessment: Patients with PBC that was classified as Nakanuma’s stage I, II, III, and IV had median ATX concentrations of 0.70, 0.80, 0.87, 1.03, and 1.70 mg/L, respectively, which demonstrated significant increases in concentration of ATX with disease stage (r = 0.53; P less than .0001). The researchers confirmed this finding using Scheuer’s classification of the disease (r = 0.43; P less than .0001).

The researchers noted that their findings were also “well correlated with other established noninvasive fibrosis markers, indicating ATX to be a reliable clinical surrogate marker to predict disease progression in patients with PBC.”

For example, autotaxin levels correlated with W. floribunda agglutinin–positive Mac-2 binding protein (r = 0.51; P less than .0001) and the fibrosis index based on four factors index (r = 0.51; P less than .0001).

Interestingly, the researchers found a sex difference in ATX levels: Not only were ATX values in female patients significantly higher than those in female controls (median, 1.00 mg/L vs. 0.82 mg/L, respectively; P less than .001) but they also were higher than those of male patients (median, 0.78 mg/L; P = .005).

According to the authors, these findings highlighted a need for sex-specific benchmarks, as well as more research to clarify why the sex disparity existed.

A further longitudinal study conducted by the authors involving 29 patients seen at their clinic showed that ATX levels increased slowly but significantly over an 18-year period, with a median increase rate of 0.03 mg/L per year (P less than .00001).

Patients who died from their disease had a significantly higher autotaxin increase rate than did survivors (0.05 mg/L per year vs. 0.02 mg/L per year, respectively; P less than .01).

Based on their findings, the researchers concluded that serum ATX levels “represent an accurate, noninvasive biomarker for estimating disease progression in patients with PBC.”

However, they said a longer longitudinal study of patients with PBC looking at ATX levels and clinical features, as well as long-term prognosis and complicating hepatocellular carcinoma, was warranted.

Two coauthors are employees of TOSOH corporation and Inova Diagnostics. The remaining authors had no conflicts to declare related to this study.

SOURCE: Joshita S et al. Scientific Reports. 2018 May 25. doi: 10.1038/s41598-018-26531-0.

Antidepressant, urologic, and antiparkinson drugs with definite anticholinergic activity were associated with an increased risk of dementia as long as 20 years after exposure in a large observational study published in The BMJ.

Kathryn Richardson, PhD, of the University of East Anglia, Norwich, England, and her colleagues said that while the associations were “moderate” given the high incidence of dementia observed in the study, they nevertheless reflected an “appreciable risk” for patients.

MarkRyanDesigns/getty images

Overall, 14,453 cases (35%) and 86,403 controls (30%) were prescribed at least one anticholinergic drug with an ACB score of 3 (definite anticholinergic activity) during the exposure period. People prescribed greater dosage quantities over time of probable (ACB category 2) and definite (ACB category 3) anticholinergics had a higher risk of dementia, the researchers reported.

For example, anticholinergic use consistent with the highest dose category (more than 1,460 defined daily doses) was associated with an adjusted odds ratio for dementia of 1.57 (95% confidence interval, 1.18-2.09) for probable and 1.31 (95% CI, 1.22-1.41) for definite anticholinergics.

However, no increased risk was found for anticholinergics used to treat gastrointestinal, cardiovascular, or respiratory conditions. The research team also found no evidence for a cumulative harm of drugs considered “possibly” anticholinergic.

“A typical patient aged 65-70 might normally expect a period incidence of dementia of around 10% over the next 15 years, so this odds ratio would be consistent with an absolute risk increase of 2% (1% to 3%) over that period, corresponding to a number needed to harm of 50 (33 to 100),” they wrote.

They suggested that their findings could be explained by the drugs being markers of prodromal symptoms or dementia risk factors. The class effect observed might also reflect differences in the way anticholinergics crossed the blood-brain barrier.

The Alzheimer’s Society supported the research. Several of the authors reported receiving personal fees from Astellas. One author declared personal fees from Thame Pharmaceuticals.

SOURCE: Richardson K et al. BMJ. 2018;360:k1315. doi: 10.1136/bmj.k1315.

Antidepressant, urologic, and antiparkinson drugs with definite anticholinergic activity were associated with an increased risk of dementia as long as 20 years after exposure in a large observational study published in The BMJ.

Kathryn Richardson, PhD, of the University of East Anglia, Norwich, England, and her colleagues said that while the associations were “moderate” given the high incidence of dementia observed in the study, they nevertheless reflected an “appreciable risk” for patients.

MarkRyanDesigns/getty images

Overall, 14,453 cases (35%) and 86,403 controls (30%) were prescribed at least one anticholinergic drug with an ACB score of 3 (definite anticholinergic activity) during the exposure period. People prescribed greater dosage quantities over time of probable (ACB category 2) and definite (ACB category 3) anticholinergics had a higher risk of dementia, the researchers reported.

For example, anticholinergic use consistent with the highest dose category (more than 1,460 defined daily doses) was associated with an adjusted odds ratio for dementia of 1.57 (95% confidence interval, 1.18-2.09) for probable and 1.31 (95% CI, 1.22-1.41) for definite anticholinergics.

However, no increased risk was found for anticholinergics used to treat gastrointestinal, cardiovascular, or respiratory conditions. The research team also found no evidence for a cumulative harm of drugs considered “possibly” anticholinergic.

“A typical patient aged 65-70 might normally expect a period incidence of dementia of around 10% over the next 15 years, so this odds ratio would be consistent with an absolute risk increase of 2% (1% to 3%) over that period, corresponding to a number needed to harm of 50 (33 to 100),” they wrote.

They suggested that their findings could be explained by the drugs being markers of prodromal symptoms or dementia risk factors. The class effect observed might also reflect differences in the way anticholinergics crossed the blood-brain barrier.

The Alzheimer’s Society supported the research. Several of the authors reported receiving personal fees from Astellas. One author declared personal fees from Thame Pharmaceuticals.

SOURCE: Richardson K et al. BMJ. 2018;360:k1315. doi: 10.1136/bmj.k1315.

Antidepressant, urologic, and antiparkinson drugs with definite anticholinergic activity were associated with an increased risk of dementia as long as 20 years after exposure in a large observational study published in The BMJ.

Kathryn Richardson, PhD, of the University of East Anglia, Norwich, England, and her colleagues said that while the associations were “moderate” given the high incidence of dementia observed in the study, they nevertheless reflected an “appreciable risk” for patients.

MarkRyanDesigns/getty images

Overall, 14,453 cases (35%) and 86,403 controls (30%) were prescribed at least one anticholinergic drug with an ACB score of 3 (definite anticholinergic activity) during the exposure period. People prescribed greater dosage quantities over time of probable (ACB category 2) and definite (ACB category 3) anticholinergics had a higher risk of dementia, the researchers reported.

For example, anticholinergic use consistent with the highest dose category (more than 1,460 defined daily doses) was associated with an adjusted odds ratio for dementia of 1.57 (95% confidence interval, 1.18-2.09) for probable and 1.31 (95% CI, 1.22-1.41) for definite anticholinergics.

However, no increased risk was found for anticholinergics used to treat gastrointestinal, cardiovascular, or respiratory conditions. The research team also found no evidence for a cumulative harm of drugs considered “possibly” anticholinergic.

“A typical patient aged 65-70 might normally expect a period incidence of dementia of around 10% over the next 15 years, so this odds ratio would be consistent with an absolute risk increase of 2% (1% to 3%) over that period, corresponding to a number needed to harm of 50 (33 to 100),” they wrote.

They suggested that their findings could be explained by the drugs being markers of prodromal symptoms or dementia risk factors. The class effect observed might also reflect differences in the way anticholinergics crossed the blood-brain barrier.

The Alzheimer’s Society supported the research. Several of the authors reported receiving personal fees from Astellas. One author declared personal fees from Thame Pharmaceuticals.

SOURCE: Richardson K et al. BMJ. 2018;360:k1315. doi: 10.1136/bmj.k1315.

Some multiple sclerosis patients who are treated with natalizumab can have small progressive multifocal leukoencephalopathy (PML) lesions seen on MRI yet have undetectable JC virus DNA in their cerebrospinal fluid, a cross-sectional, retrospective study has revealed.

The findings show that for some people with MS, PML diagnosis could be delayed if cerebrospinal fluid (CSF) sampling is negative and patients are asymptomatic, potentially resulting in worse functional outcomes and survival rates, according to the authors, led by Martijn T. Wijburg, MD, of the MS Center at VU University Medical Center in Amsterdam.

solitude72/iStockphoto

Dr. Wijburg and his coinvestigators reviewed data from Dutch and Belgian patients considered to have natalizumab (Tysabri)-associated PML during January 2007 and December 2014.

Patients were required to meet one of the following criteria:

• Definite or probable PML, based a positive PCR and MRI findings suggestive of PML, with or without PML symptoms.

• In the absence of a positive PCR, the presence of all four of the following features: high risk of PML development, such as positive anti-JCV serostatus and natalizumab treatment duration greater than 12 months; no MS disease activity prior to PML suspicion; MRI lesions highly suggestive of PML, with lesion characteristics as previously reported and absence of lesion characteristics suggestive of other diseases, as judged by an experienced neuroradiologist; and a lesion evolution on follow-up MRI scans suggestive of PML, including development of immune reconstitution inflammatory syndrome.

In the study of 56 patients (37 women), 9 patients (16.1%) had undetectable JCV DNA in CSF and 14 (25%) were asymptomatic for PML. At the time of PML diagnosis, the median age was 45 years, and the median natalizumab treatment duration was 43 months. Results showed that patients with a positive PCR had larger total PML lesion volumes than did those with undetectable JCV DNA (median volume, 22.9 mL vs. 6.7 mL; P = .008). Logistic regression showed that a lower PML lesion volume significantly increased the probability for undetectable JCV DNA.

The research team also observed a positive correlation between PML lesion volume and JCV copy numbers (Spearman’s rho, 0.32; P = .03). PML lesion volume was also higher in patients with PML symptoms and in patients with more widespread lesion dissemination. But no association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms.

The findings appear to show that patients with a smaller PML lesion volume were more likely to have a negative test result for JCV, which may lead to a delayed diagnosis of PML. Patients with smaller lesion volume were also more likely to be asymptomatic, which may further delay a diagnosis.

“This can result in a therapeutic dilemma. Unjustly excluding PML may have serious consequences (e.g., when switching from [natalizumab] to even more potent immunosuppressive treatments, such as alemtuzumab),” they wrote.

“In patients with [natalizumab-associated PML], both the probability for a positive CSF JCV PCR result and the JCV viral load are associated with the total PML lesion volume ... as a consequence, patients with smaller PML lesion volumes are more likely to have undetectable JCV DNA, and PML can thus not reliably be excluded based on a negative PCR,” they concluded.

They warned that strict pharmacovigilance by MRI “will lead to identification of smaller [PML] lesions that associate with a higher likelihood of negative polymerase chain reaction results, which hampers a formal diagnosis of [PML] and may complicate patient treatment.”

Meticulous clinical and MRI follow-up in combination with repeated CSF JCV PCR testing was warranted in these patients, the researchers advised.

They suggested that complementary PML diagnostic approaches, such as assessing intrathecal antibody synthesis to JCV by determining the CSF JCV antibody index, may also be of additional value.

“Furthermore, undetectable JCV DNA does not completely preclude the presence of JCV DNA. Further development and improvement of ultrasensitive PCR assays may improve the diagnostic accuracy in the future,” they added.

The study was supported by the Dutch Foundation for MS Research. Individual authors reported support for the research from the Charcot Foundation, the Hertie Foundation, and the National Institutes of Health. Several of the authors reported receiving consultancy fees from pharmaceutical companies.

SOURCE: Wijburg M et al. JAMA Neurol. 2018 Mar 12. doi: 10.1001/jamaneurol.2018.0094

Some multiple sclerosis patients who are treated with natalizumab can have small progressive multifocal leukoencephalopathy (PML) lesions seen on MRI yet have undetectable JC virus DNA in their cerebrospinal fluid, a cross-sectional, retrospective study has revealed.

The findings show that for some people with MS, PML diagnosis could be delayed if cerebrospinal fluid (CSF) sampling is negative and patients are asymptomatic, potentially resulting in worse functional outcomes and survival rates, according to the authors, led by Martijn T. Wijburg, MD, of the MS Center at VU University Medical Center in Amsterdam.

solitude72/iStockphoto

Dr. Wijburg and his coinvestigators reviewed data from Dutch and Belgian patients considered to have natalizumab (Tysabri)-associated PML during January 2007 and December 2014.

Patients were required to meet one of the following criteria:

• Definite or probable PML, based a positive PCR and MRI findings suggestive of PML, with or without PML symptoms.

• In the absence of a positive PCR, the presence of all four of the following features: high risk of PML development, such as positive anti-JCV serostatus and natalizumab treatment duration greater than 12 months; no MS disease activity prior to PML suspicion; MRI lesions highly suggestive of PML, with lesion characteristics as previously reported and absence of lesion characteristics suggestive of other diseases, as judged by an experienced neuroradiologist; and a lesion evolution on follow-up MRI scans suggestive of PML, including development of immune reconstitution inflammatory syndrome.

In the study of 56 patients (37 women), 9 patients (16.1%) had undetectable JCV DNA in CSF and 14 (25%) were asymptomatic for PML. At the time of PML diagnosis, the median age was 45 years, and the median natalizumab treatment duration was 43 months. Results showed that patients with a positive PCR had larger total PML lesion volumes than did those with undetectable JCV DNA (median volume, 22.9 mL vs. 6.7 mL; P = .008). Logistic regression showed that a lower PML lesion volume significantly increased the probability for undetectable JCV DNA.

The research team also observed a positive correlation between PML lesion volume and JCV copy numbers (Spearman’s rho, 0.32; P = .03). PML lesion volume was also higher in patients with PML symptoms and in patients with more widespread lesion dissemination. But no association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms.

The findings appear to show that patients with a smaller PML lesion volume were more likely to have a negative test result for JCV, which may lead to a delayed diagnosis of PML. Patients with smaller lesion volume were also more likely to be asymptomatic, which may further delay a diagnosis.

“This can result in a therapeutic dilemma. Unjustly excluding PML may have serious consequences (e.g., when switching from [natalizumab] to even more potent immunosuppressive treatments, such as alemtuzumab),” they wrote.

“In patients with [natalizumab-associated PML], both the probability for a positive CSF JCV PCR result and the JCV viral load are associated with the total PML lesion volume ... as a consequence, patients with smaller PML lesion volumes are more likely to have undetectable JCV DNA, and PML can thus not reliably be excluded based on a negative PCR,” they concluded.

They warned that strict pharmacovigilance by MRI “will lead to identification of smaller [PML] lesions that associate with a higher likelihood of negative polymerase chain reaction results, which hampers a formal diagnosis of [PML] and may complicate patient treatment.”

Meticulous clinical and MRI follow-up in combination with repeated CSF JCV PCR testing was warranted in these patients, the researchers advised.

They suggested that complementary PML diagnostic approaches, such as assessing intrathecal antibody synthesis to JCV by determining the CSF JCV antibody index, may also be of additional value.

“Furthermore, undetectable JCV DNA does not completely preclude the presence of JCV DNA. Further development and improvement of ultrasensitive PCR assays may improve the diagnostic accuracy in the future,” they added.

The study was supported by the Dutch Foundation for MS Research. Individual authors reported support for the research from the Charcot Foundation, the Hertie Foundation, and the National Institutes of Health. Several of the authors reported receiving consultancy fees from pharmaceutical companies.

SOURCE: Wijburg M et al. JAMA Neurol. 2018 Mar 12. doi: 10.1001/jamaneurol.2018.0094

Some multiple sclerosis patients who are treated with natalizumab can have small progressive multifocal leukoencephalopathy (PML) lesions seen on MRI yet have undetectable JC virus DNA in their cerebrospinal fluid, a cross-sectional, retrospective study has revealed.

The findings show that for some people with MS, PML diagnosis could be delayed if cerebrospinal fluid (CSF) sampling is negative and patients are asymptomatic, potentially resulting in worse functional outcomes and survival rates, according to the authors, led by Martijn T. Wijburg, MD, of the MS Center at VU University Medical Center in Amsterdam.

solitude72/iStockphoto

Dr. Wijburg and his coinvestigators reviewed data from Dutch and Belgian patients considered to have natalizumab (Tysabri)-associated PML during January 2007 and December 2014.

Patients were required to meet one of the following criteria:

• Definite or probable PML, based a positive PCR and MRI findings suggestive of PML, with or without PML symptoms.

• In the absence of a positive PCR, the presence of all four of the following features: high risk of PML development, such as positive anti-JCV serostatus and natalizumab treatment duration greater than 12 months; no MS disease activity prior to PML suspicion; MRI lesions highly suggestive of PML, with lesion characteristics as previously reported and absence of lesion characteristics suggestive of other diseases, as judged by an experienced neuroradiologist; and a lesion evolution on follow-up MRI scans suggestive of PML, including development of immune reconstitution inflammatory syndrome.

In the study of 56 patients (37 women), 9 patients (16.1%) had undetectable JCV DNA in CSF and 14 (25%) were asymptomatic for PML. At the time of PML diagnosis, the median age was 45 years, and the median natalizumab treatment duration was 43 months. Results showed that patients with a positive PCR had larger total PML lesion volumes than did those with undetectable JCV DNA (median volume, 22.9 mL vs. 6.7 mL; P = .008). Logistic regression showed that a lower PML lesion volume significantly increased the probability for undetectable JCV DNA.

The research team also observed a positive correlation between PML lesion volume and JCV copy numbers (Spearman’s rho, 0.32; P = .03). PML lesion volume was also higher in patients with PML symptoms and in patients with more widespread lesion dissemination. But no association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms.

The findings appear to show that patients with a smaller PML lesion volume were more likely to have a negative test result for JCV, which may lead to a delayed diagnosis of PML. Patients with smaller lesion volume were also more likely to be asymptomatic, which may further delay a diagnosis.

“This can result in a therapeutic dilemma. Unjustly excluding PML may have serious consequences (e.g., when switching from [natalizumab] to even more potent immunosuppressive treatments, such as alemtuzumab),” they wrote.

“In patients with [natalizumab-associated PML], both the probability for a positive CSF JCV PCR result and the JCV viral load are associated with the total PML lesion volume ... as a consequence, patients with smaller PML lesion volumes are more likely to have undetectable JCV DNA, and PML can thus not reliably be excluded based on a negative PCR,” they concluded.

They warned that strict pharmacovigilance by MRI “will lead to identification of smaller [PML] lesions that associate with a higher likelihood of negative polymerase chain reaction results, which hampers a formal diagnosis of [PML] and may complicate patient treatment.”

Meticulous clinical and MRI follow-up in combination with repeated CSF JCV PCR testing was warranted in these patients, the researchers advised.

They suggested that complementary PML diagnostic approaches, such as assessing intrathecal antibody synthesis to JCV by determining the CSF JCV antibody index, may also be of additional value.

“Furthermore, undetectable JCV DNA does not completely preclude the presence of JCV DNA. Further development and improvement of ultrasensitive PCR assays may improve the diagnostic accuracy in the future,” they added.

The study was supported by the Dutch Foundation for MS Research. Individual authors reported support for the research from the Charcot Foundation, the Hertie Foundation, and the National Institutes of Health. Several of the authors reported receiving consultancy fees from pharmaceutical companies.

SOURCE: Wijburg M et al. JAMA Neurol. 2018 Mar 12. doi: 10.1001/jamaneurol.2018.0094

People with early, untreated Parkinson’s disease (PD) who have low B₁₂ levels appear to have greater worsening of mobility and cognitive decline over time, suggesting that it may be worthwhile to examine the correction of low levels as a means of slowing disease progression.

Investigators led by Chadwick W. Christine, MD, of the department of neurology at the University of California, San Francisco, sought to understand what contributes to considerable variation in the progression of PD by building on previous research that revealed low serum vitamin B₁₂ levels are common in patients with moderately advanced PD and are associated with neuropathy and cognitive impairment.

tupungato/Thinkstock

[email protected]

SOURCE: Christine C et al. Movement Dis. 2018 Mar 6. doi: 10.1002/mds.27301.

People with early, untreated Parkinson’s disease (PD) who have low B₁₂ levels appear to have greater worsening of mobility and cognitive decline over time, suggesting that it may be worthwhile to examine the correction of low levels as a means of slowing disease progression.

Investigators led by Chadwick W. Christine, MD, of the department of neurology at the University of California, San Francisco, sought to understand what contributes to considerable variation in the progression of PD by building on previous research that revealed low serum vitamin B₁₂ levels are common in patients with moderately advanced PD and are associated with neuropathy and cognitive impairment.

tupungato/Thinkstock

[email protected]

SOURCE: Christine C et al. Movement Dis. 2018 Mar 6. doi: 10.1002/mds.27301.

People with early, untreated Parkinson’s disease (PD) who have low B₁₂ levels appear to have greater worsening of mobility and cognitive decline over time, suggesting that it may be worthwhile to examine the correction of low levels as a means of slowing disease progression.

Investigators led by Chadwick W. Christine, MD, of the department of neurology at the University of California, San Francisco, sought to understand what contributes to considerable variation in the progression of PD by building on previous research that revealed low serum vitamin B₁₂ levels are common in patients with moderately advanced PD and are associated with neuropathy and cognitive impairment.

tupungato/Thinkstock

[email protected]

SOURCE: Christine C et al. Movement Dis. 2018 Mar 6. doi: 10.1002/mds.27301.