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Pap screen gaps abound in SLE population
SAN FRANCISCO – Ann Igoe, MD, said at an international congress on systemic lupus erythematosus.
Why is this of relevance to rheumatologists?
“The rheumatologist is probably the main physician that lupus patients see. They may see their rheumatologist every couple of months. The question is, how often do rheumatologists say, ‘Hey, you need your Pap smear!’ I don’t think many of them address it,” said Dr. Igoe, a rheumatology fellow at Case Western Reserve University in Cleveland.
She presented a retrospective, cross-sectional, single-center study utilizing the EHRs of 604 women with SLE and 3,337 female controls who had asthma but not SLE. Sixty percent of the SLE patients were overdue for a Pap smear, compared with 51% of controls.
“We also looked at race,” Dr. Igoe said in an interview. “We were able to show that, at our institution, racial disparities do exist, that the black lupus patients had a much higher rate of HPV [human papillomavirus] positivity, compared to the white lupus patients, and they also were more behind on their Pap screening.”
Indeed, 56% of the black lupus patients were overdue for a Pap test, compared with 43% of the white SLE patients, and 46% of black women without SLE. Among the subgroup composed of black HPV-positive SLE patients, the overdue status rate soared to 70%, versus 30% in white HPV-positive SLE patients.
Dr. Igoe noted that in October 2018, the Food and Drug Administration approved an expanded indication for the quadrivalent HPV vaccine known as Gardasil 9 for women through 45 years of age. The prior upper age limit was age 26. This is an especially important development for unvaccinated women with SLE. Women with SLE have been shown to have higher rates of cervical neoplasia than in the general population, and being on potent immunosuppressive agents such as mycophenolate mofetil, azathioprine, and methotrexate further boosts that risk.
“We and others have shown that women with lupus who receive the vaccine mount a good response. So regardless of whether you’ve had HPV in the past, that doesn’t preclude you from getting the vaccine,” she noted.
The Advisory Committee on Immunization Practices and Centers for Disease Control and Prevention have yet to adopt the expanded age limit recommendation. That needs to happen, Dr. Igoe stressed.
“I’d like to see this study as a little stepping stone towards having women get their Pap screen addressed and making the Gardasil vaccine available to women who are not vaccinated,” she said.
She reported having no financial conflicts regarding her study, conducted free of commercial support.
SAN FRANCISCO – Ann Igoe, MD, said at an international congress on systemic lupus erythematosus.
Why is this of relevance to rheumatologists?
“The rheumatologist is probably the main physician that lupus patients see. They may see their rheumatologist every couple of months. The question is, how often do rheumatologists say, ‘Hey, you need your Pap smear!’ I don’t think many of them address it,” said Dr. Igoe, a rheumatology fellow at Case Western Reserve University in Cleveland.
She presented a retrospective, cross-sectional, single-center study utilizing the EHRs of 604 women with SLE and 3,337 female controls who had asthma but not SLE. Sixty percent of the SLE patients were overdue for a Pap smear, compared with 51% of controls.
“We also looked at race,” Dr. Igoe said in an interview. “We were able to show that, at our institution, racial disparities do exist, that the black lupus patients had a much higher rate of HPV [human papillomavirus] positivity, compared to the white lupus patients, and they also were more behind on their Pap screening.”
Indeed, 56% of the black lupus patients were overdue for a Pap test, compared with 43% of the white SLE patients, and 46% of black women without SLE. Among the subgroup composed of black HPV-positive SLE patients, the overdue status rate soared to 70%, versus 30% in white HPV-positive SLE patients.
Dr. Igoe noted that in October 2018, the Food and Drug Administration approved an expanded indication for the quadrivalent HPV vaccine known as Gardasil 9 for women through 45 years of age. The prior upper age limit was age 26. This is an especially important development for unvaccinated women with SLE. Women with SLE have been shown to have higher rates of cervical neoplasia than in the general population, and being on potent immunosuppressive agents such as mycophenolate mofetil, azathioprine, and methotrexate further boosts that risk.
“We and others have shown that women with lupus who receive the vaccine mount a good response. So regardless of whether you’ve had HPV in the past, that doesn’t preclude you from getting the vaccine,” she noted.
The Advisory Committee on Immunization Practices and Centers for Disease Control and Prevention have yet to adopt the expanded age limit recommendation. That needs to happen, Dr. Igoe stressed.
“I’d like to see this study as a little stepping stone towards having women get their Pap screen addressed and making the Gardasil vaccine available to women who are not vaccinated,” she said.
She reported having no financial conflicts regarding her study, conducted free of commercial support.
SAN FRANCISCO – Ann Igoe, MD, said at an international congress on systemic lupus erythematosus.
Why is this of relevance to rheumatologists?
“The rheumatologist is probably the main physician that lupus patients see. They may see their rheumatologist every couple of months. The question is, how often do rheumatologists say, ‘Hey, you need your Pap smear!’ I don’t think many of them address it,” said Dr. Igoe, a rheumatology fellow at Case Western Reserve University in Cleveland.
She presented a retrospective, cross-sectional, single-center study utilizing the EHRs of 604 women with SLE and 3,337 female controls who had asthma but not SLE. Sixty percent of the SLE patients were overdue for a Pap smear, compared with 51% of controls.
“We also looked at race,” Dr. Igoe said in an interview. “We were able to show that, at our institution, racial disparities do exist, that the black lupus patients had a much higher rate of HPV [human papillomavirus] positivity, compared to the white lupus patients, and they also were more behind on their Pap screening.”
Indeed, 56% of the black lupus patients were overdue for a Pap test, compared with 43% of the white SLE patients, and 46% of black women without SLE. Among the subgroup composed of black HPV-positive SLE patients, the overdue status rate soared to 70%, versus 30% in white HPV-positive SLE patients.
Dr. Igoe noted that in October 2018, the Food and Drug Administration approved an expanded indication for the quadrivalent HPV vaccine known as Gardasil 9 for women through 45 years of age. The prior upper age limit was age 26. This is an especially important development for unvaccinated women with SLE. Women with SLE have been shown to have higher rates of cervical neoplasia than in the general population, and being on potent immunosuppressive agents such as mycophenolate mofetil, azathioprine, and methotrexate further boosts that risk.
“We and others have shown that women with lupus who receive the vaccine mount a good response. So regardless of whether you’ve had HPV in the past, that doesn’t preclude you from getting the vaccine,” she noted.
The Advisory Committee on Immunization Practices and Centers for Disease Control and Prevention have yet to adopt the expanded age limit recommendation. That needs to happen, Dr. Igoe stressed.
“I’d like to see this study as a little stepping stone towards having women get their Pap screen addressed and making the Gardasil vaccine available to women who are not vaccinated,” she said.
She reported having no financial conflicts regarding her study, conducted free of commercial support.
REPORTING FROM LUPUS 2019
Cumulative smoking affects skin manifestations of SLE
SAN FRANCISCO – Nnenna Ezeh reported at an international congress on systemic lupus erythematosus.
“We saw in our study a suggestion of a dose-response relationship. If we tell patients, ‘The more you smoke, the more likely you are to have chronic skin disease or skin damage that’s permanent,’ it could be a way to trigger more smoking cessation strategies in their mind,” said Ms. Ezeh, of the University of Wisconsin, Madison. “We know that skin manifestations of lupus have a major negative impact on a patient’s quality of life, so this could be a way to decrease smoking by saying, ‘Not only does smoking impact your heart and put you at risk for cardiovascular disease, it also affects your skin.’ It’s a way to bridge the priorities that physicians have with the priorities that patients have.”
She presented a retrospective study of the medical records of 632 consecutive SLE patients seen at the university medical center’s ambulatory rheumatology clinic. Slightly more than 60% of them were never smokers; 8.7% had a history of low smoking exposure, defined as less than 5 pack-years; 5.8% had a medium-smoking history of 5-10 pack-years; 15% had a high-smoking history, with more than 10 pack-years; and the smoking history of 10% of the patients was unrecorded.
In a multivariate analysis adjusted for age, sex, and race, the low-smoking group was ninefold more likely than never smokers to develop any mucocutaneous manifestations of SLE, including a malar or discoid rash, mucosal ulcers, photosensitivity, alopecia, or scarring. They were also 3.7 times more likely to meet any Systemic Lupus International Collaborating Clinics (SLICC) cutaneous criteria and twofold more likely than never smokers to meet any of the American College of Rheumatology cutaneous criteria. Patients with an intermediate smoking exposure history of 5-10 pack-years were 2.3-fold more likely to meet any SLICC cutaneous criteria.
The risks of meeting SLICC chronic cutaneous criteria and SLICC Damage Index skin damage criteria rose in a linear fashion with the number of pack-years of smoking. Those SLE patients with more than a 10 pack-year smoking history were 4.2-fold more likely than never smokers to fulfill any SLICC Damage Index skin damage criteria, which consist of scarring alopecia, extensive scarring, or skin ulcers. The heaviest smokers were also at 2.1-fold increased risk of discoid lupus and 2.2-fold more likely to meet SLICC chronic cutaneous criteria, according to Ms. Ezeh.
Patients of color, who comprised 18% of the study population, were significantly more likely to smoke than white patients. Independent of their smoking history, however, they had significantly increased risks of chronic cutaneous manifestations of lupus and of irreversible skin damage.
Ms. Ezeh reported having no financial conflicts regarding her study, supported by a grant from the Rheumatology Research Foundation.
SAN FRANCISCO – Nnenna Ezeh reported at an international congress on systemic lupus erythematosus.
“We saw in our study a suggestion of a dose-response relationship. If we tell patients, ‘The more you smoke, the more likely you are to have chronic skin disease or skin damage that’s permanent,’ it could be a way to trigger more smoking cessation strategies in their mind,” said Ms. Ezeh, of the University of Wisconsin, Madison. “We know that skin manifestations of lupus have a major negative impact on a patient’s quality of life, so this could be a way to decrease smoking by saying, ‘Not only does smoking impact your heart and put you at risk for cardiovascular disease, it also affects your skin.’ It’s a way to bridge the priorities that physicians have with the priorities that patients have.”
She presented a retrospective study of the medical records of 632 consecutive SLE patients seen at the university medical center’s ambulatory rheumatology clinic. Slightly more than 60% of them were never smokers; 8.7% had a history of low smoking exposure, defined as less than 5 pack-years; 5.8% had a medium-smoking history of 5-10 pack-years; 15% had a high-smoking history, with more than 10 pack-years; and the smoking history of 10% of the patients was unrecorded.
In a multivariate analysis adjusted for age, sex, and race, the low-smoking group was ninefold more likely than never smokers to develop any mucocutaneous manifestations of SLE, including a malar or discoid rash, mucosal ulcers, photosensitivity, alopecia, or scarring. They were also 3.7 times more likely to meet any Systemic Lupus International Collaborating Clinics (SLICC) cutaneous criteria and twofold more likely than never smokers to meet any of the American College of Rheumatology cutaneous criteria. Patients with an intermediate smoking exposure history of 5-10 pack-years were 2.3-fold more likely to meet any SLICC cutaneous criteria.
The risks of meeting SLICC chronic cutaneous criteria and SLICC Damage Index skin damage criteria rose in a linear fashion with the number of pack-years of smoking. Those SLE patients with more than a 10 pack-year smoking history were 4.2-fold more likely than never smokers to fulfill any SLICC Damage Index skin damage criteria, which consist of scarring alopecia, extensive scarring, or skin ulcers. The heaviest smokers were also at 2.1-fold increased risk of discoid lupus and 2.2-fold more likely to meet SLICC chronic cutaneous criteria, according to Ms. Ezeh.
Patients of color, who comprised 18% of the study population, were significantly more likely to smoke than white patients. Independent of their smoking history, however, they had significantly increased risks of chronic cutaneous manifestations of lupus and of irreversible skin damage.
Ms. Ezeh reported having no financial conflicts regarding her study, supported by a grant from the Rheumatology Research Foundation.
SAN FRANCISCO – Nnenna Ezeh reported at an international congress on systemic lupus erythematosus.
“We saw in our study a suggestion of a dose-response relationship. If we tell patients, ‘The more you smoke, the more likely you are to have chronic skin disease or skin damage that’s permanent,’ it could be a way to trigger more smoking cessation strategies in their mind,” said Ms. Ezeh, of the University of Wisconsin, Madison. “We know that skin manifestations of lupus have a major negative impact on a patient’s quality of life, so this could be a way to decrease smoking by saying, ‘Not only does smoking impact your heart and put you at risk for cardiovascular disease, it also affects your skin.’ It’s a way to bridge the priorities that physicians have with the priorities that patients have.”
She presented a retrospective study of the medical records of 632 consecutive SLE patients seen at the university medical center’s ambulatory rheumatology clinic. Slightly more than 60% of them were never smokers; 8.7% had a history of low smoking exposure, defined as less than 5 pack-years; 5.8% had a medium-smoking history of 5-10 pack-years; 15% had a high-smoking history, with more than 10 pack-years; and the smoking history of 10% of the patients was unrecorded.
In a multivariate analysis adjusted for age, sex, and race, the low-smoking group was ninefold more likely than never smokers to develop any mucocutaneous manifestations of SLE, including a malar or discoid rash, mucosal ulcers, photosensitivity, alopecia, or scarring. They were also 3.7 times more likely to meet any Systemic Lupus International Collaborating Clinics (SLICC) cutaneous criteria and twofold more likely than never smokers to meet any of the American College of Rheumatology cutaneous criteria. Patients with an intermediate smoking exposure history of 5-10 pack-years were 2.3-fold more likely to meet any SLICC cutaneous criteria.
The risks of meeting SLICC chronic cutaneous criteria and SLICC Damage Index skin damage criteria rose in a linear fashion with the number of pack-years of smoking. Those SLE patients with more than a 10 pack-year smoking history were 4.2-fold more likely than never smokers to fulfill any SLICC Damage Index skin damage criteria, which consist of scarring alopecia, extensive scarring, or skin ulcers. The heaviest smokers were also at 2.1-fold increased risk of discoid lupus and 2.2-fold more likely to meet SLICC chronic cutaneous criteria, according to Ms. Ezeh.
Patients of color, who comprised 18% of the study population, were significantly more likely to smoke than white patients. Independent of their smoking history, however, they had significantly increased risks of chronic cutaneous manifestations of lupus and of irreversible skin damage.
Ms. Ezeh reported having no financial conflicts regarding her study, supported by a grant from the Rheumatology Research Foundation.
REPORTING FROM LUPUS 2019
Rituximab serious infection risk predicted by immunoglobulin levels
Monitoring immunoglobulin (Ig) levels at baseline and before each cycle of rituximab could reduce the risk of serious infection events (SIEs) in patients needing repeated treatment, according to research published in Arthritis & Rheumatology.
In a large, single-center, longitudinal study conducted at a tertiary referral center, having low IgG (less than 6 g/L) in particular was associated with a higher rate of SIEs, compared with having normal IgG levels (6-16 g/L). Considering 103 of 700 patients who had low levels of IgG before starting treatment with rituximab for various rheumatic and musculoskeletal diseases (RMDs), there were 16.4 SIEs per 100 patient-years. In those who developed low IgG during subsequent cycles of rituximab therapy, the SIE rate was even higher, at 21.3 per 100 patient-years. By comparison, the SIE rate for those with normal IgG levels was 9.7 per 100 patient-years.
“We really have to monitor immunoglobulins at baseline and also before we re-treat the patients, because higher IgG level is protective of serious infections,” study first author Md Yuzaiful Md Yusof, MBChB, PhD, said in an interview.
Low IgG has been linked to a higher risk of SIEs in the first 12 months of rituximab therapy but, until now, there have been limited data on infection predictors during repeated cycles of treatment. While IgG is a consistent marker of SIEs associated with repeated rituximab treatment, IgM and IgA should also be monitored to give a full picture of any hyperglobulinemia that may be present.
“There is no formal guidance on how to safely monitor patients on rituximab,” observed Dr. Md Yusof, who will present these data at the 2019 European Congress of Rheumatology in Madrid. The study’s findings could help to change that, however, as they offer a practical way to help predict and thus prevent SIEs. The study’s findings not only validate previous work, he noted, but also add new insights into why some patients treated with repeat rituximab cycles but not others may experience a higher rate of such infections.
Altogether, the investigators examined data on 700 patients with RMDs treated with rituximab who were consecutively seen during 2012-2017 at Dr. Md Yusof’s institution – the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine, which is part of the University of Leeds. Their immunoglobulin levels had been measured before starting rituximab therapy and every 4-6 months after each cycle of rituximab treatment.
Patients with any RMD being treated with at least one cycle of rituximab were eligible for inclusion in the retrospective study, with the majority (72%) taking it for rheumatoid arthritis and some for systemic lupus erythematosus (13%) or antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (7%).
One of the main aims of the study was to look for predictors of SIEs during the first 12 months and during repeated cycles of rituximab. Dr. Md Yusof and his associates also looked at how secondary hypogammaglobulinemia might affect SIE rates and the humoral response to vaccination challenge and its persistence following treatment discontinuation. Their ultimate aim was to see if these findings could then be used to develop a treatment algorithm for rituximab administration in RMDs.
Over a follow-up period encompassing 2,880 patient-years of treatment, 281 SIEs were recorded in 176 patients, giving a rate of 9.8 infections per 100 patient-years. Most (61%) of these were due to lower respiratory tract infections.
The proportion of patients experiencing their first SIE increased with time: 16% within 6 weeks of starting rituximab therapy, 35% at 12 weeks, 72% at 26 weeks, 83% at 38 weeks, and 100% by 1 year of repeated treatment.
Multivariable analysis showed that the presence of several comorbidities at baseline – notably chronic obstructive pulmonary disease, diabetes, heart failure, and prior cancer – raised the risk for SIEs with repeated rituximab therapy. The biggest factor, however, was a history of SIEs – with a sixfold increased risk of further serious infection.
Higher corticosteroid dose and factors specific to rituximab – low IgG, neutropenia, high IgM, and a longer time to retreatment – were also predictive of SIEs.
“Low IgG also results in poor humoral response to vaccination,” Dr. Md Yusof said, noting that the IgG level remains below the lower limit of normal for several years after rituximab is discontinued in most patients.
In the study, 5 of 8 (64%) patients had impaired humoral response to pneumococcal and haemophilus following vaccination challenge and 4 of 11 patients had IgG normalized after switching to another biologic disease-modifying antirheumatic drug (bDMARD).
Cyclophosphamide is commonly used as a first-line agent to induce remission in patients with severe and refractory systemic lupus erythematosus and ANCA-associated vasculitis, with patients switched to rituximab at relapse. The effect of this prior treatment was examined in 20 patients in the study, with a marked decline in almost all immunoglobulin classes seen up to 18 months. Prior treatment with immunosuppressants such as intravenous cyclophosphamide could be behind progressive reductions in Ig levels seen with repeated rituximab treatment rather than entirely because of rituximab, Dr. Md Yusof said.
Dr. Md Yusof, who is a National Institute for Health Research (NIHR) Academic Clinical Lecturer at the University of Leeds, said the value of the study, compared with others, is that hospital data for all patients treated with rituximab with at least 3 months follow-up were included, making it an almost complete data set.
“By carefully reviewing records of every patient to capture all infection episodes in the largest single-center cohort study to date, our findings provide insights on predictors of SIEs as well as a foundation for safety monitoring of rituximab,” he and his coauthors wrote.
They acknowledge reporting a higher rate of SIEs than seen in registry and clinical studies with rituximab, which may reflect a “channeling bias” as the patients comprised those with multiple comorbidities including those that represent a relative contraindication for bDMARD use. That said, the findings clearly show that Ig levels should be monitored before and after each rituximab cycle, especially in those with comorbid diseases and those with low IgG levels to start with.
They conclude that an “individualized benefit-risk assessment” is needed to determine whether rituximab should be repeated in those with low IgG as this is a “consistent predictor” of SIE and may “increase infection profiles when [rituximab] is switched to different bDMARDs.”
The research was supported by Octapharma, the National Institute for Health Research (NIHR), and NIHR Leeds Biomedical Research Centre based at Leeds Teaching Hospitals NHS Trust in England. Dr. Md Yusof had no conflicts of interest. Several coauthors disclosed financial ties to multiple pharmaceutical companies, including Roche.
SOURCE: Md Yusof MY et al. Arthritis Rheumatol. 2019 May 27. doi: 10.1002/art.40937.
Monitoring immunoglobulin (Ig) levels at baseline and before each cycle of rituximab could reduce the risk of serious infection events (SIEs) in patients needing repeated treatment, according to research published in Arthritis & Rheumatology.
In a large, single-center, longitudinal study conducted at a tertiary referral center, having low IgG (less than 6 g/L) in particular was associated with a higher rate of SIEs, compared with having normal IgG levels (6-16 g/L). Considering 103 of 700 patients who had low levels of IgG before starting treatment with rituximab for various rheumatic and musculoskeletal diseases (RMDs), there were 16.4 SIEs per 100 patient-years. In those who developed low IgG during subsequent cycles of rituximab therapy, the SIE rate was even higher, at 21.3 per 100 patient-years. By comparison, the SIE rate for those with normal IgG levels was 9.7 per 100 patient-years.
“We really have to monitor immunoglobulins at baseline and also before we re-treat the patients, because higher IgG level is protective of serious infections,” study first author Md Yuzaiful Md Yusof, MBChB, PhD, said in an interview.
Low IgG has been linked to a higher risk of SIEs in the first 12 months of rituximab therapy but, until now, there have been limited data on infection predictors during repeated cycles of treatment. While IgG is a consistent marker of SIEs associated with repeated rituximab treatment, IgM and IgA should also be monitored to give a full picture of any hyperglobulinemia that may be present.
“There is no formal guidance on how to safely monitor patients on rituximab,” observed Dr. Md Yusof, who will present these data at the 2019 European Congress of Rheumatology in Madrid. The study’s findings could help to change that, however, as they offer a practical way to help predict and thus prevent SIEs. The study’s findings not only validate previous work, he noted, but also add new insights into why some patients treated with repeat rituximab cycles but not others may experience a higher rate of such infections.
Altogether, the investigators examined data on 700 patients with RMDs treated with rituximab who were consecutively seen during 2012-2017 at Dr. Md Yusof’s institution – the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine, which is part of the University of Leeds. Their immunoglobulin levels had been measured before starting rituximab therapy and every 4-6 months after each cycle of rituximab treatment.
Patients with any RMD being treated with at least one cycle of rituximab were eligible for inclusion in the retrospective study, with the majority (72%) taking it for rheumatoid arthritis and some for systemic lupus erythematosus (13%) or antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (7%).
One of the main aims of the study was to look for predictors of SIEs during the first 12 months and during repeated cycles of rituximab. Dr. Md Yusof and his associates also looked at how secondary hypogammaglobulinemia might affect SIE rates and the humoral response to vaccination challenge and its persistence following treatment discontinuation. Their ultimate aim was to see if these findings could then be used to develop a treatment algorithm for rituximab administration in RMDs.
Over a follow-up period encompassing 2,880 patient-years of treatment, 281 SIEs were recorded in 176 patients, giving a rate of 9.8 infections per 100 patient-years. Most (61%) of these were due to lower respiratory tract infections.
The proportion of patients experiencing their first SIE increased with time: 16% within 6 weeks of starting rituximab therapy, 35% at 12 weeks, 72% at 26 weeks, 83% at 38 weeks, and 100% by 1 year of repeated treatment.
Multivariable analysis showed that the presence of several comorbidities at baseline – notably chronic obstructive pulmonary disease, diabetes, heart failure, and prior cancer – raised the risk for SIEs with repeated rituximab therapy. The biggest factor, however, was a history of SIEs – with a sixfold increased risk of further serious infection.
Higher corticosteroid dose and factors specific to rituximab – low IgG, neutropenia, high IgM, and a longer time to retreatment – were also predictive of SIEs.
“Low IgG also results in poor humoral response to vaccination,” Dr. Md Yusof said, noting that the IgG level remains below the lower limit of normal for several years after rituximab is discontinued in most patients.
In the study, 5 of 8 (64%) patients had impaired humoral response to pneumococcal and haemophilus following vaccination challenge and 4 of 11 patients had IgG normalized after switching to another biologic disease-modifying antirheumatic drug (bDMARD).
Cyclophosphamide is commonly used as a first-line agent to induce remission in patients with severe and refractory systemic lupus erythematosus and ANCA-associated vasculitis, with patients switched to rituximab at relapse. The effect of this prior treatment was examined in 20 patients in the study, with a marked decline in almost all immunoglobulin classes seen up to 18 months. Prior treatment with immunosuppressants such as intravenous cyclophosphamide could be behind progressive reductions in Ig levels seen with repeated rituximab treatment rather than entirely because of rituximab, Dr. Md Yusof said.
Dr. Md Yusof, who is a National Institute for Health Research (NIHR) Academic Clinical Lecturer at the University of Leeds, said the value of the study, compared with others, is that hospital data for all patients treated with rituximab with at least 3 months follow-up were included, making it an almost complete data set.
“By carefully reviewing records of every patient to capture all infection episodes in the largest single-center cohort study to date, our findings provide insights on predictors of SIEs as well as a foundation for safety monitoring of rituximab,” he and his coauthors wrote.
They acknowledge reporting a higher rate of SIEs than seen in registry and clinical studies with rituximab, which may reflect a “channeling bias” as the patients comprised those with multiple comorbidities including those that represent a relative contraindication for bDMARD use. That said, the findings clearly show that Ig levels should be monitored before and after each rituximab cycle, especially in those with comorbid diseases and those with low IgG levels to start with.
They conclude that an “individualized benefit-risk assessment” is needed to determine whether rituximab should be repeated in those with low IgG as this is a “consistent predictor” of SIE and may “increase infection profiles when [rituximab] is switched to different bDMARDs.”
The research was supported by Octapharma, the National Institute for Health Research (NIHR), and NIHR Leeds Biomedical Research Centre based at Leeds Teaching Hospitals NHS Trust in England. Dr. Md Yusof had no conflicts of interest. Several coauthors disclosed financial ties to multiple pharmaceutical companies, including Roche.
SOURCE: Md Yusof MY et al. Arthritis Rheumatol. 2019 May 27. doi: 10.1002/art.40937.
Monitoring immunoglobulin (Ig) levels at baseline and before each cycle of rituximab could reduce the risk of serious infection events (SIEs) in patients needing repeated treatment, according to research published in Arthritis & Rheumatology.
In a large, single-center, longitudinal study conducted at a tertiary referral center, having low IgG (less than 6 g/L) in particular was associated with a higher rate of SIEs, compared with having normal IgG levels (6-16 g/L). Considering 103 of 700 patients who had low levels of IgG before starting treatment with rituximab for various rheumatic and musculoskeletal diseases (RMDs), there were 16.4 SIEs per 100 patient-years. In those who developed low IgG during subsequent cycles of rituximab therapy, the SIE rate was even higher, at 21.3 per 100 patient-years. By comparison, the SIE rate for those with normal IgG levels was 9.7 per 100 patient-years.
“We really have to monitor immunoglobulins at baseline and also before we re-treat the patients, because higher IgG level is protective of serious infections,” study first author Md Yuzaiful Md Yusof, MBChB, PhD, said in an interview.
Low IgG has been linked to a higher risk of SIEs in the first 12 months of rituximab therapy but, until now, there have been limited data on infection predictors during repeated cycles of treatment. While IgG is a consistent marker of SIEs associated with repeated rituximab treatment, IgM and IgA should also be monitored to give a full picture of any hyperglobulinemia that may be present.
“There is no formal guidance on how to safely monitor patients on rituximab,” observed Dr. Md Yusof, who will present these data at the 2019 European Congress of Rheumatology in Madrid. The study’s findings could help to change that, however, as they offer a practical way to help predict and thus prevent SIEs. The study’s findings not only validate previous work, he noted, but also add new insights into why some patients treated with repeat rituximab cycles but not others may experience a higher rate of such infections.
Altogether, the investigators examined data on 700 patients with RMDs treated with rituximab who were consecutively seen during 2012-2017 at Dr. Md Yusof’s institution – the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine, which is part of the University of Leeds. Their immunoglobulin levels had been measured before starting rituximab therapy and every 4-6 months after each cycle of rituximab treatment.
Patients with any RMD being treated with at least one cycle of rituximab were eligible for inclusion in the retrospective study, with the majority (72%) taking it for rheumatoid arthritis and some for systemic lupus erythematosus (13%) or antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (7%).
One of the main aims of the study was to look for predictors of SIEs during the first 12 months and during repeated cycles of rituximab. Dr. Md Yusof and his associates also looked at how secondary hypogammaglobulinemia might affect SIE rates and the humoral response to vaccination challenge and its persistence following treatment discontinuation. Their ultimate aim was to see if these findings could then be used to develop a treatment algorithm for rituximab administration in RMDs.
Over a follow-up period encompassing 2,880 patient-years of treatment, 281 SIEs were recorded in 176 patients, giving a rate of 9.8 infections per 100 patient-years. Most (61%) of these were due to lower respiratory tract infections.
The proportion of patients experiencing their first SIE increased with time: 16% within 6 weeks of starting rituximab therapy, 35% at 12 weeks, 72% at 26 weeks, 83% at 38 weeks, and 100% by 1 year of repeated treatment.
Multivariable analysis showed that the presence of several comorbidities at baseline – notably chronic obstructive pulmonary disease, diabetes, heart failure, and prior cancer – raised the risk for SIEs with repeated rituximab therapy. The biggest factor, however, was a history of SIEs – with a sixfold increased risk of further serious infection.
Higher corticosteroid dose and factors specific to rituximab – low IgG, neutropenia, high IgM, and a longer time to retreatment – were also predictive of SIEs.
“Low IgG also results in poor humoral response to vaccination,” Dr. Md Yusof said, noting that the IgG level remains below the lower limit of normal for several years after rituximab is discontinued in most patients.
In the study, 5 of 8 (64%) patients had impaired humoral response to pneumococcal and haemophilus following vaccination challenge and 4 of 11 patients had IgG normalized after switching to another biologic disease-modifying antirheumatic drug (bDMARD).
Cyclophosphamide is commonly used as a first-line agent to induce remission in patients with severe and refractory systemic lupus erythematosus and ANCA-associated vasculitis, with patients switched to rituximab at relapse. The effect of this prior treatment was examined in 20 patients in the study, with a marked decline in almost all immunoglobulin classes seen up to 18 months. Prior treatment with immunosuppressants such as intravenous cyclophosphamide could be behind progressive reductions in Ig levels seen with repeated rituximab treatment rather than entirely because of rituximab, Dr. Md Yusof said.
Dr. Md Yusof, who is a National Institute for Health Research (NIHR) Academic Clinical Lecturer at the University of Leeds, said the value of the study, compared with others, is that hospital data for all patients treated with rituximab with at least 3 months follow-up were included, making it an almost complete data set.
“By carefully reviewing records of every patient to capture all infection episodes in the largest single-center cohort study to date, our findings provide insights on predictors of SIEs as well as a foundation for safety monitoring of rituximab,” he and his coauthors wrote.
They acknowledge reporting a higher rate of SIEs than seen in registry and clinical studies with rituximab, which may reflect a “channeling bias” as the patients comprised those with multiple comorbidities including those that represent a relative contraindication for bDMARD use. That said, the findings clearly show that Ig levels should be monitored before and after each rituximab cycle, especially in those with comorbid diseases and those with low IgG levels to start with.
They conclude that an “individualized benefit-risk assessment” is needed to determine whether rituximab should be repeated in those with low IgG as this is a “consistent predictor” of SIE and may “increase infection profiles when [rituximab] is switched to different bDMARDs.”
The research was supported by Octapharma, the National Institute for Health Research (NIHR), and NIHR Leeds Biomedical Research Centre based at Leeds Teaching Hospitals NHS Trust in England. Dr. Md Yusof had no conflicts of interest. Several coauthors disclosed financial ties to multiple pharmaceutical companies, including Roche.
SOURCE: Md Yusof MY et al. Arthritis Rheumatol. 2019 May 27. doi: 10.1002/art.40937.
FROM ARTHRITIS & RHEUMATOLOGY
Key clinical point: Immunoglobulin should be monitored at baseline and before each rituximab cycle to identify patients at risk of serious infection events (SIEs).
Major finding: SIE rates per 100 patient-years were 16.4 and 21.3 in patients with low (less than 6 g/L) IgG at baseline and during rituximab cycles versus 9.7 for patients with normal (6–16 g/L) IgG levels.
Study details: A retrospective, single-center, longitudinal study involving 700 rituximab-treated patients with rheumatoid arthritis and other rheumatic and musculoskeletal diseases.
Disclosures: The research was supported by Octapharma, the National Institute for Health Research (NIHR), and NIHR Leeds Biomedical Research Centre based at Leeds Teaching Hospitals NHS Trust in the United Kingdom. Dr. Md Yusof had no conflicts of interest. Several coauthors disclosed financial ties to multiple pharmaceutical companies, including Roche.
Source: Md Yusof MY et al. Arthritis Rheumatol. 2019 May 27. doi: 10.1002/art.40937.
Check for complementopathies in lupus pregnancy
SAN FRANCISCO – It’s important to check for complementopathies in pregnant women with lupus, according to Michelle Petri, MD, a professor of rheumatology at Johns Hopkins University, Baltimore.
A new diagnosis being developed at Hopkins and elsewhere, complementopathies involve an inappropriate activation of the alternative pathway of complement (APC), either from a mutation in a complement control protein, or, in the case of lupus, an autoantibody against one. They’ve been implicated as a major cause of hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, a condition to which women with lupus are particularly prone.
Hopkins has developed a serum test to diagnose inappropriate APC activation in a few hours, the modified Ham test. When HELLP develops in a woman with a complementopathy, the complement inhibitor eculizumab (Soliris) is proving to be a safe alternative to pregnancy termination.
“I urge you to think about using the modified Ham test, because if it is positive, you can treat HELLP without having to stop the pregnancy,” said Dr. Petri, also codirector of the Hopkins Lupus Pregnancy Center.
Lupus management has come a long way from the days when women were counseled to avoid or terminate pregnancy. Risks remain, “but many pregnancies are successful. I think that for every woman with lupus, we do want to offer the possibility of successful pregnancy,” she said.
Disease control is key. Preterm birth, the most common adverse outcome in lupus, correlates closely with disease activity, and disease activity can be controlled with hydroxychloroquine, and, when needed, azathioprine and tacrolimus for renal flairs.
“But these kinds of basic lessons – we need hydroxychloroquine in pregnancy; we must control disease activity – are not heard out in the real world. Claims data have shown that pregnant women with lupus actually take fewer prescribed medications, and they have fewer rheumatology visits.” It’s a problem that needs to be addressed, Dr. Petri said.
Vitamin D is also important. Hopkins has shown that supplementation to hit a level of 40 ng/mL reduces both global and renal disease activity without toxicity; studies in the general population have shown reduced preeclampsia, preterm birth, and low birth weight, all concerns in lupus.
“I haven’t convinced the world of lupus how important vitamin D is,” but “I actually love it just as much as I love hydroxychloroquine,” Dr. Petri said.
Cosupplementation with calcium complicates matters. Together, they seem to reduce the risk of preeclampsia, but increase the risk of preterm birth. More needs to be known, so “for all of us with pregnancy cohorts, it’s time to start to record vitamin D and calcium levels so we can look at this,” she said.
Dr. Petri has worked with numerous companies.
SAN FRANCISCO – It’s important to check for complementopathies in pregnant women with lupus, according to Michelle Petri, MD, a professor of rheumatology at Johns Hopkins University, Baltimore.
A new diagnosis being developed at Hopkins and elsewhere, complementopathies involve an inappropriate activation of the alternative pathway of complement (APC), either from a mutation in a complement control protein, or, in the case of lupus, an autoantibody against one. They’ve been implicated as a major cause of hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, a condition to which women with lupus are particularly prone.
Hopkins has developed a serum test to diagnose inappropriate APC activation in a few hours, the modified Ham test. When HELLP develops in a woman with a complementopathy, the complement inhibitor eculizumab (Soliris) is proving to be a safe alternative to pregnancy termination.
“I urge you to think about using the modified Ham test, because if it is positive, you can treat HELLP without having to stop the pregnancy,” said Dr. Petri, also codirector of the Hopkins Lupus Pregnancy Center.
Lupus management has come a long way from the days when women were counseled to avoid or terminate pregnancy. Risks remain, “but many pregnancies are successful. I think that for every woman with lupus, we do want to offer the possibility of successful pregnancy,” she said.
Disease control is key. Preterm birth, the most common adverse outcome in lupus, correlates closely with disease activity, and disease activity can be controlled with hydroxychloroquine, and, when needed, azathioprine and tacrolimus for renal flairs.
“But these kinds of basic lessons – we need hydroxychloroquine in pregnancy; we must control disease activity – are not heard out in the real world. Claims data have shown that pregnant women with lupus actually take fewer prescribed medications, and they have fewer rheumatology visits.” It’s a problem that needs to be addressed, Dr. Petri said.
Vitamin D is also important. Hopkins has shown that supplementation to hit a level of 40 ng/mL reduces both global and renal disease activity without toxicity; studies in the general population have shown reduced preeclampsia, preterm birth, and low birth weight, all concerns in lupus.
“I haven’t convinced the world of lupus how important vitamin D is,” but “I actually love it just as much as I love hydroxychloroquine,” Dr. Petri said.
Cosupplementation with calcium complicates matters. Together, they seem to reduce the risk of preeclampsia, but increase the risk of preterm birth. More needs to be known, so “for all of us with pregnancy cohorts, it’s time to start to record vitamin D and calcium levels so we can look at this,” she said.
Dr. Petri has worked with numerous companies.
SAN FRANCISCO – It’s important to check for complementopathies in pregnant women with lupus, according to Michelle Petri, MD, a professor of rheumatology at Johns Hopkins University, Baltimore.
A new diagnosis being developed at Hopkins and elsewhere, complementopathies involve an inappropriate activation of the alternative pathway of complement (APC), either from a mutation in a complement control protein, or, in the case of lupus, an autoantibody against one. They’ve been implicated as a major cause of hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, a condition to which women with lupus are particularly prone.
Hopkins has developed a serum test to diagnose inappropriate APC activation in a few hours, the modified Ham test. When HELLP develops in a woman with a complementopathy, the complement inhibitor eculizumab (Soliris) is proving to be a safe alternative to pregnancy termination.
“I urge you to think about using the modified Ham test, because if it is positive, you can treat HELLP without having to stop the pregnancy,” said Dr. Petri, also codirector of the Hopkins Lupus Pregnancy Center.
Lupus management has come a long way from the days when women were counseled to avoid or terminate pregnancy. Risks remain, “but many pregnancies are successful. I think that for every woman with lupus, we do want to offer the possibility of successful pregnancy,” she said.
Disease control is key. Preterm birth, the most common adverse outcome in lupus, correlates closely with disease activity, and disease activity can be controlled with hydroxychloroquine, and, when needed, azathioprine and tacrolimus for renal flairs.
“But these kinds of basic lessons – we need hydroxychloroquine in pregnancy; we must control disease activity – are not heard out in the real world. Claims data have shown that pregnant women with lupus actually take fewer prescribed medications, and they have fewer rheumatology visits.” It’s a problem that needs to be addressed, Dr. Petri said.
Vitamin D is also important. Hopkins has shown that supplementation to hit a level of 40 ng/mL reduces both global and renal disease activity without toxicity; studies in the general population have shown reduced preeclampsia, preterm birth, and low birth weight, all concerns in lupus.
“I haven’t convinced the world of lupus how important vitamin D is,” but “I actually love it just as much as I love hydroxychloroquine,” Dr. Petri said.
Cosupplementation with calcium complicates matters. Together, they seem to reduce the risk of preeclampsia, but increase the risk of preterm birth. More needs to be known, so “for all of us with pregnancy cohorts, it’s time to start to record vitamin D and calcium levels so we can look at this,” she said.
Dr. Petri has worked with numerous companies.
EXPERT ANALYSIS FROM LUPUS 2019
Warfarin found to increase adverse outcomes among patients with IPF
DALLAS – Warfarin appears to increase the risk of lung transplant or death for patients with fibrotic lung disease who need anticoagulation therapy, Christopher King, MD, said at the American Thoracic Society’s international conference.
Compared with direct oral anticoagulation (DOAC), warfarin doubled the risk of those outcomes, even after the researchers controlled for multiple morbidities that accompany the need for anticoagulation, said Dr. King, medical director of the transplant and advanced lung disease critical care program at Inova Fairfax (Va.) Hospital.
“The need for anticoagulation in patients with interstitial lung disease is already associated with an increased risk of death or transplant,” he said. Warfarin – but not oral anticoagulation – seems to increase that risk even more “no matter how you analyze it,” he said.
“We know now that fibrosis and coagulation are entwined, and there’s background epidemiologic data showing an increased incidence of venous thromboembolism and acute coronary syndrome in patients with pulmonary fibrosis. This suggests that a dysregulated coagulation cascade may play a role in the pathogenesis of fibrosis.”
The relationship has been explored for the last decade or so. Two recent meta-analyses came to similar conclusions.
In 2013, a 125-patient retrospective cohort study compared clinical characteristics and survival among patients with idiopathic pulmonary fibrosis (IPF) who received anticoagulant therapy with those who did not (Sarcoidosis Vasc Diffuse Lung Dis. 2013 Aug 1;30[2]:121-7). Those who got the treatment had worse survival outcomes at 1 and 3 years than did those who received no therapy (84% vs. 53% and 89% vs. 64%, respectively).
In 2016, a post hoc analysis of three placebo-controlled studies determined that any anticoagulant use independently increased the risk of death among patients with IPF, compared with nonuse: 15.6% vs 6.3% all-cause mortality (Eur Respir J. 2016. doi: 10.1183/13993003.02087-2015).
But these investigations didn’t parse out the types of anticoagulation. Direct oral anticoagulation (DOAC) is much more common now, however, and Dr. King and colleagues wanted to find out how warfarin and DOAC compared.
They retrospectively analyzed data from the Pulmonary Fibrosis Foundation’s database and compared the risk of lung transplant and death for patients on anticoagulation or no anticoagulation and for those receiving DOACs versus warfarin versus no anticoagulation.
The study comprised 1,918 patients, 91% of whom were not on anticoagulation therapy. The remaining 164 were either taking DOAC (n = 83) or warfarin (n = 81). Both of these groups were significantly older than those not on anticoagulation (70 vs. 67 years). As expected , they were significantly more likely to have cardiac arrhythmias, heart failure, or pulmonary embolism or deep vein thrombosis and significantly more likely to be on immunosuppressant therapy or steroids. Their diffusing capacity of lung for carbon dioxide was also significantly lower.
There were no significant lung disease–related differences in anticoagulation therapy, other than a trend toward more use among those with connective tissue disease–associated interstitial lung disease.
Over 2 years, the entire cohort experienced 110 deaths (5.7%), 52 transplants (2.7%), and 29 withdrawals (1.5%). Among patients with IPF, there were 80 deaths (6.7%), 43 transplants (3.6%) and 20 withdrawals (1.7%).
In an unadjusted analysis, anticoagulation more than doubled the risk of an event, compared with no anticoagulation (hazard ratio, 2.4). This was slightly attenuated, but still significant, in a multivariate model that controlled for age, gender, oxygen use, gastroesophageal reflux disease, obstructive sleep apnea, arrhythmia, cancer, heart failure, obesity, venous thromboembolism, and antifibrotics (HR, 1.88).
A second whole-cohort analysis looked at the survival ratios for both warfarin and DOAC, compared with no treatment. In the fully adjusted model, warfarin was associated with a significantly increased risk HR (2.28) but DOAC was not.
The investigators then examined risk in only patients with lung disease. Among those with IPF, the fully adjusted model showed that warfarin nearly tripled the risk of transplant or death (HR, 2.8), while DOAC had no significant effect.
The reason for this association remains unclear, Dr. King said. “Renal failure may be a big reason patients get warfarin instead of DOAC. It’s difficult to say whether these patients were frail or prone to bleeding. Even something like the care team not being as up to date with treatment could be affecting the numbers. And is it the direct effect of warfarin on fibrotic lung disease? Or maybe DOAC has some beneficial effect on pulmonary fibrosis? We don’t know.
“But what we can take away from this is that warfarin is associated with worse outcomes than DOAC in patients with IPF. It seems reasonable to use DOAC over warfarin if there’s no specific contraindication to DOAC. If you have a patient with pulmonary thrombosis who has indications for anticoagulation I would use DOAC, based on the evidence that we now have available.”
Dr. King had no disclosures.
DALLAS – Warfarin appears to increase the risk of lung transplant or death for patients with fibrotic lung disease who need anticoagulation therapy, Christopher King, MD, said at the American Thoracic Society’s international conference.
Compared with direct oral anticoagulation (DOAC), warfarin doubled the risk of those outcomes, even after the researchers controlled for multiple morbidities that accompany the need for anticoagulation, said Dr. King, medical director of the transplant and advanced lung disease critical care program at Inova Fairfax (Va.) Hospital.
“The need for anticoagulation in patients with interstitial lung disease is already associated with an increased risk of death or transplant,” he said. Warfarin – but not oral anticoagulation – seems to increase that risk even more “no matter how you analyze it,” he said.
“We know now that fibrosis and coagulation are entwined, and there’s background epidemiologic data showing an increased incidence of venous thromboembolism and acute coronary syndrome in patients with pulmonary fibrosis. This suggests that a dysregulated coagulation cascade may play a role in the pathogenesis of fibrosis.”
The relationship has been explored for the last decade or so. Two recent meta-analyses came to similar conclusions.
In 2013, a 125-patient retrospective cohort study compared clinical characteristics and survival among patients with idiopathic pulmonary fibrosis (IPF) who received anticoagulant therapy with those who did not (Sarcoidosis Vasc Diffuse Lung Dis. 2013 Aug 1;30[2]:121-7). Those who got the treatment had worse survival outcomes at 1 and 3 years than did those who received no therapy (84% vs. 53% and 89% vs. 64%, respectively).
In 2016, a post hoc analysis of three placebo-controlled studies determined that any anticoagulant use independently increased the risk of death among patients with IPF, compared with nonuse: 15.6% vs 6.3% all-cause mortality (Eur Respir J. 2016. doi: 10.1183/13993003.02087-2015).
But these investigations didn’t parse out the types of anticoagulation. Direct oral anticoagulation (DOAC) is much more common now, however, and Dr. King and colleagues wanted to find out how warfarin and DOAC compared.
They retrospectively analyzed data from the Pulmonary Fibrosis Foundation’s database and compared the risk of lung transplant and death for patients on anticoagulation or no anticoagulation and for those receiving DOACs versus warfarin versus no anticoagulation.
The study comprised 1,918 patients, 91% of whom were not on anticoagulation therapy. The remaining 164 were either taking DOAC (n = 83) or warfarin (n = 81). Both of these groups were significantly older than those not on anticoagulation (70 vs. 67 years). As expected , they were significantly more likely to have cardiac arrhythmias, heart failure, or pulmonary embolism or deep vein thrombosis and significantly more likely to be on immunosuppressant therapy or steroids. Their diffusing capacity of lung for carbon dioxide was also significantly lower.
There were no significant lung disease–related differences in anticoagulation therapy, other than a trend toward more use among those with connective tissue disease–associated interstitial lung disease.
Over 2 years, the entire cohort experienced 110 deaths (5.7%), 52 transplants (2.7%), and 29 withdrawals (1.5%). Among patients with IPF, there were 80 deaths (6.7%), 43 transplants (3.6%) and 20 withdrawals (1.7%).
In an unadjusted analysis, anticoagulation more than doubled the risk of an event, compared with no anticoagulation (hazard ratio, 2.4). This was slightly attenuated, but still significant, in a multivariate model that controlled for age, gender, oxygen use, gastroesophageal reflux disease, obstructive sleep apnea, arrhythmia, cancer, heart failure, obesity, venous thromboembolism, and antifibrotics (HR, 1.88).
A second whole-cohort analysis looked at the survival ratios for both warfarin and DOAC, compared with no treatment. In the fully adjusted model, warfarin was associated with a significantly increased risk HR (2.28) but DOAC was not.
The investigators then examined risk in only patients with lung disease. Among those with IPF, the fully adjusted model showed that warfarin nearly tripled the risk of transplant or death (HR, 2.8), while DOAC had no significant effect.
The reason for this association remains unclear, Dr. King said. “Renal failure may be a big reason patients get warfarin instead of DOAC. It’s difficult to say whether these patients were frail or prone to bleeding. Even something like the care team not being as up to date with treatment could be affecting the numbers. And is it the direct effect of warfarin on fibrotic lung disease? Or maybe DOAC has some beneficial effect on pulmonary fibrosis? We don’t know.
“But what we can take away from this is that warfarin is associated with worse outcomes than DOAC in patients with IPF. It seems reasonable to use DOAC over warfarin if there’s no specific contraindication to DOAC. If you have a patient with pulmonary thrombosis who has indications for anticoagulation I would use DOAC, based on the evidence that we now have available.”
Dr. King had no disclosures.
DALLAS – Warfarin appears to increase the risk of lung transplant or death for patients with fibrotic lung disease who need anticoagulation therapy, Christopher King, MD, said at the American Thoracic Society’s international conference.
Compared with direct oral anticoagulation (DOAC), warfarin doubled the risk of those outcomes, even after the researchers controlled for multiple morbidities that accompany the need for anticoagulation, said Dr. King, medical director of the transplant and advanced lung disease critical care program at Inova Fairfax (Va.) Hospital.
“The need for anticoagulation in patients with interstitial lung disease is already associated with an increased risk of death or transplant,” he said. Warfarin – but not oral anticoagulation – seems to increase that risk even more “no matter how you analyze it,” he said.
“We know now that fibrosis and coagulation are entwined, and there’s background epidemiologic data showing an increased incidence of venous thromboembolism and acute coronary syndrome in patients with pulmonary fibrosis. This suggests that a dysregulated coagulation cascade may play a role in the pathogenesis of fibrosis.”
The relationship has been explored for the last decade or so. Two recent meta-analyses came to similar conclusions.
In 2013, a 125-patient retrospective cohort study compared clinical characteristics and survival among patients with idiopathic pulmonary fibrosis (IPF) who received anticoagulant therapy with those who did not (Sarcoidosis Vasc Diffuse Lung Dis. 2013 Aug 1;30[2]:121-7). Those who got the treatment had worse survival outcomes at 1 and 3 years than did those who received no therapy (84% vs. 53% and 89% vs. 64%, respectively).
In 2016, a post hoc analysis of three placebo-controlled studies determined that any anticoagulant use independently increased the risk of death among patients with IPF, compared with nonuse: 15.6% vs 6.3% all-cause mortality (Eur Respir J. 2016. doi: 10.1183/13993003.02087-2015).
But these investigations didn’t parse out the types of anticoagulation. Direct oral anticoagulation (DOAC) is much more common now, however, and Dr. King and colleagues wanted to find out how warfarin and DOAC compared.
They retrospectively analyzed data from the Pulmonary Fibrosis Foundation’s database and compared the risk of lung transplant and death for patients on anticoagulation or no anticoagulation and for those receiving DOACs versus warfarin versus no anticoagulation.
The study comprised 1,918 patients, 91% of whom were not on anticoagulation therapy. The remaining 164 were either taking DOAC (n = 83) or warfarin (n = 81). Both of these groups were significantly older than those not on anticoagulation (70 vs. 67 years). As expected , they were significantly more likely to have cardiac arrhythmias, heart failure, or pulmonary embolism or deep vein thrombosis and significantly more likely to be on immunosuppressant therapy or steroids. Their diffusing capacity of lung for carbon dioxide was also significantly lower.
There were no significant lung disease–related differences in anticoagulation therapy, other than a trend toward more use among those with connective tissue disease–associated interstitial lung disease.
Over 2 years, the entire cohort experienced 110 deaths (5.7%), 52 transplants (2.7%), and 29 withdrawals (1.5%). Among patients with IPF, there were 80 deaths (6.7%), 43 transplants (3.6%) and 20 withdrawals (1.7%).
In an unadjusted analysis, anticoagulation more than doubled the risk of an event, compared with no anticoagulation (hazard ratio, 2.4). This was slightly attenuated, but still significant, in a multivariate model that controlled for age, gender, oxygen use, gastroesophageal reflux disease, obstructive sleep apnea, arrhythmia, cancer, heart failure, obesity, venous thromboembolism, and antifibrotics (HR, 1.88).
A second whole-cohort analysis looked at the survival ratios for both warfarin and DOAC, compared with no treatment. In the fully adjusted model, warfarin was associated with a significantly increased risk HR (2.28) but DOAC was not.
The investigators then examined risk in only patients with lung disease. Among those with IPF, the fully adjusted model showed that warfarin nearly tripled the risk of transplant or death (HR, 2.8), while DOAC had no significant effect.
The reason for this association remains unclear, Dr. King said. “Renal failure may be a big reason patients get warfarin instead of DOAC. It’s difficult to say whether these patients were frail or prone to bleeding. Even something like the care team not being as up to date with treatment could be affecting the numbers. And is it the direct effect of warfarin on fibrotic lung disease? Or maybe DOAC has some beneficial effect on pulmonary fibrosis? We don’t know.
“But what we can take away from this is that warfarin is associated with worse outcomes than DOAC in patients with IPF. It seems reasonable to use DOAC over warfarin if there’s no specific contraindication to DOAC. If you have a patient with pulmonary thrombosis who has indications for anticoagulation I would use DOAC, based on the evidence that we now have available.”
Dr. King had no disclosures.
REPORTING FROM ATS 2019
Antimalarials in pregnancy and lactation
According to the World Health Organization, there were about 219 million cases of malaria and an estimated 660,000 deaths in 2010. Although huge, this was a 26% decrease from the rates in 2000. Six countries in Africa account for 47% of malaria cases: Cote d’Ivoire, Democratic Republic of the Congo, Mozambique, Nigeria, Uganda, and the United Republic of Tanzania. The second-most affected region in the world is Southeast Asia, which includes Myanmar, India, and Indonesia. In comparison, about 1,500 malaria cases and 5 deaths are reported annually in the United States, mostly from returned travelers.
if they will be traveling in any of the above regions. Malaria during pregnancy increases the risk for adverse pregnancy outcomes, including maternal anemia, prematurity, spontaneous abortion, and stillbirth.
As stated by the Centers for Disease Control and Prevention, no antimalarial agent is 100% protective. Therefore, whatever agent is used must be combined with personal protective measures such as wearing insect repellent, long sleeves, and long pants; sleeping in a mosquito-free setting; or using an insecticide-treated bed net.
There are nine antimalarial drugs available in the United States.
Atovaquone/Proguanil Hcl (Malarone and as generic)
This agent is good for last-minute travelers because the drug is started 1-2 days before traveling to areas where malaria transmission occurs. The combination can be classified as compatible in pregnancy. No reports in breastfeeding with atovaquone or the combination have been found. Proguanil is not available in the United States as a single agent.
Chloroquine (generic)
This is the drug of choice to prevent and treat sensitive malaria species during pregnancy. The drug crosses the placenta producing fetal concentrations that are similar to those in the mother. The drug appears to be low risk for embryo-fetal harm.
It is compatible in breastfeeding.
Dapsone (generic)
This agent does not appear to represent a major risk of harm to the fetus. Although it has been used in combination with pyrimethamine (an antiparasitic) or trimethoprim (an antibiotic) to prevent malaria, the efficacy of the combination has not been confirmed.
In breastfeeding, there is one case of mild hemolytic anemia in the mother and her breastfeeding infant that may have been caused by the drug.
Hydroxychloroquine (generic)
This agent is used for the treatment of malaria, systemic erythematosus, and rheumatoid arthritis. For antimalarial prophylaxis, 400 mg/week appears to be low risk for embryo-fetal harm. Doses used to treat malaria have been 200-400 mg/day.
Because very low concentrations of the drug have been found in breast milk, breastfeeding is probably compatible.
Mefloquine (generic)
This agent is a quinoline-methanol agent that does not appear to cause embryo-fetal harm based on a large number of pregnancy exposures.
There are no reports of its use while breastfeeding.
Primaquine (generic)
This agent is best avoided in pregnancy. There is no human pregnancy data, but it may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD). Because the fetus is relatively G6PD deficient, it is best avoided in pregnancy regardless of the mother’s status.
There are no reports describing the use of the drug during lactation. Both the mother and baby should be tested for G6PD deficiency before the drug is used during breastfeeding.
Pyrimethamine (generic)
This agent has been used for the treatment or prophylaxis of malaria. Most studies have found this agent to be relatively safe and effective.
It is excreted into breast milk and has been effective in eliminating malaria parasites from breastfeeding infants.
Quinidine (generic)
Reports linking the use of this agent with congenital defects have not been found. Although the drug has data on its use as an antiarrhythmic, its published use to treat malaria is limited.
The drug is excreted into breast milk, but there are no reports of its during breastfeeding.
Quinine (generic)
This agent has a large amount of human pregnancy data (more than 1,000 exposures) that found no increased risk of birth defects. The drug has been replaced by newer agents but still may be used for chloroquine-resistant malaria.
The drug appears to be compatible during breastfeeding.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].
According to the World Health Organization, there were about 219 million cases of malaria and an estimated 660,000 deaths in 2010. Although huge, this was a 26% decrease from the rates in 2000. Six countries in Africa account for 47% of malaria cases: Cote d’Ivoire, Democratic Republic of the Congo, Mozambique, Nigeria, Uganda, and the United Republic of Tanzania. The second-most affected region in the world is Southeast Asia, which includes Myanmar, India, and Indonesia. In comparison, about 1,500 malaria cases and 5 deaths are reported annually in the United States, mostly from returned travelers.
if they will be traveling in any of the above regions. Malaria during pregnancy increases the risk for adverse pregnancy outcomes, including maternal anemia, prematurity, spontaneous abortion, and stillbirth.
As stated by the Centers for Disease Control and Prevention, no antimalarial agent is 100% protective. Therefore, whatever agent is used must be combined with personal protective measures such as wearing insect repellent, long sleeves, and long pants; sleeping in a mosquito-free setting; or using an insecticide-treated bed net.
There are nine antimalarial drugs available in the United States.
Atovaquone/Proguanil Hcl (Malarone and as generic)
This agent is good for last-minute travelers because the drug is started 1-2 days before traveling to areas where malaria transmission occurs. The combination can be classified as compatible in pregnancy. No reports in breastfeeding with atovaquone or the combination have been found. Proguanil is not available in the United States as a single agent.
Chloroquine (generic)
This is the drug of choice to prevent and treat sensitive malaria species during pregnancy. The drug crosses the placenta producing fetal concentrations that are similar to those in the mother. The drug appears to be low risk for embryo-fetal harm.
It is compatible in breastfeeding.
Dapsone (generic)
This agent does not appear to represent a major risk of harm to the fetus. Although it has been used in combination with pyrimethamine (an antiparasitic) or trimethoprim (an antibiotic) to prevent malaria, the efficacy of the combination has not been confirmed.
In breastfeeding, there is one case of mild hemolytic anemia in the mother and her breastfeeding infant that may have been caused by the drug.
Hydroxychloroquine (generic)
This agent is used for the treatment of malaria, systemic erythematosus, and rheumatoid arthritis. For antimalarial prophylaxis, 400 mg/week appears to be low risk for embryo-fetal harm. Doses used to treat malaria have been 200-400 mg/day.
Because very low concentrations of the drug have been found in breast milk, breastfeeding is probably compatible.
Mefloquine (generic)
This agent is a quinoline-methanol agent that does not appear to cause embryo-fetal harm based on a large number of pregnancy exposures.
There are no reports of its use while breastfeeding.
Primaquine (generic)
This agent is best avoided in pregnancy. There is no human pregnancy data, but it may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD). Because the fetus is relatively G6PD deficient, it is best avoided in pregnancy regardless of the mother’s status.
There are no reports describing the use of the drug during lactation. Both the mother and baby should be tested for G6PD deficiency before the drug is used during breastfeeding.
Pyrimethamine (generic)
This agent has been used for the treatment or prophylaxis of malaria. Most studies have found this agent to be relatively safe and effective.
It is excreted into breast milk and has been effective in eliminating malaria parasites from breastfeeding infants.
Quinidine (generic)
Reports linking the use of this agent with congenital defects have not been found. Although the drug has data on its use as an antiarrhythmic, its published use to treat malaria is limited.
The drug is excreted into breast milk, but there are no reports of its during breastfeeding.
Quinine (generic)
This agent has a large amount of human pregnancy data (more than 1,000 exposures) that found no increased risk of birth defects. The drug has been replaced by newer agents but still may be used for chloroquine-resistant malaria.
The drug appears to be compatible during breastfeeding.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].
According to the World Health Organization, there were about 219 million cases of malaria and an estimated 660,000 deaths in 2010. Although huge, this was a 26% decrease from the rates in 2000. Six countries in Africa account for 47% of malaria cases: Cote d’Ivoire, Democratic Republic of the Congo, Mozambique, Nigeria, Uganda, and the United Republic of Tanzania. The second-most affected region in the world is Southeast Asia, which includes Myanmar, India, and Indonesia. In comparison, about 1,500 malaria cases and 5 deaths are reported annually in the United States, mostly from returned travelers.
if they will be traveling in any of the above regions. Malaria during pregnancy increases the risk for adverse pregnancy outcomes, including maternal anemia, prematurity, spontaneous abortion, and stillbirth.
As stated by the Centers for Disease Control and Prevention, no antimalarial agent is 100% protective. Therefore, whatever agent is used must be combined with personal protective measures such as wearing insect repellent, long sleeves, and long pants; sleeping in a mosquito-free setting; or using an insecticide-treated bed net.
There are nine antimalarial drugs available in the United States.
Atovaquone/Proguanil Hcl (Malarone and as generic)
This agent is good for last-minute travelers because the drug is started 1-2 days before traveling to areas where malaria transmission occurs. The combination can be classified as compatible in pregnancy. No reports in breastfeeding with atovaquone or the combination have been found. Proguanil is not available in the United States as a single agent.
Chloroquine (generic)
This is the drug of choice to prevent and treat sensitive malaria species during pregnancy. The drug crosses the placenta producing fetal concentrations that are similar to those in the mother. The drug appears to be low risk for embryo-fetal harm.
It is compatible in breastfeeding.
Dapsone (generic)
This agent does not appear to represent a major risk of harm to the fetus. Although it has been used in combination with pyrimethamine (an antiparasitic) or trimethoprim (an antibiotic) to prevent malaria, the efficacy of the combination has not been confirmed.
In breastfeeding, there is one case of mild hemolytic anemia in the mother and her breastfeeding infant that may have been caused by the drug.
Hydroxychloroquine (generic)
This agent is used for the treatment of malaria, systemic erythematosus, and rheumatoid arthritis. For antimalarial prophylaxis, 400 mg/week appears to be low risk for embryo-fetal harm. Doses used to treat malaria have been 200-400 mg/day.
Because very low concentrations of the drug have been found in breast milk, breastfeeding is probably compatible.
Mefloquine (generic)
This agent is a quinoline-methanol agent that does not appear to cause embryo-fetal harm based on a large number of pregnancy exposures.
There are no reports of its use while breastfeeding.
Primaquine (generic)
This agent is best avoided in pregnancy. There is no human pregnancy data, but it may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD). Because the fetus is relatively G6PD deficient, it is best avoided in pregnancy regardless of the mother’s status.
There are no reports describing the use of the drug during lactation. Both the mother and baby should be tested for G6PD deficiency before the drug is used during breastfeeding.
Pyrimethamine (generic)
This agent has been used for the treatment or prophylaxis of malaria. Most studies have found this agent to be relatively safe and effective.
It is excreted into breast milk and has been effective in eliminating malaria parasites from breastfeeding infants.
Quinidine (generic)
Reports linking the use of this agent with congenital defects have not been found. Although the drug has data on its use as an antiarrhythmic, its published use to treat malaria is limited.
The drug is excreted into breast milk, but there are no reports of its during breastfeeding.
Quinine (generic)
This agent has a large amount of human pregnancy data (more than 1,000 exposures) that found no increased risk of birth defects. The drug has been replaced by newer agents but still may be used for chloroquine-resistant malaria.
The drug appears to be compatible during breastfeeding.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].
Nintedanib cut lung function decline in interstitial lung disease with systemic sclerosis
DALLAS – Nintedanib, a tyrosine kinase inhibitor, decreased by 44% the annual rate of lung function decline among patients with interstitial lung disease associated with systemic sclerosis, a year-long study has found.
In a placebo-controlled 52-week trial, forced vital capacity (FVC) in patients who took nintedanib (Ofev) declined by a mean of 52 mL – significantly less than the mean 93 mL decline seen among those who were given placebo, Oliver Distler, MD, said at the annual meeting of the American Thoracic Society.
“These are people in their mid-40s and -50s,” said Dr. Distler of the University of Zürich. “They have a long time to go. If there is an annual preservation of lung function by 40%, if you have that every year, it becomes very surely clinically significant. A decline in FVC is also a good surrogate marker of mortality in interstitial lung disease associated with systemic sclerosis. Assuming the effects are ongoing above the 1 year we looked at, then indeed these results are clinically important.”
The study was simultaneously published in the New England Journal of Medicine. Nintedanib is already approved for idiopathic pulmonary fibrosis. But some data suggest that it also exerts antifibrotic and anti-inflammatory effects in animal models of systemic sclerosis and inflammatory lung disease (ILD). SENSCIS (the Safety and Efficacy of Nintedanib in Systemic Sclerosis trial) investigated the molecule’s use in patients with ILD associated with systemic sclerosis.
Conducted in 32 countries, SENSCIS comprised 576 patients with the disorder, whose sclerosis affected at least 10% of their lungs. They were assigned to 52 weeks of either placebo or 150 mg nintedanib twice weekly. However, patients stayed on their blinded treatment until the last patient enrolled had finished the year of treatment; some patients took the drug for 100 weeks, Dr. Distler said. The primary endpoint was annual rate of decline in the forced vital capacity (FEV). Secondary endpoints included changes of the modified Rodnan skin score and in the total score on the St. George’s Respiratory Questionnaire.
Patients were a mean of 54 years old, with a mean disease duration of about 3 years. About half had diffuse cutaneous systemic sclerosis; the sclerosis was limited in the remainder. The mean extent of lung fibrosis was about 36%. Half were taking mycophenolate at baseline, which was allowed as background treatment, along with up to 10 mg/day of prednisone. Any patient who experienced clinically significant lung function deterioration could receive additional therapy at the investigator’s discretion.
The mean baseline FEV for these patients was 72.5% of predicted value. The mean diffusing capacity of the lungs for carbon monoxide was 53% of expected capacity.
Most patients completed the study (80% of the active group and 89% of the placebo group). The mean drug exposure duration was 10 months in the active group and 11 in the placebo group.
Improvement began early in treatment, with the efficacy curves separating by week 12 and continuing to diverge. After 52 weeks of therapy, the annual rate of change was 41 mL less in the active group than in the placebo group (–54.4 mL vs. –93.3 mL). The mean adjusted absolute change from baseline was –54.6 mL in the active group and –101 mL in the placebo at week 52. Significantly fewer patients taking nintedanib also lost more than 10% of FVC by week 52 (16.7% vs. 18%).
The St. George’s Respiratory Questionnaire score improved about one point in the active group and declined about one point in the placebo group.
Nintedanib was equally effective across a number of subgroups, including those divided by sex, age, and race. Antitopoisomerase antibodies and so-called antitopoisomerase I antibody status did not affect nintedanib’s action. Nintedanib also significantly improved scores on the Health Assessment Questionnaire without Disability Index and dyspnea.
More patients in the active group than in on placebo discontinued treatment because of a serious adverse event (16% vs. 8.7%). The most common of these were diarrhea (75.7% vs. 31%), nausea (31.6% vs. 13.5%), and vomiting (24.7% vs.10.4%). Skin ulcers occurred in about 18% of each group. Patients in the active group were significantly more likely to develop elevated alanine and aspartate aminotransferase of up to three times normal levels (4.9% vs. 0.7%).
Treatment did not significantly affect mortality rates, however. Over the treatment period, 10 patients in the nintedanib group and 9 in the placebo group died (3.5% vs. 3.1%).
The study was sponsored by Boehringer Ingelheim. Dr. Distler was the primary investigator on the trial.
SOURCE: Distler O et al. ATS 2019, Abstract A7360.
DALLAS – Nintedanib, a tyrosine kinase inhibitor, decreased by 44% the annual rate of lung function decline among patients with interstitial lung disease associated with systemic sclerosis, a year-long study has found.
In a placebo-controlled 52-week trial, forced vital capacity (FVC) in patients who took nintedanib (Ofev) declined by a mean of 52 mL – significantly less than the mean 93 mL decline seen among those who were given placebo, Oliver Distler, MD, said at the annual meeting of the American Thoracic Society.
“These are people in their mid-40s and -50s,” said Dr. Distler of the University of Zürich. “They have a long time to go. If there is an annual preservation of lung function by 40%, if you have that every year, it becomes very surely clinically significant. A decline in FVC is also a good surrogate marker of mortality in interstitial lung disease associated with systemic sclerosis. Assuming the effects are ongoing above the 1 year we looked at, then indeed these results are clinically important.”
The study was simultaneously published in the New England Journal of Medicine. Nintedanib is already approved for idiopathic pulmonary fibrosis. But some data suggest that it also exerts antifibrotic and anti-inflammatory effects in animal models of systemic sclerosis and inflammatory lung disease (ILD). SENSCIS (the Safety and Efficacy of Nintedanib in Systemic Sclerosis trial) investigated the molecule’s use in patients with ILD associated with systemic sclerosis.
Conducted in 32 countries, SENSCIS comprised 576 patients with the disorder, whose sclerosis affected at least 10% of their lungs. They were assigned to 52 weeks of either placebo or 150 mg nintedanib twice weekly. However, patients stayed on their blinded treatment until the last patient enrolled had finished the year of treatment; some patients took the drug for 100 weeks, Dr. Distler said. The primary endpoint was annual rate of decline in the forced vital capacity (FEV). Secondary endpoints included changes of the modified Rodnan skin score and in the total score on the St. George’s Respiratory Questionnaire.
Patients were a mean of 54 years old, with a mean disease duration of about 3 years. About half had diffuse cutaneous systemic sclerosis; the sclerosis was limited in the remainder. The mean extent of lung fibrosis was about 36%. Half were taking mycophenolate at baseline, which was allowed as background treatment, along with up to 10 mg/day of prednisone. Any patient who experienced clinically significant lung function deterioration could receive additional therapy at the investigator’s discretion.
The mean baseline FEV for these patients was 72.5% of predicted value. The mean diffusing capacity of the lungs for carbon monoxide was 53% of expected capacity.
Most patients completed the study (80% of the active group and 89% of the placebo group). The mean drug exposure duration was 10 months in the active group and 11 in the placebo group.
Improvement began early in treatment, with the efficacy curves separating by week 12 and continuing to diverge. After 52 weeks of therapy, the annual rate of change was 41 mL less in the active group than in the placebo group (–54.4 mL vs. –93.3 mL). The mean adjusted absolute change from baseline was –54.6 mL in the active group and –101 mL in the placebo at week 52. Significantly fewer patients taking nintedanib also lost more than 10% of FVC by week 52 (16.7% vs. 18%).
The St. George’s Respiratory Questionnaire score improved about one point in the active group and declined about one point in the placebo group.
Nintedanib was equally effective across a number of subgroups, including those divided by sex, age, and race. Antitopoisomerase antibodies and so-called antitopoisomerase I antibody status did not affect nintedanib’s action. Nintedanib also significantly improved scores on the Health Assessment Questionnaire without Disability Index and dyspnea.
More patients in the active group than in on placebo discontinued treatment because of a serious adverse event (16% vs. 8.7%). The most common of these were diarrhea (75.7% vs. 31%), nausea (31.6% vs. 13.5%), and vomiting (24.7% vs.10.4%). Skin ulcers occurred in about 18% of each group. Patients in the active group were significantly more likely to develop elevated alanine and aspartate aminotransferase of up to three times normal levels (4.9% vs. 0.7%).
Treatment did not significantly affect mortality rates, however. Over the treatment period, 10 patients in the nintedanib group and 9 in the placebo group died (3.5% vs. 3.1%).
The study was sponsored by Boehringer Ingelheim. Dr. Distler was the primary investigator on the trial.
SOURCE: Distler O et al. ATS 2019, Abstract A7360.
DALLAS – Nintedanib, a tyrosine kinase inhibitor, decreased by 44% the annual rate of lung function decline among patients with interstitial lung disease associated with systemic sclerosis, a year-long study has found.
In a placebo-controlled 52-week trial, forced vital capacity (FVC) in patients who took nintedanib (Ofev) declined by a mean of 52 mL – significantly less than the mean 93 mL decline seen among those who were given placebo, Oliver Distler, MD, said at the annual meeting of the American Thoracic Society.
“These are people in their mid-40s and -50s,” said Dr. Distler of the University of Zürich. “They have a long time to go. If there is an annual preservation of lung function by 40%, if you have that every year, it becomes very surely clinically significant. A decline in FVC is also a good surrogate marker of mortality in interstitial lung disease associated with systemic sclerosis. Assuming the effects are ongoing above the 1 year we looked at, then indeed these results are clinically important.”
The study was simultaneously published in the New England Journal of Medicine. Nintedanib is already approved for idiopathic pulmonary fibrosis. But some data suggest that it also exerts antifibrotic and anti-inflammatory effects in animal models of systemic sclerosis and inflammatory lung disease (ILD). SENSCIS (the Safety and Efficacy of Nintedanib in Systemic Sclerosis trial) investigated the molecule’s use in patients with ILD associated with systemic sclerosis.
Conducted in 32 countries, SENSCIS comprised 576 patients with the disorder, whose sclerosis affected at least 10% of their lungs. They were assigned to 52 weeks of either placebo or 150 mg nintedanib twice weekly. However, patients stayed on their blinded treatment until the last patient enrolled had finished the year of treatment; some patients took the drug for 100 weeks, Dr. Distler said. The primary endpoint was annual rate of decline in the forced vital capacity (FEV). Secondary endpoints included changes of the modified Rodnan skin score and in the total score on the St. George’s Respiratory Questionnaire.
Patients were a mean of 54 years old, with a mean disease duration of about 3 years. About half had diffuse cutaneous systemic sclerosis; the sclerosis was limited in the remainder. The mean extent of lung fibrosis was about 36%. Half were taking mycophenolate at baseline, which was allowed as background treatment, along with up to 10 mg/day of prednisone. Any patient who experienced clinically significant lung function deterioration could receive additional therapy at the investigator’s discretion.
The mean baseline FEV for these patients was 72.5% of predicted value. The mean diffusing capacity of the lungs for carbon monoxide was 53% of expected capacity.
Most patients completed the study (80% of the active group and 89% of the placebo group). The mean drug exposure duration was 10 months in the active group and 11 in the placebo group.
Improvement began early in treatment, with the efficacy curves separating by week 12 and continuing to diverge. After 52 weeks of therapy, the annual rate of change was 41 mL less in the active group than in the placebo group (–54.4 mL vs. –93.3 mL). The mean adjusted absolute change from baseline was –54.6 mL in the active group and –101 mL in the placebo at week 52. Significantly fewer patients taking nintedanib also lost more than 10% of FVC by week 52 (16.7% vs. 18%).
The St. George’s Respiratory Questionnaire score improved about one point in the active group and declined about one point in the placebo group.
Nintedanib was equally effective across a number of subgroups, including those divided by sex, age, and race. Antitopoisomerase antibodies and so-called antitopoisomerase I antibody status did not affect nintedanib’s action. Nintedanib also significantly improved scores on the Health Assessment Questionnaire without Disability Index and dyspnea.
More patients in the active group than in on placebo discontinued treatment because of a serious adverse event (16% vs. 8.7%). The most common of these were diarrhea (75.7% vs. 31%), nausea (31.6% vs. 13.5%), and vomiting (24.7% vs.10.4%). Skin ulcers occurred in about 18% of each group. Patients in the active group were significantly more likely to develop elevated alanine and aspartate aminotransferase of up to three times normal levels (4.9% vs. 0.7%).
Treatment did not significantly affect mortality rates, however. Over the treatment period, 10 patients in the nintedanib group and 9 in the placebo group died (3.5% vs. 3.1%).
The study was sponsored by Boehringer Ingelheim. Dr. Distler was the primary investigator on the trial.
SOURCE: Distler O et al. ATS 2019, Abstract A7360.
AT ATS 2019
Key clinical point: The tyrosine kinase inhibitor nintedanib may be a useful treatment for interstitial lung disease associated with systemic sclerosis (SS-ILD).
Major finding: Nintedanib decreased the annual rate of lung function decline by 44% among patients with SS-ILD.
Study details: The randomized, placebo-controlled study comprised 576 patients.
Disclosures: The trial was sponsored by Boehringer Ingelheim. Dr. Distler is the primary investigator.
Source: Distler O et al. ATS 2019, Abstract A7360.
Significant increase in low-attenuation coronary plaques found in lupus
SAN FRANCISCO – according to an investigation from Johns Hopkins University, Baltimore.
All of the 102 lupus patients in the coronary artery CT angiography study also had positive plaque remodeling, meaning that at least one low-attenuation plaque was growing into the lumen wall, not the lumen itself, which makes them difficult to detect on standard imaging. Low-attenuation plaques were defined in the study as a plaque larger than 1 mm2 with a radiodensity below 30 Hounsfield units.
Low-attenuation plaques are inherently unstable; they’re fatty, necrotic, and have a high risk of rupturing; their presence in the lumen wall is especially worrisome. In the general population, they sometimes regress, scarring down over time and no longer posing a threat. That didn’t happen in the 30 lupus patients who had follow-up CT angiographies, some 9 years after their first.
The team conducted the study to help understand why cardiovascular disease is so common in lupus, and the leading cause of death. Hopkins investigators have shown previously that statins have no effect on the risk or plaque occurrence and progression, and the cardiovascular risk doesn’t always seem to correlate with disease control. For those and other reasons, the current thinking at Hopkins is that cardiovascular disease in lupus is somehow different than in the general population, said George Stojan, MD, an assistant professor of rheumatology at the school and codirector of the Hopkins Lupus Center.
The goal is “to figure out exactly what to look for when we assess the risk; I don’t think we understand that at this point. We assume patients with lupus behave exactly like patients who don’t have lupus, but they obviously don’t. They do not respond to statins. They have a higher risk no matter what you do for them, even when their disease activity is low, and how much plaque they have over time doesn’t really correlate with disease activity,” he said at an international conference on systemic lupus erythematosus.
“Once we understand” the mechanism, “then we can try to [alter] it. Maybe we can look at new drugs, like the PCSK9 inhibitors which have shown a lot of promise in the general population.” At this point, however, “we don’t really know how to intervene,” Dr. Stojan said.
In the meantime, positive remodeling and low-attenuation, noncalcified plaques (LANCPs) might be something to look for when assessing systemic lupus erythematosus cardiovascular risk. “A simple coronary calcium score, something that all doctors do,” is not enough in lupus, nor is simply checking for lumen obstruction. Also, it’s important not to be misled by an overall reduction in noncalcified plaques. “Low-attenuation, noncalcified plaques don’t [regress] over time in lupus, and they are the ones that lead to cardiovascular events,” he said.
The CT angiography findings were compared with findings in 100 healthy controls who had two CT angiograms in a University of California, Los Angeles, cohort. Overall, there was a mean of 458 LANCPs among lupus patients, versus 42 among controls, a more than 900% difference (P less than .001).
Women with lupus aged under 44 years had a mean of 63 LANCPs; none were detected in healthy women under 44 years. Among women aged 45-59 years, there was a mean of 451 LANCPs in the lupus group versus 53 in the control arm. The findings were highly statistically significant, and almost statistically significant for women 60 years or older, 695 lesions among lupus patients versus 22 (P = .0576).
There were only nine men with lupus in the study, but the findings were similar versus male controls.
While mean LANCP volume regressed over time in the control group (mean, –6.90 mm3; P = .0002), a mean regression of –13.56 mm3 in the lupus group was not statistically significant (P = .4570).
Both controls and lupus patients had a positive remodeling index. It progressed in the lupus group over time, and regressed in controls, but the findings were not statistically significant.
“Statins did nothing for the lupus patients. They didn’t affect progress of coronary plaques at all. We still treat patients because theoretically we don’t have anything better, but we know that they don’t really work in this population,” Dr. Stojan said
The work is funded by the National Institutes of Health. Dr. Stojan didn’t report any relevant disclosures.
SOURCE: Stojan G et al. Lupus Sci Med. 2019;6[suppl 1]:A200, Abstract 274.
SAN FRANCISCO – according to an investigation from Johns Hopkins University, Baltimore.
All of the 102 lupus patients in the coronary artery CT angiography study also had positive plaque remodeling, meaning that at least one low-attenuation plaque was growing into the lumen wall, not the lumen itself, which makes them difficult to detect on standard imaging. Low-attenuation plaques were defined in the study as a plaque larger than 1 mm2 with a radiodensity below 30 Hounsfield units.
Low-attenuation plaques are inherently unstable; they’re fatty, necrotic, and have a high risk of rupturing; their presence in the lumen wall is especially worrisome. In the general population, they sometimes regress, scarring down over time and no longer posing a threat. That didn’t happen in the 30 lupus patients who had follow-up CT angiographies, some 9 years after their first.
The team conducted the study to help understand why cardiovascular disease is so common in lupus, and the leading cause of death. Hopkins investigators have shown previously that statins have no effect on the risk or plaque occurrence and progression, and the cardiovascular risk doesn’t always seem to correlate with disease control. For those and other reasons, the current thinking at Hopkins is that cardiovascular disease in lupus is somehow different than in the general population, said George Stojan, MD, an assistant professor of rheumatology at the school and codirector of the Hopkins Lupus Center.
The goal is “to figure out exactly what to look for when we assess the risk; I don’t think we understand that at this point. We assume patients with lupus behave exactly like patients who don’t have lupus, but they obviously don’t. They do not respond to statins. They have a higher risk no matter what you do for them, even when their disease activity is low, and how much plaque they have over time doesn’t really correlate with disease activity,” he said at an international conference on systemic lupus erythematosus.
“Once we understand” the mechanism, “then we can try to [alter] it. Maybe we can look at new drugs, like the PCSK9 inhibitors which have shown a lot of promise in the general population.” At this point, however, “we don’t really know how to intervene,” Dr. Stojan said.
In the meantime, positive remodeling and low-attenuation, noncalcified plaques (LANCPs) might be something to look for when assessing systemic lupus erythematosus cardiovascular risk. “A simple coronary calcium score, something that all doctors do,” is not enough in lupus, nor is simply checking for lumen obstruction. Also, it’s important not to be misled by an overall reduction in noncalcified plaques. “Low-attenuation, noncalcified plaques don’t [regress] over time in lupus, and they are the ones that lead to cardiovascular events,” he said.
The CT angiography findings were compared with findings in 100 healthy controls who had two CT angiograms in a University of California, Los Angeles, cohort. Overall, there was a mean of 458 LANCPs among lupus patients, versus 42 among controls, a more than 900% difference (P less than .001).
Women with lupus aged under 44 years had a mean of 63 LANCPs; none were detected in healthy women under 44 years. Among women aged 45-59 years, there was a mean of 451 LANCPs in the lupus group versus 53 in the control arm. The findings were highly statistically significant, and almost statistically significant for women 60 years or older, 695 lesions among lupus patients versus 22 (P = .0576).
There were only nine men with lupus in the study, but the findings were similar versus male controls.
While mean LANCP volume regressed over time in the control group (mean, –6.90 mm3; P = .0002), a mean regression of –13.56 mm3 in the lupus group was not statistically significant (P = .4570).
Both controls and lupus patients had a positive remodeling index. It progressed in the lupus group over time, and regressed in controls, but the findings were not statistically significant.
“Statins did nothing for the lupus patients. They didn’t affect progress of coronary plaques at all. We still treat patients because theoretically we don’t have anything better, but we know that they don’t really work in this population,” Dr. Stojan said
The work is funded by the National Institutes of Health. Dr. Stojan didn’t report any relevant disclosures.
SOURCE: Stojan G et al. Lupus Sci Med. 2019;6[suppl 1]:A200, Abstract 274.
SAN FRANCISCO – according to an investigation from Johns Hopkins University, Baltimore.
All of the 102 lupus patients in the coronary artery CT angiography study also had positive plaque remodeling, meaning that at least one low-attenuation plaque was growing into the lumen wall, not the lumen itself, which makes them difficult to detect on standard imaging. Low-attenuation plaques were defined in the study as a plaque larger than 1 mm2 with a radiodensity below 30 Hounsfield units.
Low-attenuation plaques are inherently unstable; they’re fatty, necrotic, and have a high risk of rupturing; their presence in the lumen wall is especially worrisome. In the general population, they sometimes regress, scarring down over time and no longer posing a threat. That didn’t happen in the 30 lupus patients who had follow-up CT angiographies, some 9 years after their first.
The team conducted the study to help understand why cardiovascular disease is so common in lupus, and the leading cause of death. Hopkins investigators have shown previously that statins have no effect on the risk or plaque occurrence and progression, and the cardiovascular risk doesn’t always seem to correlate with disease control. For those and other reasons, the current thinking at Hopkins is that cardiovascular disease in lupus is somehow different than in the general population, said George Stojan, MD, an assistant professor of rheumatology at the school and codirector of the Hopkins Lupus Center.
The goal is “to figure out exactly what to look for when we assess the risk; I don’t think we understand that at this point. We assume patients with lupus behave exactly like patients who don’t have lupus, but they obviously don’t. They do not respond to statins. They have a higher risk no matter what you do for them, even when their disease activity is low, and how much plaque they have over time doesn’t really correlate with disease activity,” he said at an international conference on systemic lupus erythematosus.
“Once we understand” the mechanism, “then we can try to [alter] it. Maybe we can look at new drugs, like the PCSK9 inhibitors which have shown a lot of promise in the general population.” At this point, however, “we don’t really know how to intervene,” Dr. Stojan said.
In the meantime, positive remodeling and low-attenuation, noncalcified plaques (LANCPs) might be something to look for when assessing systemic lupus erythematosus cardiovascular risk. “A simple coronary calcium score, something that all doctors do,” is not enough in lupus, nor is simply checking for lumen obstruction. Also, it’s important not to be misled by an overall reduction in noncalcified plaques. “Low-attenuation, noncalcified plaques don’t [regress] over time in lupus, and they are the ones that lead to cardiovascular events,” he said.
The CT angiography findings were compared with findings in 100 healthy controls who had two CT angiograms in a University of California, Los Angeles, cohort. Overall, there was a mean of 458 LANCPs among lupus patients, versus 42 among controls, a more than 900% difference (P less than .001).
Women with lupus aged under 44 years had a mean of 63 LANCPs; none were detected in healthy women under 44 years. Among women aged 45-59 years, there was a mean of 451 LANCPs in the lupus group versus 53 in the control arm. The findings were highly statistically significant, and almost statistically significant for women 60 years or older, 695 lesions among lupus patients versus 22 (P = .0576).
There were only nine men with lupus in the study, but the findings were similar versus male controls.
While mean LANCP volume regressed over time in the control group (mean, –6.90 mm3; P = .0002), a mean regression of –13.56 mm3 in the lupus group was not statistically significant (P = .4570).
Both controls and lupus patients had a positive remodeling index. It progressed in the lupus group over time, and regressed in controls, but the findings were not statistically significant.
“Statins did nothing for the lupus patients. They didn’t affect progress of coronary plaques at all. We still treat patients because theoretically we don’t have anything better, but we know that they don’t really work in this population,” Dr. Stojan said
The work is funded by the National Institutes of Health. Dr. Stojan didn’t report any relevant disclosures.
SOURCE: Stojan G et al. Lupus Sci Med. 2019;6[suppl 1]:A200, Abstract 274.
REPORTING FROM LUPUS 2019
Key clinical point: Positive remodeling and low-attenuation, noncalcified plaques might be something to look for when assessing systemic lupus erythematosus cardiovascular risk.
Major finding: There was a mean of 458 low-attenuation, noncalcified plaques among lupus patients versus 42 among controls, a more than 900% difference (P less than .001)
Study details: Coronary CT angiography in 102 lupus patients and 100 healthy controls
Disclosures: The National Institutes of Health funded the work. The lead investigator didn’t report any relevant disclosures.
Source: Stojan G et al. Lupus Sci Med. 2019;6[suppl 1]:A200, Abstract 274.
Walk-in ultrasound helps to avoid unnecessary steroids for giant cell arteritis
BIRMINGHAM, England – More than half of all patients referred to a fast-track giant cell arteritis (GCA) clinic that offers a walk-in ultrasonography service avoided use of glucocorticoids, according to a report given at the annual conference of the British Society for Rheumatology.
The clinic, an initiative run by the University Hospital Coventry and Warwickshire (UHCW) NHS Trust for the past 6 years, provides same-day diagnosis and treatment for suspected GCA.
“Walk-in ultrasound helps to avoid steroids completely in a significant proportion of patients,” said study author and presenter Shirish Dubey, MBBS, a consultant rheumatologist at the UHCW NHS Trust. Of 652 patients seen at the UHCW GCA fast-track clinic between 2014 and 2017, 143 (22%) were diagnosed with GCA. Over 400 had not been exposed to glucocorticoids and 369 (57%) were able to avoid unnecessary glucocorticoid use in the cohort, Dr. Dubey reported.
The old NHS paradigm for managing patients with suspected GCA was that when they presented to their primary care physicians, they would be started on immediate glucocorticoid therapy while waiting for an urgent specialist referral. However, that referral could take anywhere from a couple of days to a couple of weeks to happen, Dr. Dubey explained. Patients would then undergo possible temporal artery biopsy (TAB) and only then, following confirmation of a GCA diagnosis, would a management plan be agreed upon.
UCHW introduced its fast-track pathway for the diagnosis of GCA in mid-2013. The pathway called for patients with suspected GCA aged 50 years or older who had two or more features present, such as an abrupt, new-onset headache or facial pain, scalp pain and tenderness, jaw claudication, or visual symptoms. Primary care physicians could make urgent referrals to the service via an on-call rheumatology trainee or ophthalmology senior house officer.
“Patients are normally steroid-naive and seen on the same day,” Dr. Dubey said. Doppler ultrasound of the temporal artery results in around 80% of diagnoses, with TAB still needed in some cases.
One of the downsides of the fast-track process perhaps is the increasing number of referrals. “One thing we find is that we have become a glorified headache service,” Dr. Dubey said. However, many patients do not have GCA and, when there is a low clinical probability and the ultrasound is negative, the patient is usually reassured and discharged with no need for glucocorticoids. Although the number of referrals have increased – 98 patients in 2014, 154 in 2015, 123 in 2016, and 277 in 2017 – the number of those diagnosed with GCA has remained around the same.
To see how ultrasound was faring in real-life practice, the UHCW NHS Trust team compared Doppler ultrasound findings against the final clinical diagnosis for the period 2014 to 2017. A sensitivity of just under 48% and specificity of 98% was recorded. The positive and negative predictive values were 87% and 88%, respectively.
The specificity of ultrasound was lower than that reported previously in the literature, the UHCW NHS Trust team pointed out in its abstract, but it does compare similarly with other real-world studies. The use of glucocorticoids affected the ultrasound results, with better sensitivity (55%) when these drugs were not used prior to the scan.
The use of TAB versus a clinical diagnosis in 100 patients seen over the same time period showed it had a sensitivity of 37% and a specificity of 100%, with positive and negative predictive values of 100% and 62%. The sensitivity of TAB is again low, Dr. Dubey said, but that could be because TAB is performed only when the diagnosis is uncertain.
This was an unselected cohort of patients, but overall there were good positive and negative predictive values. The UHCW NHS Trust team suggested that ultrasound can assist and reassure clinicians trying to diagnose or exclude GCA in their patients.
Regular multidisciplinary team meetings including rheumatology, ophthalmology, and vascular Doppler physiologists are key to the fast-track service, Dr. Dubey pointed out.
Despite the shortcomings of the retrospective study, Dr. Dubey stressed that the team was confident that none of the patients who had been ruled out as having GCA were subsequently diagnosed as having GCA.
Importantly, he said, the use of ultrasound had made a big difference in cost; the group plans to formally evaluate costs of ultrasound versus TAB.
The study received no commercial funding. Dr. Dubey had no conflicts of interest to disclose.
SOURCE: Pinnell J et al. Rheumatology. 2019;58(suppl 3):Abstract 038.
BIRMINGHAM, England – More than half of all patients referred to a fast-track giant cell arteritis (GCA) clinic that offers a walk-in ultrasonography service avoided use of glucocorticoids, according to a report given at the annual conference of the British Society for Rheumatology.
The clinic, an initiative run by the University Hospital Coventry and Warwickshire (UHCW) NHS Trust for the past 6 years, provides same-day diagnosis and treatment for suspected GCA.
“Walk-in ultrasound helps to avoid steroids completely in a significant proportion of patients,” said study author and presenter Shirish Dubey, MBBS, a consultant rheumatologist at the UHCW NHS Trust. Of 652 patients seen at the UHCW GCA fast-track clinic between 2014 and 2017, 143 (22%) were diagnosed with GCA. Over 400 had not been exposed to glucocorticoids and 369 (57%) were able to avoid unnecessary glucocorticoid use in the cohort, Dr. Dubey reported.
The old NHS paradigm for managing patients with suspected GCA was that when they presented to their primary care physicians, they would be started on immediate glucocorticoid therapy while waiting for an urgent specialist referral. However, that referral could take anywhere from a couple of days to a couple of weeks to happen, Dr. Dubey explained. Patients would then undergo possible temporal artery biopsy (TAB) and only then, following confirmation of a GCA diagnosis, would a management plan be agreed upon.
UCHW introduced its fast-track pathway for the diagnosis of GCA in mid-2013. The pathway called for patients with suspected GCA aged 50 years or older who had two or more features present, such as an abrupt, new-onset headache or facial pain, scalp pain and tenderness, jaw claudication, or visual symptoms. Primary care physicians could make urgent referrals to the service via an on-call rheumatology trainee or ophthalmology senior house officer.
“Patients are normally steroid-naive and seen on the same day,” Dr. Dubey said. Doppler ultrasound of the temporal artery results in around 80% of diagnoses, with TAB still needed in some cases.
One of the downsides of the fast-track process perhaps is the increasing number of referrals. “One thing we find is that we have become a glorified headache service,” Dr. Dubey said. However, many patients do not have GCA and, when there is a low clinical probability and the ultrasound is negative, the patient is usually reassured and discharged with no need for glucocorticoids. Although the number of referrals have increased – 98 patients in 2014, 154 in 2015, 123 in 2016, and 277 in 2017 – the number of those diagnosed with GCA has remained around the same.
To see how ultrasound was faring in real-life practice, the UHCW NHS Trust team compared Doppler ultrasound findings against the final clinical diagnosis for the period 2014 to 2017. A sensitivity of just under 48% and specificity of 98% was recorded. The positive and negative predictive values were 87% and 88%, respectively.
The specificity of ultrasound was lower than that reported previously in the literature, the UHCW NHS Trust team pointed out in its abstract, but it does compare similarly with other real-world studies. The use of glucocorticoids affected the ultrasound results, with better sensitivity (55%) when these drugs were not used prior to the scan.
The use of TAB versus a clinical diagnosis in 100 patients seen over the same time period showed it had a sensitivity of 37% and a specificity of 100%, with positive and negative predictive values of 100% and 62%. The sensitivity of TAB is again low, Dr. Dubey said, but that could be because TAB is performed only when the diagnosis is uncertain.
This was an unselected cohort of patients, but overall there were good positive and negative predictive values. The UHCW NHS Trust team suggested that ultrasound can assist and reassure clinicians trying to diagnose or exclude GCA in their patients.
Regular multidisciplinary team meetings including rheumatology, ophthalmology, and vascular Doppler physiologists are key to the fast-track service, Dr. Dubey pointed out.
Despite the shortcomings of the retrospective study, Dr. Dubey stressed that the team was confident that none of the patients who had been ruled out as having GCA were subsequently diagnosed as having GCA.
Importantly, he said, the use of ultrasound had made a big difference in cost; the group plans to formally evaluate costs of ultrasound versus TAB.
The study received no commercial funding. Dr. Dubey had no conflicts of interest to disclose.
SOURCE: Pinnell J et al. Rheumatology. 2019;58(suppl 3):Abstract 038.
BIRMINGHAM, England – More than half of all patients referred to a fast-track giant cell arteritis (GCA) clinic that offers a walk-in ultrasonography service avoided use of glucocorticoids, according to a report given at the annual conference of the British Society for Rheumatology.
The clinic, an initiative run by the University Hospital Coventry and Warwickshire (UHCW) NHS Trust for the past 6 years, provides same-day diagnosis and treatment for suspected GCA.
“Walk-in ultrasound helps to avoid steroids completely in a significant proportion of patients,” said study author and presenter Shirish Dubey, MBBS, a consultant rheumatologist at the UHCW NHS Trust. Of 652 patients seen at the UHCW GCA fast-track clinic between 2014 and 2017, 143 (22%) were diagnosed with GCA. Over 400 had not been exposed to glucocorticoids and 369 (57%) were able to avoid unnecessary glucocorticoid use in the cohort, Dr. Dubey reported.
The old NHS paradigm for managing patients with suspected GCA was that when they presented to their primary care physicians, they would be started on immediate glucocorticoid therapy while waiting for an urgent specialist referral. However, that referral could take anywhere from a couple of days to a couple of weeks to happen, Dr. Dubey explained. Patients would then undergo possible temporal artery biopsy (TAB) and only then, following confirmation of a GCA diagnosis, would a management plan be agreed upon.
UCHW introduced its fast-track pathway for the diagnosis of GCA in mid-2013. The pathway called for patients with suspected GCA aged 50 years or older who had two or more features present, such as an abrupt, new-onset headache or facial pain, scalp pain and tenderness, jaw claudication, or visual symptoms. Primary care physicians could make urgent referrals to the service via an on-call rheumatology trainee or ophthalmology senior house officer.
“Patients are normally steroid-naive and seen on the same day,” Dr. Dubey said. Doppler ultrasound of the temporal artery results in around 80% of diagnoses, with TAB still needed in some cases.
One of the downsides of the fast-track process perhaps is the increasing number of referrals. “One thing we find is that we have become a glorified headache service,” Dr. Dubey said. However, many patients do not have GCA and, when there is a low clinical probability and the ultrasound is negative, the patient is usually reassured and discharged with no need for glucocorticoids. Although the number of referrals have increased – 98 patients in 2014, 154 in 2015, 123 in 2016, and 277 in 2017 – the number of those diagnosed with GCA has remained around the same.
To see how ultrasound was faring in real-life practice, the UHCW NHS Trust team compared Doppler ultrasound findings against the final clinical diagnosis for the period 2014 to 2017. A sensitivity of just under 48% and specificity of 98% was recorded. The positive and negative predictive values were 87% and 88%, respectively.
The specificity of ultrasound was lower than that reported previously in the literature, the UHCW NHS Trust team pointed out in its abstract, but it does compare similarly with other real-world studies. The use of glucocorticoids affected the ultrasound results, with better sensitivity (55%) when these drugs were not used prior to the scan.
The use of TAB versus a clinical diagnosis in 100 patients seen over the same time period showed it had a sensitivity of 37% and a specificity of 100%, with positive and negative predictive values of 100% and 62%. The sensitivity of TAB is again low, Dr. Dubey said, but that could be because TAB is performed only when the diagnosis is uncertain.
This was an unselected cohort of patients, but overall there were good positive and negative predictive values. The UHCW NHS Trust team suggested that ultrasound can assist and reassure clinicians trying to diagnose or exclude GCA in their patients.
Regular multidisciplinary team meetings including rheumatology, ophthalmology, and vascular Doppler physiologists are key to the fast-track service, Dr. Dubey pointed out.
Despite the shortcomings of the retrospective study, Dr. Dubey stressed that the team was confident that none of the patients who had been ruled out as having GCA were subsequently diagnosed as having GCA.
Importantly, he said, the use of ultrasound had made a big difference in cost; the group plans to formally evaluate costs of ultrasound versus TAB.
The study received no commercial funding. Dr. Dubey had no conflicts of interest to disclose.
SOURCE: Pinnell J et al. Rheumatology. 2019;58(suppl 3):Abstract 038.
REPORTING FROM BSR 2019
Intradermal etanercept improves discoid lupus
BIRMINGHAM, ENGLAND – Intradermal delivery of a tumor necrosis factor inhibitor (TNFi) could offer patients with discoid lupus erythematosus (DLE) a much-needed additional treatment option, according to results of a phase 2, “proof-of-concept” study.
Overall, 14 (56%) of the 25 patients in the study achieved a 20% or greater reduction in disease activity from baseline to week 12 via intradermal injection of etanercept (Enbrel), which was assessed via the modified limited Score of Activity and Damage in DLE (ML-SADDLE). About half (48%) and one-fifth (20%) also achieved greater reductions of 50% and 70%, respectively.
“Discoid lupus is a chronic form of cutaneous lupus. Usually it occurs in visible areas like the face and scalp, causing scarring, so it’s really disabling and affects patients’ quality of life,” observed the lead study investigator Md Yuzaiful Md Yusof, MBChB, PhD, NIHR Academic Clinical Lecturer at the University of Leeds, England.
“It’s also one of the most resistant manifestations of lupus,” he said during a poster presentation at the annual conference of the British Society for Rheumatology. “Usually, when people have discoid lupus, the dermatologist gives antimalarial treatment, but only 50% of people respond to these drugs. So, what happens to the rest of them?” Basically, it is trial and error, Dr. Md Yusof said; some patients may be given disease-modifying antirheumatic drugs and in some patients this may work well, but in others there may be toxicity that contraindicates treatment.
B-cell therapy with rituximab (Rituxan) has not been successful, he said. In a previous study of 35 patients with refractory discoid lupus, none of the patients responded to rituximab and half of them actually flared after taking the drug.
There is a pathologic case for using anti-TNF therapy in DLE, but the use of TNFis is not without concern. Such treatment can increase antinuclear antibody production and make lupus worse. “In order to overcome this, as the lesion is quite small, we don’t need to use a systemic approach,” Dr. Md Yusof explained in an interview. “If you give directly, it should just be confined to the lesion and not absorbed, that’s the whole idea of thinking outside the box.” He noted that if it worked, such treatment would be for inducing remission and not for maintenance.
The study, “Targeted therapy using intradermal injection of etanercept for remission induction in discoid lupus erythematosus” (TARGET-DLE) was designed to test the validity of using intradermal rather than subcutaneous TNFi therapy in patients with discoid lupus.
Dr. Md Yusof noted that only 25 patients needed to be recruited into the single-arm, prospective trial as a “Simon’s two-stage minimized design” was used (Control Clin Trials. 1989;10[1]:1-10). This involved treating the first few patients to see if a response occurred and if it did, carrying on with treating the others, but if no response occurred in at least two patients, the trial would stop completely.
Adult patients were eligible for inclusion if they had one or more active DLE lesions and had not responded to antimalarial treatment. Stable doses of DMARDs and up to 10 mg of oral prednisolone daily was permitted if already being taken prior to entering the study.
Etanercept was injected intradermally around the most symptomatic lesion once a week for up to 12 weeks. The dosage was determined based on the radius of the selected discoid lesion. Over an 18-month period, all 25 patients were recruited, including 18 women. The median age of patients was 47 years, and six had systemic lupus erythematosus. The median number of prior DMARDs was 5 but ranged from 1 to 16, indicating a very resistant patient population.
The primary endpoint was at least 6 of the 25 patients having at least a 20% reduction in ML-SADDLE at week 12; 14 (56%) patients achieved this.
“We didn’t use CLASI [Cutaneous Lupus Area and Severity Index Activity Score] because that only includes erythema and atrophy,” Dr. Md Yusof explained. “In discoid lupus, induration is quite important as well, so that’s why we used ML-SADDLE. We called it ‘modified limited’ because the original SADDLE score is based on the whole organ score, but we only calculated the one lesion that we wanted to treat.”
In addition to meeting the primary endpoint, several secondary endpoints were met, including significant improvements in scores on visual analog scales as determined by pre- and posttreatment scoring by physicians (53.1 mm vs. 23.2 mm; P less than .001) and patients (56.9 mm vs. 29.7 mm; P = .001). Mean Dermatology Life Quality Index (DLQI) score significantly improved between pre- and post treatment, as did blood perfusion under the skin based on laser Doppler imaging and infrared thermography. However, no difference was seen with optical coherence tomography.
“There were only four grade 3/4 toxicities, and importantly, none of the SLE patients got worse, and none with DLE only converted into SLE,” Dr. Md Yusof reported. Of the four grade 3/4 adverse events, two were chest infections, one was heart failure, and one was a worsening of chilblains.
“It was a full-powered phase 2 trial, and because it was positive, now we can go to phase 3 trial,” he added.
Before conducting a phase 3 trial, however, Dr. Md Yusof wants to refine how the TNFi is delivered. Perhaps an intradermal patch with microneedles could be used. This would be left on the skin for a short amount of time to allow drug delivery and then removed. It could help ensure that all patients comply with treatment and perhaps even self-administer, he noted.
“The median compliance rate was 80%, which is not too bad, but I think when we come to run a phase 3 trial, I’m looking to improve the drug delivery,” he said. Changing the delivery method will need to be validated before a phase 3 trial can be started.
The study was not commercially funded. Dr. Md Yusof had no disclosures. Pfizer provided the study drug free of charge.
SOURCE: Md Yusof MY et al. Rheumatology. 2019;58(suppl 3): Abstract 244. doi: 10.1093/rheumatology/kez107.060.
BIRMINGHAM, ENGLAND – Intradermal delivery of a tumor necrosis factor inhibitor (TNFi) could offer patients with discoid lupus erythematosus (DLE) a much-needed additional treatment option, according to results of a phase 2, “proof-of-concept” study.
Overall, 14 (56%) of the 25 patients in the study achieved a 20% or greater reduction in disease activity from baseline to week 12 via intradermal injection of etanercept (Enbrel), which was assessed via the modified limited Score of Activity and Damage in DLE (ML-SADDLE). About half (48%) and one-fifth (20%) also achieved greater reductions of 50% and 70%, respectively.
“Discoid lupus is a chronic form of cutaneous lupus. Usually it occurs in visible areas like the face and scalp, causing scarring, so it’s really disabling and affects patients’ quality of life,” observed the lead study investigator Md Yuzaiful Md Yusof, MBChB, PhD, NIHR Academic Clinical Lecturer at the University of Leeds, England.
“It’s also one of the most resistant manifestations of lupus,” he said during a poster presentation at the annual conference of the British Society for Rheumatology. “Usually, when people have discoid lupus, the dermatologist gives antimalarial treatment, but only 50% of people respond to these drugs. So, what happens to the rest of them?” Basically, it is trial and error, Dr. Md Yusof said; some patients may be given disease-modifying antirheumatic drugs and in some patients this may work well, but in others there may be toxicity that contraindicates treatment.
B-cell therapy with rituximab (Rituxan) has not been successful, he said. In a previous study of 35 patients with refractory discoid lupus, none of the patients responded to rituximab and half of them actually flared after taking the drug.
There is a pathologic case for using anti-TNF therapy in DLE, but the use of TNFis is not without concern. Such treatment can increase antinuclear antibody production and make lupus worse. “In order to overcome this, as the lesion is quite small, we don’t need to use a systemic approach,” Dr. Md Yusof explained in an interview. “If you give directly, it should just be confined to the lesion and not absorbed, that’s the whole idea of thinking outside the box.” He noted that if it worked, such treatment would be for inducing remission and not for maintenance.
The study, “Targeted therapy using intradermal injection of etanercept for remission induction in discoid lupus erythematosus” (TARGET-DLE) was designed to test the validity of using intradermal rather than subcutaneous TNFi therapy in patients with discoid lupus.
Dr. Md Yusof noted that only 25 patients needed to be recruited into the single-arm, prospective trial as a “Simon’s two-stage minimized design” was used (Control Clin Trials. 1989;10[1]:1-10). This involved treating the first few patients to see if a response occurred and if it did, carrying on with treating the others, but if no response occurred in at least two patients, the trial would stop completely.
Adult patients were eligible for inclusion if they had one or more active DLE lesions and had not responded to antimalarial treatment. Stable doses of DMARDs and up to 10 mg of oral prednisolone daily was permitted if already being taken prior to entering the study.
Etanercept was injected intradermally around the most symptomatic lesion once a week for up to 12 weeks. The dosage was determined based on the radius of the selected discoid lesion. Over an 18-month period, all 25 patients were recruited, including 18 women. The median age of patients was 47 years, and six had systemic lupus erythematosus. The median number of prior DMARDs was 5 but ranged from 1 to 16, indicating a very resistant patient population.
The primary endpoint was at least 6 of the 25 patients having at least a 20% reduction in ML-SADDLE at week 12; 14 (56%) patients achieved this.
“We didn’t use CLASI [Cutaneous Lupus Area and Severity Index Activity Score] because that only includes erythema and atrophy,” Dr. Md Yusof explained. “In discoid lupus, induration is quite important as well, so that’s why we used ML-SADDLE. We called it ‘modified limited’ because the original SADDLE score is based on the whole organ score, but we only calculated the one lesion that we wanted to treat.”
In addition to meeting the primary endpoint, several secondary endpoints were met, including significant improvements in scores on visual analog scales as determined by pre- and posttreatment scoring by physicians (53.1 mm vs. 23.2 mm; P less than .001) and patients (56.9 mm vs. 29.7 mm; P = .001). Mean Dermatology Life Quality Index (DLQI) score significantly improved between pre- and post treatment, as did blood perfusion under the skin based on laser Doppler imaging and infrared thermography. However, no difference was seen with optical coherence tomography.
“There were only four grade 3/4 toxicities, and importantly, none of the SLE patients got worse, and none with DLE only converted into SLE,” Dr. Md Yusof reported. Of the four grade 3/4 adverse events, two were chest infections, one was heart failure, and one was a worsening of chilblains.
“It was a full-powered phase 2 trial, and because it was positive, now we can go to phase 3 trial,” he added.
Before conducting a phase 3 trial, however, Dr. Md Yusof wants to refine how the TNFi is delivered. Perhaps an intradermal patch with microneedles could be used. This would be left on the skin for a short amount of time to allow drug delivery and then removed. It could help ensure that all patients comply with treatment and perhaps even self-administer, he noted.
“The median compliance rate was 80%, which is not too bad, but I think when we come to run a phase 3 trial, I’m looking to improve the drug delivery,” he said. Changing the delivery method will need to be validated before a phase 3 trial can be started.
The study was not commercially funded. Dr. Md Yusof had no disclosures. Pfizer provided the study drug free of charge.
SOURCE: Md Yusof MY et al. Rheumatology. 2019;58(suppl 3): Abstract 244. doi: 10.1093/rheumatology/kez107.060.
BIRMINGHAM, ENGLAND – Intradermal delivery of a tumor necrosis factor inhibitor (TNFi) could offer patients with discoid lupus erythematosus (DLE) a much-needed additional treatment option, according to results of a phase 2, “proof-of-concept” study.
Overall, 14 (56%) of the 25 patients in the study achieved a 20% or greater reduction in disease activity from baseline to week 12 via intradermal injection of etanercept (Enbrel), which was assessed via the modified limited Score of Activity and Damage in DLE (ML-SADDLE). About half (48%) and one-fifth (20%) also achieved greater reductions of 50% and 70%, respectively.
“Discoid lupus is a chronic form of cutaneous lupus. Usually it occurs in visible areas like the face and scalp, causing scarring, so it’s really disabling and affects patients’ quality of life,” observed the lead study investigator Md Yuzaiful Md Yusof, MBChB, PhD, NIHR Academic Clinical Lecturer at the University of Leeds, England.
“It’s also one of the most resistant manifestations of lupus,” he said during a poster presentation at the annual conference of the British Society for Rheumatology. “Usually, when people have discoid lupus, the dermatologist gives antimalarial treatment, but only 50% of people respond to these drugs. So, what happens to the rest of them?” Basically, it is trial and error, Dr. Md Yusof said; some patients may be given disease-modifying antirheumatic drugs and in some patients this may work well, but in others there may be toxicity that contraindicates treatment.
B-cell therapy with rituximab (Rituxan) has not been successful, he said. In a previous study of 35 patients with refractory discoid lupus, none of the patients responded to rituximab and half of them actually flared after taking the drug.
There is a pathologic case for using anti-TNF therapy in DLE, but the use of TNFis is not without concern. Such treatment can increase antinuclear antibody production and make lupus worse. “In order to overcome this, as the lesion is quite small, we don’t need to use a systemic approach,” Dr. Md Yusof explained in an interview. “If you give directly, it should just be confined to the lesion and not absorbed, that’s the whole idea of thinking outside the box.” He noted that if it worked, such treatment would be for inducing remission and not for maintenance.
The study, “Targeted therapy using intradermal injection of etanercept for remission induction in discoid lupus erythematosus” (TARGET-DLE) was designed to test the validity of using intradermal rather than subcutaneous TNFi therapy in patients with discoid lupus.
Dr. Md Yusof noted that only 25 patients needed to be recruited into the single-arm, prospective trial as a “Simon’s two-stage minimized design” was used (Control Clin Trials. 1989;10[1]:1-10). This involved treating the first few patients to see if a response occurred and if it did, carrying on with treating the others, but if no response occurred in at least two patients, the trial would stop completely.
Adult patients were eligible for inclusion if they had one or more active DLE lesions and had not responded to antimalarial treatment. Stable doses of DMARDs and up to 10 mg of oral prednisolone daily was permitted if already being taken prior to entering the study.
Etanercept was injected intradermally around the most symptomatic lesion once a week for up to 12 weeks. The dosage was determined based on the radius of the selected discoid lesion. Over an 18-month period, all 25 patients were recruited, including 18 women. The median age of patients was 47 years, and six had systemic lupus erythematosus. The median number of prior DMARDs was 5 but ranged from 1 to 16, indicating a very resistant patient population.
The primary endpoint was at least 6 of the 25 patients having at least a 20% reduction in ML-SADDLE at week 12; 14 (56%) patients achieved this.
“We didn’t use CLASI [Cutaneous Lupus Area and Severity Index Activity Score] because that only includes erythema and atrophy,” Dr. Md Yusof explained. “In discoid lupus, induration is quite important as well, so that’s why we used ML-SADDLE. We called it ‘modified limited’ because the original SADDLE score is based on the whole organ score, but we only calculated the one lesion that we wanted to treat.”
In addition to meeting the primary endpoint, several secondary endpoints were met, including significant improvements in scores on visual analog scales as determined by pre- and posttreatment scoring by physicians (53.1 mm vs. 23.2 mm; P less than .001) and patients (56.9 mm vs. 29.7 mm; P = .001). Mean Dermatology Life Quality Index (DLQI) score significantly improved between pre- and post treatment, as did blood perfusion under the skin based on laser Doppler imaging and infrared thermography. However, no difference was seen with optical coherence tomography.
“There were only four grade 3/4 toxicities, and importantly, none of the SLE patients got worse, and none with DLE only converted into SLE,” Dr. Md Yusof reported. Of the four grade 3/4 adverse events, two were chest infections, one was heart failure, and one was a worsening of chilblains.
“It was a full-powered phase 2 trial, and because it was positive, now we can go to phase 3 trial,” he added.
Before conducting a phase 3 trial, however, Dr. Md Yusof wants to refine how the TNFi is delivered. Perhaps an intradermal patch with microneedles could be used. This would be left on the skin for a short amount of time to allow drug delivery and then removed. It could help ensure that all patients comply with treatment and perhaps even self-administer, he noted.
“The median compliance rate was 80%, which is not too bad, but I think when we come to run a phase 3 trial, I’m looking to improve the drug delivery,” he said. Changing the delivery method will need to be validated before a phase 3 trial can be started.
The study was not commercially funded. Dr. Md Yusof had no disclosures. Pfizer provided the study drug free of charge.
SOURCE: Md Yusof MY et al. Rheumatology. 2019;58(suppl 3): Abstract 244. doi: 10.1093/rheumatology/kez107.060.
REPORTING FROM BSR 2019