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FDA urged to bring rheumatologists into gadolinium safety discussion
CHICAGO – The Food and Drug Administration’s updated safety warning about gadolinium-based contrast agents was dismissed as too little, too late during a postsession discussion at the annual meeting of the American College of Rheumatology.
The class warning that “gadolinium is retained for months or years in brain, bone, and other organs,” a directive that a new patient medication guide be given to everyone before receiving a gadolinium-based contrast agent, and a request that manufacturers conduct human and animal studies to further assess the safety of these products, was highlighted at the FDA update session on safety issues in the treatment of rheumatic disease.
The request for further studies grew out of the FDA Advisory Committee on Medical Imaging’s Fall 2017 meeting, which concluded that, “based on available data, there is insufficient evidence of a causal relationship between adverse events and gadolinium retention and recommended the need for additional studies to inform regulatory action,” explained Rachel L. Glaser, MD, a medical officer in the agency’s division of pulmonary, allergy, and rheumatology products and a practicing rheumatologist.
Jonathan Kay, MD, rose from the audience to take the FDA to task for delegating matters related to gadolinium-based contrast agent safety to the radiologists comprising the Advisory Committee on Medical Imaging. “I think the FDA ought to bring this matter to a group of physicians who actually care for patients to get our input on this. Maybe the Arthritis Advisory Committee,” he said.
“It’s been known for more than 15 years that gadolinium deposits in the bone, and for more than 5 years that gadolinium deposits in the brain of patients who’ve received multiple magnetic resonance studies. I’m concerned that the FDA has this issue in the purview of the radiologists because radiologists administer these contrast agents and then don’t see the patients back in follow-up, whereas rheumatologists do,” noted Dr. Kay, professor of medicine and director of clinical research in rheumatology at the University of Massachusetts, Worcester.
He blasted the FDA’s call for further human and animal studies, noting “nephrogenic systemic fibrosis was the human experiment that was done with gadolinium contrast, showing that these agents, when they deposit in tissue, are extremely toxic. I can’t see other human studies being done to determine the potential consequences of these agents when they deposit long term in brain, bone, and other tissues. And the animal studies have already been done demonstrating the danger of these compounds. Might you take this out of the realm of radiologists and involve physicians who take care of patients chronically and observe the long-term consequences of these toxic effects?”
Dr. Glaser responded that the deliberations of the agency’s Advisory Committee on Medical Imaging are reviewed under the purview of the FDA’s Center for Drug Evaluation and Research. “That does include radiologists, but also other clinical reviewers of various backgrounds, including pharmacologists and toxicologists.”
Dr. Kay did not relent, further commenting that he has personally seen “over 150 patients with the devastating consequences of nephrogenic systemic fibrosis.” He added that a prominent radiologist has stated in a public forum that the risk of getting injured from crossing the street is greater than that from getting an MRI with gadolinium. “That’s completely wrong,” he declared.
Dr. Glaser and Dr. Kay reported having no financial conflicts.
CHICAGO – The Food and Drug Administration’s updated safety warning about gadolinium-based contrast agents was dismissed as too little, too late during a postsession discussion at the annual meeting of the American College of Rheumatology.
The class warning that “gadolinium is retained for months or years in brain, bone, and other organs,” a directive that a new patient medication guide be given to everyone before receiving a gadolinium-based contrast agent, and a request that manufacturers conduct human and animal studies to further assess the safety of these products, was highlighted at the FDA update session on safety issues in the treatment of rheumatic disease.
The request for further studies grew out of the FDA Advisory Committee on Medical Imaging’s Fall 2017 meeting, which concluded that, “based on available data, there is insufficient evidence of a causal relationship between adverse events and gadolinium retention and recommended the need for additional studies to inform regulatory action,” explained Rachel L. Glaser, MD, a medical officer in the agency’s division of pulmonary, allergy, and rheumatology products and a practicing rheumatologist.
Jonathan Kay, MD, rose from the audience to take the FDA to task for delegating matters related to gadolinium-based contrast agent safety to the radiologists comprising the Advisory Committee on Medical Imaging. “I think the FDA ought to bring this matter to a group of physicians who actually care for patients to get our input on this. Maybe the Arthritis Advisory Committee,” he said.
“It’s been known for more than 15 years that gadolinium deposits in the bone, and for more than 5 years that gadolinium deposits in the brain of patients who’ve received multiple magnetic resonance studies. I’m concerned that the FDA has this issue in the purview of the radiologists because radiologists administer these contrast agents and then don’t see the patients back in follow-up, whereas rheumatologists do,” noted Dr. Kay, professor of medicine and director of clinical research in rheumatology at the University of Massachusetts, Worcester.
He blasted the FDA’s call for further human and animal studies, noting “nephrogenic systemic fibrosis was the human experiment that was done with gadolinium contrast, showing that these agents, when they deposit in tissue, are extremely toxic. I can’t see other human studies being done to determine the potential consequences of these agents when they deposit long term in brain, bone, and other tissues. And the animal studies have already been done demonstrating the danger of these compounds. Might you take this out of the realm of radiologists and involve physicians who take care of patients chronically and observe the long-term consequences of these toxic effects?”
Dr. Glaser responded that the deliberations of the agency’s Advisory Committee on Medical Imaging are reviewed under the purview of the FDA’s Center for Drug Evaluation and Research. “That does include radiologists, but also other clinical reviewers of various backgrounds, including pharmacologists and toxicologists.”
Dr. Kay did not relent, further commenting that he has personally seen “over 150 patients with the devastating consequences of nephrogenic systemic fibrosis.” He added that a prominent radiologist has stated in a public forum that the risk of getting injured from crossing the street is greater than that from getting an MRI with gadolinium. “That’s completely wrong,” he declared.
Dr. Glaser and Dr. Kay reported having no financial conflicts.
CHICAGO – The Food and Drug Administration’s updated safety warning about gadolinium-based contrast agents was dismissed as too little, too late during a postsession discussion at the annual meeting of the American College of Rheumatology.
The class warning that “gadolinium is retained for months or years in brain, bone, and other organs,” a directive that a new patient medication guide be given to everyone before receiving a gadolinium-based contrast agent, and a request that manufacturers conduct human and animal studies to further assess the safety of these products, was highlighted at the FDA update session on safety issues in the treatment of rheumatic disease.
The request for further studies grew out of the FDA Advisory Committee on Medical Imaging’s Fall 2017 meeting, which concluded that, “based on available data, there is insufficient evidence of a causal relationship between adverse events and gadolinium retention and recommended the need for additional studies to inform regulatory action,” explained Rachel L. Glaser, MD, a medical officer in the agency’s division of pulmonary, allergy, and rheumatology products and a practicing rheumatologist.
Jonathan Kay, MD, rose from the audience to take the FDA to task for delegating matters related to gadolinium-based contrast agent safety to the radiologists comprising the Advisory Committee on Medical Imaging. “I think the FDA ought to bring this matter to a group of physicians who actually care for patients to get our input on this. Maybe the Arthritis Advisory Committee,” he said.
“It’s been known for more than 15 years that gadolinium deposits in the bone, and for more than 5 years that gadolinium deposits in the brain of patients who’ve received multiple magnetic resonance studies. I’m concerned that the FDA has this issue in the purview of the radiologists because radiologists administer these contrast agents and then don’t see the patients back in follow-up, whereas rheumatologists do,” noted Dr. Kay, professor of medicine and director of clinical research in rheumatology at the University of Massachusetts, Worcester.
He blasted the FDA’s call for further human and animal studies, noting “nephrogenic systemic fibrosis was the human experiment that was done with gadolinium contrast, showing that these agents, when they deposit in tissue, are extremely toxic. I can’t see other human studies being done to determine the potential consequences of these agents when they deposit long term in brain, bone, and other tissues. And the animal studies have already been done demonstrating the danger of these compounds. Might you take this out of the realm of radiologists and involve physicians who take care of patients chronically and observe the long-term consequences of these toxic effects?”
Dr. Glaser responded that the deliberations of the agency’s Advisory Committee on Medical Imaging are reviewed under the purview of the FDA’s Center for Drug Evaluation and Research. “That does include radiologists, but also other clinical reviewers of various backgrounds, including pharmacologists and toxicologists.”
Dr. Kay did not relent, further commenting that he has personally seen “over 150 patients with the devastating consequences of nephrogenic systemic fibrosis.” He added that a prominent radiologist has stated in a public forum that the risk of getting injured from crossing the street is greater than that from getting an MRI with gadolinium. “That’s completely wrong,” he declared.
Dr. Glaser and Dr. Kay reported having no financial conflicts.
EXPERT ANALYSIS FROM THE ACR ANNUAL MEETING
Montreal Cognitive Assessment fares well for rapid, reliable screening in SLE
CHICAGO – The Montreal Cognitive Assessment Test provides persuasive advantages over the standard neuropsychological test battery often recommended in guidelines as a screening tool for cognitive impairment in patients with systemic lupus erythematosus, Nicolas Paez-Venegas, MD, asserted at the annual meeting of the American College of Rheumatology.
The MoCA, as it’s known, offers brevity, simplicity, and none of the considerable expense and inconvenience of bringing in a trained specialist to administer a neuropsychological battery. Moreover, in a comparative efficacy study, the MoCA outperformed two other brief screening tools for cognitive impairment – the Mini-Mental State Examination and the Cognitive Symptom Inventory – and showed excellent correspondence with the results of the formal neuropsychological battery, reported Dr. Paez-Venegas, a psychiatrist at the Jalisco Institute of Mental Health, in Zapopan, Mexico.
He presented a cross-sectional study that pitted the three brief screening tests against a gold-standard neuropsychological battery in 44 patients with systemic lupus erythematosus (SLE) according to the 2012 Systemic Lupus International Collaborating Clinics Criteria, none of whom had any known medical or psychiatric comorbidities.
The MoCA proved to have the best congruence with the findings of the neuropsychological battery, with an area under the curve of 99.4%, 84% sensitivity, and 100% specificity for cognitive impairment. The Mini-Mental State Examination had 55% sensitivity and 100% specificity, while the Cognitive Symptom Inventory displayed 55% sensitivity and 31% specificity.
“We therefore encourage rheumatologists to apply the MoCA test as a valuable and easily implemented tool for detecting cognitive impairment as part of an integrated approach in SLE,” Dr. Paez-Venegas said.
Periodic screening for cognitive impairment in patients with SLE is an important aspect of patient management because cognitive impairment is a common manifestation of the disease, affecting up to two-thirds of patients, and it can have a serious impact upon quality of life and self-concept. Because such screening isn’t a one-time event, resort to a neuropsychological battery becomes particularly problematic. The battery employed in this study included the Wechsler Adult Intelligence Scale–Fourth Edition test, the Digit-Symbol test, the Finger-Tapping test of motor control, the Stroop test, Trail Making A and B, the Paced Auditory Serial Addition test, letter-number sequencing, the Wechsler Vocabulary test, the Rey-Osterrieth complex figure test, semantic and phonemic fluency tests, and a test of verbal Spanish comprehension. The battery is a comprehensive tool often employed in research studies but is not well suited for use in a busy clinical practice.
Overall, 70% of the SLE patients demonstrated cognitive impairment in one or more domains on the neuropsychological battery. Processing speed was the most frequently affected domain, involving 23 of the 44 patients. Only a single patient displayed abnormal motor control.
The MoCA test assesses attention, executive function, concentration, language, memory, abstraction, orientation, visuospatial cognitive capacity, and calculation.
Dr. Paez-Venegas’s study was published online earlier this year (J Clin Rheumatol 2018 Jul 18. doi: 10.1097/RHU.0000000000000876). He reported having no financial conflicts regarding his study.
SOURCE: Paez-Venegas N et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 708.
CHICAGO – The Montreal Cognitive Assessment Test provides persuasive advantages over the standard neuropsychological test battery often recommended in guidelines as a screening tool for cognitive impairment in patients with systemic lupus erythematosus, Nicolas Paez-Venegas, MD, asserted at the annual meeting of the American College of Rheumatology.
The MoCA, as it’s known, offers brevity, simplicity, and none of the considerable expense and inconvenience of bringing in a trained specialist to administer a neuropsychological battery. Moreover, in a comparative efficacy study, the MoCA outperformed two other brief screening tools for cognitive impairment – the Mini-Mental State Examination and the Cognitive Symptom Inventory – and showed excellent correspondence with the results of the formal neuropsychological battery, reported Dr. Paez-Venegas, a psychiatrist at the Jalisco Institute of Mental Health, in Zapopan, Mexico.
He presented a cross-sectional study that pitted the three brief screening tests against a gold-standard neuropsychological battery in 44 patients with systemic lupus erythematosus (SLE) according to the 2012 Systemic Lupus International Collaborating Clinics Criteria, none of whom had any known medical or psychiatric comorbidities.
The MoCA proved to have the best congruence with the findings of the neuropsychological battery, with an area under the curve of 99.4%, 84% sensitivity, and 100% specificity for cognitive impairment. The Mini-Mental State Examination had 55% sensitivity and 100% specificity, while the Cognitive Symptom Inventory displayed 55% sensitivity and 31% specificity.
“We therefore encourage rheumatologists to apply the MoCA test as a valuable and easily implemented tool for detecting cognitive impairment as part of an integrated approach in SLE,” Dr. Paez-Venegas said.
Periodic screening for cognitive impairment in patients with SLE is an important aspect of patient management because cognitive impairment is a common manifestation of the disease, affecting up to two-thirds of patients, and it can have a serious impact upon quality of life and self-concept. Because such screening isn’t a one-time event, resort to a neuropsychological battery becomes particularly problematic. The battery employed in this study included the Wechsler Adult Intelligence Scale–Fourth Edition test, the Digit-Symbol test, the Finger-Tapping test of motor control, the Stroop test, Trail Making A and B, the Paced Auditory Serial Addition test, letter-number sequencing, the Wechsler Vocabulary test, the Rey-Osterrieth complex figure test, semantic and phonemic fluency tests, and a test of verbal Spanish comprehension. The battery is a comprehensive tool often employed in research studies but is not well suited for use in a busy clinical practice.
Overall, 70% of the SLE patients demonstrated cognitive impairment in one or more domains on the neuropsychological battery. Processing speed was the most frequently affected domain, involving 23 of the 44 patients. Only a single patient displayed abnormal motor control.
The MoCA test assesses attention, executive function, concentration, language, memory, abstraction, orientation, visuospatial cognitive capacity, and calculation.
Dr. Paez-Venegas’s study was published online earlier this year (J Clin Rheumatol 2018 Jul 18. doi: 10.1097/RHU.0000000000000876). He reported having no financial conflicts regarding his study.
SOURCE: Paez-Venegas N et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 708.
CHICAGO – The Montreal Cognitive Assessment Test provides persuasive advantages over the standard neuropsychological test battery often recommended in guidelines as a screening tool for cognitive impairment in patients with systemic lupus erythematosus, Nicolas Paez-Venegas, MD, asserted at the annual meeting of the American College of Rheumatology.
The MoCA, as it’s known, offers brevity, simplicity, and none of the considerable expense and inconvenience of bringing in a trained specialist to administer a neuropsychological battery. Moreover, in a comparative efficacy study, the MoCA outperformed two other brief screening tools for cognitive impairment – the Mini-Mental State Examination and the Cognitive Symptom Inventory – and showed excellent correspondence with the results of the formal neuropsychological battery, reported Dr. Paez-Venegas, a psychiatrist at the Jalisco Institute of Mental Health, in Zapopan, Mexico.
He presented a cross-sectional study that pitted the three brief screening tests against a gold-standard neuropsychological battery in 44 patients with systemic lupus erythematosus (SLE) according to the 2012 Systemic Lupus International Collaborating Clinics Criteria, none of whom had any known medical or psychiatric comorbidities.
The MoCA proved to have the best congruence with the findings of the neuropsychological battery, with an area under the curve of 99.4%, 84% sensitivity, and 100% specificity for cognitive impairment. The Mini-Mental State Examination had 55% sensitivity and 100% specificity, while the Cognitive Symptom Inventory displayed 55% sensitivity and 31% specificity.
“We therefore encourage rheumatologists to apply the MoCA test as a valuable and easily implemented tool for detecting cognitive impairment as part of an integrated approach in SLE,” Dr. Paez-Venegas said.
Periodic screening for cognitive impairment in patients with SLE is an important aspect of patient management because cognitive impairment is a common manifestation of the disease, affecting up to two-thirds of patients, and it can have a serious impact upon quality of life and self-concept. Because such screening isn’t a one-time event, resort to a neuropsychological battery becomes particularly problematic. The battery employed in this study included the Wechsler Adult Intelligence Scale–Fourth Edition test, the Digit-Symbol test, the Finger-Tapping test of motor control, the Stroop test, Trail Making A and B, the Paced Auditory Serial Addition test, letter-number sequencing, the Wechsler Vocabulary test, the Rey-Osterrieth complex figure test, semantic and phonemic fluency tests, and a test of verbal Spanish comprehension. The battery is a comprehensive tool often employed in research studies but is not well suited for use in a busy clinical practice.
Overall, 70% of the SLE patients demonstrated cognitive impairment in one or more domains on the neuropsychological battery. Processing speed was the most frequently affected domain, involving 23 of the 44 patients. Only a single patient displayed abnormal motor control.
The MoCA test assesses attention, executive function, concentration, language, memory, abstraction, orientation, visuospatial cognitive capacity, and calculation.
Dr. Paez-Venegas’s study was published online earlier this year (J Clin Rheumatol 2018 Jul 18. doi: 10.1097/RHU.0000000000000876). He reported having no financial conflicts regarding his study.
SOURCE: Paez-Venegas N et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 708.
REPORTING FROM THE ACR ANNUAL MEETING
Key clinical point:
Major finding: The Montreal Cognitive Assessment Test showed 84% sensitivity and 100% specificity for cognitive impairment in systemic lupus erythematosus patients.
Study details: This comparative effectiveness study included 44 systemic lupus erythematosus patients assessed for cognitive impairment using three different tools.
Disclosures: The presenter reported having no financial conflicts regarding this study, which was conducted free of commercial support.
Source: Paez-Venegas N et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 708.
Short-term lung function better predicts mortality risk in SSc
In addition to known risk factors, early reductions in lung function and diffusing capacity increased mortality risk in patients with systemic sclerosis and comorbid interstitial lung disease over 2 years in an analysis of data from the Scleroderma Lung Studies I and II.
First author Elizabeth R. Volkmann, MD, of the University of California, Los Angeles, and her colleagues also reported that although early treatment with cyclophosphamide or mycophenolate mofetil in these studies led to shorter-term improvement in surrogate measures of outcomes for systemic sclerosis and comorbid interstitial lung disease (SSc-ILD), either medication might not improve long-term outcomes. The findings were reported in the Annals of the Rheumatic Diseases.
The investigators identified specific factors linked to an increased risk of death over a median follow-up of 8 years in 158 systemic sclerosis-interstitial lung disease patients in the Scleroderma Lung Study I and median follow-up of 3.6 years in 142 patients in Scleroderma Lung Study II, both of which were randomized, controlled trials.
After follow-up was complete, 42% of participants in Scleroderma Lung Study I and 21% of participants in Scleroderma Lung Study II died, with the most common cause of death being complications related to systemic sclerosis. In addition, no statistical difference was seen in time to death between the intervention arms of both trials.
In building a risk prediction model based on findings from both trials, the investigators confirmed several known mortality risk predictors in systemic sclerosis, including increased age and baseline skin score, but also found that changes in forced vital capacity and diffusing capacity for carbon monoxide over 2 years were separately linked with a greater risk of death.
“These findings suggest that short-term changes in surrogate measures of systemic sclerosis-interstitial lung disease progression may have important effects on long-term outcomes,” the researchers wrote.
The researchers acknowledged the results emphasize the need to determine optimal length of treatment in patients with systemic sclerosis and comorbid interstitial lung disease.
“Systemic sclerosis providers should closely monitor lung function when interstitial lung disease is present to accurately identify declines in lung function and promptly intervene to improve patient outcomes,” the researchers concluded.
The study was funded by the National Institutes of Health and the Scleroderma Foundation. The authors reported no conflicts of interest.
SOURCE: Volkmann ER et al. Ann Rheum Dis. 2018 Nov 8. doi: 10.1136/annrheumdis-2018-213708.
In addition to known risk factors, early reductions in lung function and diffusing capacity increased mortality risk in patients with systemic sclerosis and comorbid interstitial lung disease over 2 years in an analysis of data from the Scleroderma Lung Studies I and II.
First author Elizabeth R. Volkmann, MD, of the University of California, Los Angeles, and her colleagues also reported that although early treatment with cyclophosphamide or mycophenolate mofetil in these studies led to shorter-term improvement in surrogate measures of outcomes for systemic sclerosis and comorbid interstitial lung disease (SSc-ILD), either medication might not improve long-term outcomes. The findings were reported in the Annals of the Rheumatic Diseases.
The investigators identified specific factors linked to an increased risk of death over a median follow-up of 8 years in 158 systemic sclerosis-interstitial lung disease patients in the Scleroderma Lung Study I and median follow-up of 3.6 years in 142 patients in Scleroderma Lung Study II, both of which were randomized, controlled trials.
After follow-up was complete, 42% of participants in Scleroderma Lung Study I and 21% of participants in Scleroderma Lung Study II died, with the most common cause of death being complications related to systemic sclerosis. In addition, no statistical difference was seen in time to death between the intervention arms of both trials.
In building a risk prediction model based on findings from both trials, the investigators confirmed several known mortality risk predictors in systemic sclerosis, including increased age and baseline skin score, but also found that changes in forced vital capacity and diffusing capacity for carbon monoxide over 2 years were separately linked with a greater risk of death.
“These findings suggest that short-term changes in surrogate measures of systemic sclerosis-interstitial lung disease progression may have important effects on long-term outcomes,” the researchers wrote.
The researchers acknowledged the results emphasize the need to determine optimal length of treatment in patients with systemic sclerosis and comorbid interstitial lung disease.
“Systemic sclerosis providers should closely monitor lung function when interstitial lung disease is present to accurately identify declines in lung function and promptly intervene to improve patient outcomes,” the researchers concluded.
The study was funded by the National Institutes of Health and the Scleroderma Foundation. The authors reported no conflicts of interest.
SOURCE: Volkmann ER et al. Ann Rheum Dis. 2018 Nov 8. doi: 10.1136/annrheumdis-2018-213708.
In addition to known risk factors, early reductions in lung function and diffusing capacity increased mortality risk in patients with systemic sclerosis and comorbid interstitial lung disease over 2 years in an analysis of data from the Scleroderma Lung Studies I and II.
First author Elizabeth R. Volkmann, MD, of the University of California, Los Angeles, and her colleagues also reported that although early treatment with cyclophosphamide or mycophenolate mofetil in these studies led to shorter-term improvement in surrogate measures of outcomes for systemic sclerosis and comorbid interstitial lung disease (SSc-ILD), either medication might not improve long-term outcomes. The findings were reported in the Annals of the Rheumatic Diseases.
The investigators identified specific factors linked to an increased risk of death over a median follow-up of 8 years in 158 systemic sclerosis-interstitial lung disease patients in the Scleroderma Lung Study I and median follow-up of 3.6 years in 142 patients in Scleroderma Lung Study II, both of which were randomized, controlled trials.
After follow-up was complete, 42% of participants in Scleroderma Lung Study I and 21% of participants in Scleroderma Lung Study II died, with the most common cause of death being complications related to systemic sclerosis. In addition, no statistical difference was seen in time to death between the intervention arms of both trials.
In building a risk prediction model based on findings from both trials, the investigators confirmed several known mortality risk predictors in systemic sclerosis, including increased age and baseline skin score, but also found that changes in forced vital capacity and diffusing capacity for carbon monoxide over 2 years were separately linked with a greater risk of death.
“These findings suggest that short-term changes in surrogate measures of systemic sclerosis-interstitial lung disease progression may have important effects on long-term outcomes,” the researchers wrote.
The researchers acknowledged the results emphasize the need to determine optimal length of treatment in patients with systemic sclerosis and comorbid interstitial lung disease.
“Systemic sclerosis providers should closely monitor lung function when interstitial lung disease is present to accurately identify declines in lung function and promptly intervene to improve patient outcomes,” the researchers concluded.
The study was funded by the National Institutes of Health and the Scleroderma Foundation. The authors reported no conflicts of interest.
SOURCE: Volkmann ER et al. Ann Rheum Dis. 2018 Nov 8. doi: 10.1136/annrheumdis-2018-213708.
FROM ANNALS OF THE RHEUMATIC DISEASES
Key clinical point:
Major finding: Declines in forced vital capacity and diffusing capacity for carbon monoxide were significant, independent predictors of death over the study duration.
Study details: A long-term follow-up analysis of two independent randomized, controlled trials, which consisted of 158 and 142 adults, respectively.
Disclosures: The study was funded by the National Institutes of Health and the Scleroderma Foundation. The authors reported no conflicts of interest.
Source: Volkmann ER et al. Ann Rheum Dis. 2018 Nov 8. doi: 10.1136/annrheumdis-2018-213708.
High incidence of treatment-resistant hypertension in SLE comes with high mortality
CHICAGO – Patients with systemic lupus erythematosus (SLE) have an incidence of treatment-resistant hypertension (TRH) twice the rate of matched controls, and all-cause mortality in affected SLE patients is sharply higher than in individuals whose SLE is not complicated by comorbid TRH, Annette Oeser reported at the annual meeting of the American College of Rheumatology.
TRH is thus an important yet underappreciated comorbidity for clinicians to recognize in patients with SLE, added Ms. Oeser of Vanderbilt University, Nashville, Tenn.
She presented a single-center, retrospective study of 1,044 SLE patients and 5,241 controls matched by age, race, and sex. During an average of 6 and maximum of 17 years of follow-up, 10% of SLE patients and 5% of controls developed TRH. The incidence was 14.7 cases per 1,000 person-years in the SLE population and 7.4 per 1,000 in controls. Of note, the incidence curves began to diverge within the first months following diagnosis of the autoimmune disease.
TRH was defined in the conventional way as an inability to achieve a blood pressure of 140/90 mm Hg or less while on three antihypertensive drugs having different mechanisms or as the simultaneous use of four or more antihypertensive agents, noted Ms. Oeser, the study coordinator, who presented the findings on behalf of senior investigator Cecilia P. Chung, MD, a rheumatologist at Vanderbilt.
The SLE patients with TRH were older than those without TRH by a margin of 47 versus 41 years of age. A total of 45% of SLE patients with TRH were black, compared with 21% of those without TRH. The group with SLE and TRH also had a higher C-reactive protein (10.2 versus 3.3 mg/L), a higher erythrocyte sedimentation rate (40 versus 24 mm/hr), a lower estimated glomerular filtration rate (65.0 versus 88.2 mL/min per 1.73 m2), and a higher creatinine (1.1 versus 0.8 mg/day).
Overall, 25% of SLE patients with TRH died during follow-up, as did 10% of those without resistant hypertension, for an unadjusted 289% increased risk of all-cause mortality. Upon adjustment for age, sex, calendar year, end-stage renal disease, and creatinine, the SLE patients with TRH still remained at a 78% increased risk of mortality.
Ms. Oeser and Dr. Chung reported having no financial conflicts regarding the study, which was supported by Vanderbilt University, the Rheumatology Research Foundation, the National Institutes of Health, and the Lupus Research Alliance.
SOURCE: Chung CP et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 706.
CHICAGO – Patients with systemic lupus erythematosus (SLE) have an incidence of treatment-resistant hypertension (TRH) twice the rate of matched controls, and all-cause mortality in affected SLE patients is sharply higher than in individuals whose SLE is not complicated by comorbid TRH, Annette Oeser reported at the annual meeting of the American College of Rheumatology.
TRH is thus an important yet underappreciated comorbidity for clinicians to recognize in patients with SLE, added Ms. Oeser of Vanderbilt University, Nashville, Tenn.
She presented a single-center, retrospective study of 1,044 SLE patients and 5,241 controls matched by age, race, and sex. During an average of 6 and maximum of 17 years of follow-up, 10% of SLE patients and 5% of controls developed TRH. The incidence was 14.7 cases per 1,000 person-years in the SLE population and 7.4 per 1,000 in controls. Of note, the incidence curves began to diverge within the first months following diagnosis of the autoimmune disease.
TRH was defined in the conventional way as an inability to achieve a blood pressure of 140/90 mm Hg or less while on three antihypertensive drugs having different mechanisms or as the simultaneous use of four or more antihypertensive agents, noted Ms. Oeser, the study coordinator, who presented the findings on behalf of senior investigator Cecilia P. Chung, MD, a rheumatologist at Vanderbilt.
The SLE patients with TRH were older than those without TRH by a margin of 47 versus 41 years of age. A total of 45% of SLE patients with TRH were black, compared with 21% of those without TRH. The group with SLE and TRH also had a higher C-reactive protein (10.2 versus 3.3 mg/L), a higher erythrocyte sedimentation rate (40 versus 24 mm/hr), a lower estimated glomerular filtration rate (65.0 versus 88.2 mL/min per 1.73 m2), and a higher creatinine (1.1 versus 0.8 mg/day).
Overall, 25% of SLE patients with TRH died during follow-up, as did 10% of those without resistant hypertension, for an unadjusted 289% increased risk of all-cause mortality. Upon adjustment for age, sex, calendar year, end-stage renal disease, and creatinine, the SLE patients with TRH still remained at a 78% increased risk of mortality.
Ms. Oeser and Dr. Chung reported having no financial conflicts regarding the study, which was supported by Vanderbilt University, the Rheumatology Research Foundation, the National Institutes of Health, and the Lupus Research Alliance.
SOURCE: Chung CP et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 706.
CHICAGO – Patients with systemic lupus erythematosus (SLE) have an incidence of treatment-resistant hypertension (TRH) twice the rate of matched controls, and all-cause mortality in affected SLE patients is sharply higher than in individuals whose SLE is not complicated by comorbid TRH, Annette Oeser reported at the annual meeting of the American College of Rheumatology.
TRH is thus an important yet underappreciated comorbidity for clinicians to recognize in patients with SLE, added Ms. Oeser of Vanderbilt University, Nashville, Tenn.
She presented a single-center, retrospective study of 1,044 SLE patients and 5,241 controls matched by age, race, and sex. During an average of 6 and maximum of 17 years of follow-up, 10% of SLE patients and 5% of controls developed TRH. The incidence was 14.7 cases per 1,000 person-years in the SLE population and 7.4 per 1,000 in controls. Of note, the incidence curves began to diverge within the first months following diagnosis of the autoimmune disease.
TRH was defined in the conventional way as an inability to achieve a blood pressure of 140/90 mm Hg or less while on three antihypertensive drugs having different mechanisms or as the simultaneous use of four or more antihypertensive agents, noted Ms. Oeser, the study coordinator, who presented the findings on behalf of senior investigator Cecilia P. Chung, MD, a rheumatologist at Vanderbilt.
The SLE patients with TRH were older than those without TRH by a margin of 47 versus 41 years of age. A total of 45% of SLE patients with TRH were black, compared with 21% of those without TRH. The group with SLE and TRH also had a higher C-reactive protein (10.2 versus 3.3 mg/L), a higher erythrocyte sedimentation rate (40 versus 24 mm/hr), a lower estimated glomerular filtration rate (65.0 versus 88.2 mL/min per 1.73 m2), and a higher creatinine (1.1 versus 0.8 mg/day).
Overall, 25% of SLE patients with TRH died during follow-up, as did 10% of those without resistant hypertension, for an unadjusted 289% increased risk of all-cause mortality. Upon adjustment for age, sex, calendar year, end-stage renal disease, and creatinine, the SLE patients with TRH still remained at a 78% increased risk of mortality.
Ms. Oeser and Dr. Chung reported having no financial conflicts regarding the study, which was supported by Vanderbilt University, the Rheumatology Research Foundation, the National Institutes of Health, and the Lupus Research Alliance.
SOURCE: Chung CP et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 706.
REPORTING FROM THE ACR ANNUAL MEETING
Key clinical point: Treatment-resistant hypertension is an important yet underappreciated comorbidity for clinicians to recognize in patients with systemic lupus erythematosus.
Major finding: The incidence rate of treatment-resistant hypertension was twice as great in patients with systemic lupus erythematosus compared with matched controls.
Study details: This retrospective, single-center study included 1,044 systemic lupus erythematosus patients and 5,241 matched controls.
Disclosures: The presenter reported having no financial conflicts regarding the study, which was supported by Vanderbilt University, the Rheumatology Research Foundation, the National Institutes of Health, and the Lupus Research Alliance.
Source: Chung CP et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 706.
Development of reversible B-cell inhibitor XmAb5871 for SLE moves forward
CHICAGO – The novel reversible B-cell inhibitor XmAb5871 showed promise for delaying loss of improvement after steroid therapy in patients with systemic lupus erythematosus in a randomized, placebo-controlled, phase 2 study.
Patients with moderate to severe nonorgan-threatening systemic lupus erythematosus (SLE) who underwent biweekly treatment with XmAb5871 after intramuscular glucocorticoid therapy more often achieved the trial’s primary endpoint of no loss of improvement through day 225 than did patients who took placebo. Overall, 21 (42%) of 50 patients who were randomized to receive active treatment reached this outcome, compared with 12 (29%) of 42 who received placebo based on the “efficacy-evaluable” patient population, defined as those who completed day 225, had a loss of improvement, or discontinued because of a drug-related adverse even. The difference between the treatment and placebo groups with respect to loss of improvement through day 225 reflected a positive trend, but did not reach statistical significance (P = .18), Debra J. Zack, MD, of Xencor in Monrovia, Calif., and her colleagues reported in a poster at the annual meeting of the American College of Rheumatology.
Of the patients who didn’t achieve the primary endpoint, 23 (46%) in the XmAb5871 arm versus 30 (71%) in the placebo arm experienced loss of improvement at any visit, the investigators noted. Six patients in the treatment arm discontinued for toxicity and were also considered nonresponders.
Treatment with XmAb5871 also led to a longer median time to loss of improvement of 230 days in comparison with the 130 days observed in placebo-treated patients. The difference was statistically significant in the efficacy-evaluable population (hazard ratio, 0.53; P = .025) and nearly statistically significant in the intent-to-treat (ITT) population of 52 patients in each group (HR, 0.59; P = .06), they noted.
Maintenance of improvement, which was another secondary endpoint, did not differ significantly between the groups in the efficacy-evaluable population (58.0% vs. 40.5%, respectively; P = .11), but did differ significantly with treatment versus placebo at both day 225 (response rates of 44.0% vs. 23.1%, respectively; P = .06) and at day 169 (57.7% vs. 34.6%; P = .02) in the ITT population, they said.
Of note, patients in the treatment group stayed in the study longer (median of 6.9 vs. 3.6 months) and received more infusions (median of 15.0 vs. 8.5).
“Antigen-activated B cells are down-regulated by engagement of immune complexes with the inhibitory Fcy receptor FcyRIIB on the B cell surface. XmAb5871 is an anti-CD19 monoclonal antibody engineered to enhance binding to FcyRIIB,” they explained, adding that the study was designed using unique methodology to minimize background medication and placebo responses to allow for better interpretation of the results in patients with complex, heterogeneous disease.
Participants were adults with a median age of 44.5 years; most (99 of 104) were women. All received an intramuscular glucocorticoid injection at the start of the screening period as background immunosuppressants were stopped, and those who experienced at least a 4-point decrease on the SLE disease activity index or at least a 1-grade decrease in at least one British Isles Lupus Activity Group A or B score were eligible for enrollment. Background immunosuppressants had to be stopped by the time of enrollment, but patients were allowed to remain on hydroxychloroquine and prednisone 10 mg or less daily or the equivalent.
Those enrolled were randomized to receive intravenous XmAb5871 at a dose of 5 mg/kg or placebo every 14 days for up to 16 doses until day 225 or loss of improvement (at which time patients could receive standard of care and withdraw from the study); all received intramuscular glucocorticoids (Depo-Medrol 80 mg [methylprednisolone acetate]) on days 1 and 15.
XmAb5871 was well tolerated in this study and had a safety profile consistent with that seen in previous SLE studies, with the exception of six withdrawals caused by infusion reactions, the investigators said. They noted that a subcutaneous formulation showed no infusion reactions or gastrointestinal-related infusion reactions in a bioavailability study of 40 healthy subjects, and so a formulation for subcutaneous injection will be used in future studies.
The vast majority of the 149 treatment-related adverse events that occurred in 41 patients in the current study (including 26% in placebo group patients) were mild or moderate in severity. A total of 13 serious adverse events (SAEs) occurred in 11 patients, and included fever, SLE flare (lung), atrial fibrillation, worsening hypertension, iron deficiency anemia, pneumonia (occurring 36 days, or 10 half-lives, after the last dose), infusion-related reaction, and vertigo in the XmAb5871 patients, and anemia SLE flare, SLE flare (enteritis), angioedema, and migraine headache in the placebo group.
“All SAEs were considered not or unlikely related except the infusion-related reaction. There were no deaths and no opportunistic infections,” they wrote.
Although the primary endpoint of loss of improvement by day 225 was not significantly better in the treatment group in this study, a positive trend was noted, the median time to loss of improvement was extended by 76%, and the risk of increased SLE disease activity was reduced by 47% in those who received XmAb5871, they said, concluding that the findings support further evaluation of the agent in patients with SLE.
The study was supported by Xencor.
SOURCE: Zack DJ et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract L14.
CHICAGO – The novel reversible B-cell inhibitor XmAb5871 showed promise for delaying loss of improvement after steroid therapy in patients with systemic lupus erythematosus in a randomized, placebo-controlled, phase 2 study.
Patients with moderate to severe nonorgan-threatening systemic lupus erythematosus (SLE) who underwent biweekly treatment with XmAb5871 after intramuscular glucocorticoid therapy more often achieved the trial’s primary endpoint of no loss of improvement through day 225 than did patients who took placebo. Overall, 21 (42%) of 50 patients who were randomized to receive active treatment reached this outcome, compared with 12 (29%) of 42 who received placebo based on the “efficacy-evaluable” patient population, defined as those who completed day 225, had a loss of improvement, or discontinued because of a drug-related adverse even. The difference between the treatment and placebo groups with respect to loss of improvement through day 225 reflected a positive trend, but did not reach statistical significance (P = .18), Debra J. Zack, MD, of Xencor in Monrovia, Calif., and her colleagues reported in a poster at the annual meeting of the American College of Rheumatology.
Of the patients who didn’t achieve the primary endpoint, 23 (46%) in the XmAb5871 arm versus 30 (71%) in the placebo arm experienced loss of improvement at any visit, the investigators noted. Six patients in the treatment arm discontinued for toxicity and were also considered nonresponders.
Treatment with XmAb5871 also led to a longer median time to loss of improvement of 230 days in comparison with the 130 days observed in placebo-treated patients. The difference was statistically significant in the efficacy-evaluable population (hazard ratio, 0.53; P = .025) and nearly statistically significant in the intent-to-treat (ITT) population of 52 patients in each group (HR, 0.59; P = .06), they noted.
Maintenance of improvement, which was another secondary endpoint, did not differ significantly between the groups in the efficacy-evaluable population (58.0% vs. 40.5%, respectively; P = .11), but did differ significantly with treatment versus placebo at both day 225 (response rates of 44.0% vs. 23.1%, respectively; P = .06) and at day 169 (57.7% vs. 34.6%; P = .02) in the ITT population, they said.
Of note, patients in the treatment group stayed in the study longer (median of 6.9 vs. 3.6 months) and received more infusions (median of 15.0 vs. 8.5).
“Antigen-activated B cells are down-regulated by engagement of immune complexes with the inhibitory Fcy receptor FcyRIIB on the B cell surface. XmAb5871 is an anti-CD19 monoclonal antibody engineered to enhance binding to FcyRIIB,” they explained, adding that the study was designed using unique methodology to minimize background medication and placebo responses to allow for better interpretation of the results in patients with complex, heterogeneous disease.
Participants were adults with a median age of 44.5 years; most (99 of 104) were women. All received an intramuscular glucocorticoid injection at the start of the screening period as background immunosuppressants were stopped, and those who experienced at least a 4-point decrease on the SLE disease activity index or at least a 1-grade decrease in at least one British Isles Lupus Activity Group A or B score were eligible for enrollment. Background immunosuppressants had to be stopped by the time of enrollment, but patients were allowed to remain on hydroxychloroquine and prednisone 10 mg or less daily or the equivalent.
Those enrolled were randomized to receive intravenous XmAb5871 at a dose of 5 mg/kg or placebo every 14 days for up to 16 doses until day 225 or loss of improvement (at which time patients could receive standard of care and withdraw from the study); all received intramuscular glucocorticoids (Depo-Medrol 80 mg [methylprednisolone acetate]) on days 1 and 15.
XmAb5871 was well tolerated in this study and had a safety profile consistent with that seen in previous SLE studies, with the exception of six withdrawals caused by infusion reactions, the investigators said. They noted that a subcutaneous formulation showed no infusion reactions or gastrointestinal-related infusion reactions in a bioavailability study of 40 healthy subjects, and so a formulation for subcutaneous injection will be used in future studies.
The vast majority of the 149 treatment-related adverse events that occurred in 41 patients in the current study (including 26% in placebo group patients) were mild or moderate in severity. A total of 13 serious adverse events (SAEs) occurred in 11 patients, and included fever, SLE flare (lung), atrial fibrillation, worsening hypertension, iron deficiency anemia, pneumonia (occurring 36 days, or 10 half-lives, after the last dose), infusion-related reaction, and vertigo in the XmAb5871 patients, and anemia SLE flare, SLE flare (enteritis), angioedema, and migraine headache in the placebo group.
“All SAEs were considered not or unlikely related except the infusion-related reaction. There were no deaths and no opportunistic infections,” they wrote.
Although the primary endpoint of loss of improvement by day 225 was not significantly better in the treatment group in this study, a positive trend was noted, the median time to loss of improvement was extended by 76%, and the risk of increased SLE disease activity was reduced by 47% in those who received XmAb5871, they said, concluding that the findings support further evaluation of the agent in patients with SLE.
The study was supported by Xencor.
SOURCE: Zack DJ et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract L14.
CHICAGO – The novel reversible B-cell inhibitor XmAb5871 showed promise for delaying loss of improvement after steroid therapy in patients with systemic lupus erythematosus in a randomized, placebo-controlled, phase 2 study.
Patients with moderate to severe nonorgan-threatening systemic lupus erythematosus (SLE) who underwent biweekly treatment with XmAb5871 after intramuscular glucocorticoid therapy more often achieved the trial’s primary endpoint of no loss of improvement through day 225 than did patients who took placebo. Overall, 21 (42%) of 50 patients who were randomized to receive active treatment reached this outcome, compared with 12 (29%) of 42 who received placebo based on the “efficacy-evaluable” patient population, defined as those who completed day 225, had a loss of improvement, or discontinued because of a drug-related adverse even. The difference between the treatment and placebo groups with respect to loss of improvement through day 225 reflected a positive trend, but did not reach statistical significance (P = .18), Debra J. Zack, MD, of Xencor in Monrovia, Calif., and her colleagues reported in a poster at the annual meeting of the American College of Rheumatology.
Of the patients who didn’t achieve the primary endpoint, 23 (46%) in the XmAb5871 arm versus 30 (71%) in the placebo arm experienced loss of improvement at any visit, the investigators noted. Six patients in the treatment arm discontinued for toxicity and were also considered nonresponders.
Treatment with XmAb5871 also led to a longer median time to loss of improvement of 230 days in comparison with the 130 days observed in placebo-treated patients. The difference was statistically significant in the efficacy-evaluable population (hazard ratio, 0.53; P = .025) and nearly statistically significant in the intent-to-treat (ITT) population of 52 patients in each group (HR, 0.59; P = .06), they noted.
Maintenance of improvement, which was another secondary endpoint, did not differ significantly between the groups in the efficacy-evaluable population (58.0% vs. 40.5%, respectively; P = .11), but did differ significantly with treatment versus placebo at both day 225 (response rates of 44.0% vs. 23.1%, respectively; P = .06) and at day 169 (57.7% vs. 34.6%; P = .02) in the ITT population, they said.
Of note, patients in the treatment group stayed in the study longer (median of 6.9 vs. 3.6 months) and received more infusions (median of 15.0 vs. 8.5).
“Antigen-activated B cells are down-regulated by engagement of immune complexes with the inhibitory Fcy receptor FcyRIIB on the B cell surface. XmAb5871 is an anti-CD19 monoclonal antibody engineered to enhance binding to FcyRIIB,” they explained, adding that the study was designed using unique methodology to minimize background medication and placebo responses to allow for better interpretation of the results in patients with complex, heterogeneous disease.
Participants were adults with a median age of 44.5 years; most (99 of 104) were women. All received an intramuscular glucocorticoid injection at the start of the screening period as background immunosuppressants were stopped, and those who experienced at least a 4-point decrease on the SLE disease activity index or at least a 1-grade decrease in at least one British Isles Lupus Activity Group A or B score were eligible for enrollment. Background immunosuppressants had to be stopped by the time of enrollment, but patients were allowed to remain on hydroxychloroquine and prednisone 10 mg or less daily or the equivalent.
Those enrolled were randomized to receive intravenous XmAb5871 at a dose of 5 mg/kg or placebo every 14 days for up to 16 doses until day 225 or loss of improvement (at which time patients could receive standard of care and withdraw from the study); all received intramuscular glucocorticoids (Depo-Medrol 80 mg [methylprednisolone acetate]) on days 1 and 15.
XmAb5871 was well tolerated in this study and had a safety profile consistent with that seen in previous SLE studies, with the exception of six withdrawals caused by infusion reactions, the investigators said. They noted that a subcutaneous formulation showed no infusion reactions or gastrointestinal-related infusion reactions in a bioavailability study of 40 healthy subjects, and so a formulation for subcutaneous injection will be used in future studies.
The vast majority of the 149 treatment-related adverse events that occurred in 41 patients in the current study (including 26% in placebo group patients) were mild or moderate in severity. A total of 13 serious adverse events (SAEs) occurred in 11 patients, and included fever, SLE flare (lung), atrial fibrillation, worsening hypertension, iron deficiency anemia, pneumonia (occurring 36 days, or 10 half-lives, after the last dose), infusion-related reaction, and vertigo in the XmAb5871 patients, and anemia SLE flare, SLE flare (enteritis), angioedema, and migraine headache in the placebo group.
“All SAEs were considered not or unlikely related except the infusion-related reaction. There were no deaths and no opportunistic infections,” they wrote.
Although the primary endpoint of loss of improvement by day 225 was not significantly better in the treatment group in this study, a positive trend was noted, the median time to loss of improvement was extended by 76%, and the risk of increased SLE disease activity was reduced by 47% in those who received XmAb5871, they said, concluding that the findings support further evaluation of the agent in patients with SLE.
The study was supported by Xencor.
SOURCE: Zack DJ et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract L14.
REPORTING FROM THE ACR ANNUAL MEETING
Key clinical point: XmAb5871 shows promise in systemic lupus erythematosus.
Major finding: There was no loss of improvement through day 225 in 42% of patients treated with XmAb5871 versus 29% with placebo.
Study details: A randomized, placebo-controlled, phase 2 study.
Disclosures: The study was supported by Xencor. Dr. Zack is an employee of Xencor.
Source: Zack DJ et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract L14.
Careful follow-up is key in lupus psychosis
Psychosis, a rare manifestation of systemic lupus erythematosus (SLE), generally appears early in the disease course. But treatment can lead to good outcomes for most patients with careful follow-up, according to a large international study.
The findings “confirm and expand upon the results of previous cross-sectional and historical studies of psychosis in SLE,” John G. Hanly, MD, and his associates wrote in Arthritis & Rheumatology.
The prospective study involved 1,826 patients enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) network who were seen at 31 centers across 10 countries, including the United States and Canada.
Patients were followed for an average of 7.4 years, the majority were women (88.8%), almost half the cohort were white (48.8%), and the mean age was 35.1 years, reported Dr. Hanly, of Dalhousie University, Halifax, N.S., and his associates.
The researchers used the American College of Rheumatology definition of psychosis: delusions or hallucinations without insight; (ii) causing clinical distress or impairment in social, occupational or other relevant areas of functioning; (iii) disturbance should not occur exclusively during delirium; (iv) not better accounted for by another mental disorder.
During study follow-up, 28 patients experienced 31 psychotic events (1.53%); 26 of these patients had one event, one patient had two, and one had three events, Dr. Hanly and his associates said.
Using two attribution models, the investigators found that most psychotic events were directly attributed to SLE, and (80%) had their first episode either in the year prior to or within 3 years following a diagnosis of SLE.
The factors positively associated with psychosis on multivariate analysis were African ancestry (hazard ratio, 4.59; 95% confidence interval, 1.79-11.76), previous SLE neuropsychiatric events (HR, 3.59; 95% CI, 1.16-11.14), male sex (HR 3, 95% CI, 1.20-7.50), and younger age at the time of SLE diagnosis (per 10 years, HR, 1.45; 95% CI. 1.01-2.07).
More than 80% of the psychotic events had resolved by the second annual assessment after onset of the event, the investigators reported.
In terms of impact on quality of life, all subscales of the 36-Item Short-Form Health Survey (SF-36) were negatively affected in patients with lupus psychosis.
However, the investigators said.
“Psychosis is an infrequent manifestation of [neuropsychiatric SLE]. Generally, it occurs early after SLE onset and has a significant negative impact on health status,” they concluded. “As determined by patient and physician report, the short- and long-term outlook is good for most patients, though careful follow-up is required.”
Dr. Hanly disclosed grant support from the Canadian Institutes of Health. His associates reported financial support from several entities, including the Basque Government, the Danish Rheumatism Association, the Hopkins Lupus Cohort, and the National Institute for Health Research/Wellcome Trust Birmingham Clinical Research Facility.
SOURCE: Hanly JG et al. Arthritis Rheumatol. 2018. doi: 10.1002/art.40764.
Psychosis, a rare manifestation of systemic lupus erythematosus (SLE), generally appears early in the disease course. But treatment can lead to good outcomes for most patients with careful follow-up, according to a large international study.
The findings “confirm and expand upon the results of previous cross-sectional and historical studies of psychosis in SLE,” John G. Hanly, MD, and his associates wrote in Arthritis & Rheumatology.
The prospective study involved 1,826 patients enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) network who were seen at 31 centers across 10 countries, including the United States and Canada.
Patients were followed for an average of 7.4 years, the majority were women (88.8%), almost half the cohort were white (48.8%), and the mean age was 35.1 years, reported Dr. Hanly, of Dalhousie University, Halifax, N.S., and his associates.
The researchers used the American College of Rheumatology definition of psychosis: delusions or hallucinations without insight; (ii) causing clinical distress or impairment in social, occupational or other relevant areas of functioning; (iii) disturbance should not occur exclusively during delirium; (iv) not better accounted for by another mental disorder.
During study follow-up, 28 patients experienced 31 psychotic events (1.53%); 26 of these patients had one event, one patient had two, and one had three events, Dr. Hanly and his associates said.
Using two attribution models, the investigators found that most psychotic events were directly attributed to SLE, and (80%) had their first episode either in the year prior to or within 3 years following a diagnosis of SLE.
The factors positively associated with psychosis on multivariate analysis were African ancestry (hazard ratio, 4.59; 95% confidence interval, 1.79-11.76), previous SLE neuropsychiatric events (HR, 3.59; 95% CI, 1.16-11.14), male sex (HR 3, 95% CI, 1.20-7.50), and younger age at the time of SLE diagnosis (per 10 years, HR, 1.45; 95% CI. 1.01-2.07).
More than 80% of the psychotic events had resolved by the second annual assessment after onset of the event, the investigators reported.
In terms of impact on quality of life, all subscales of the 36-Item Short-Form Health Survey (SF-36) were negatively affected in patients with lupus psychosis.
However, the investigators said.
“Psychosis is an infrequent manifestation of [neuropsychiatric SLE]. Generally, it occurs early after SLE onset and has a significant negative impact on health status,” they concluded. “As determined by patient and physician report, the short- and long-term outlook is good for most patients, though careful follow-up is required.”
Dr. Hanly disclosed grant support from the Canadian Institutes of Health. His associates reported financial support from several entities, including the Basque Government, the Danish Rheumatism Association, the Hopkins Lupus Cohort, and the National Institute for Health Research/Wellcome Trust Birmingham Clinical Research Facility.
SOURCE: Hanly JG et al. Arthritis Rheumatol. 2018. doi: 10.1002/art.40764.
Psychosis, a rare manifestation of systemic lupus erythematosus (SLE), generally appears early in the disease course. But treatment can lead to good outcomes for most patients with careful follow-up, according to a large international study.
The findings “confirm and expand upon the results of previous cross-sectional and historical studies of psychosis in SLE,” John G. Hanly, MD, and his associates wrote in Arthritis & Rheumatology.
The prospective study involved 1,826 patients enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) network who were seen at 31 centers across 10 countries, including the United States and Canada.
Patients were followed for an average of 7.4 years, the majority were women (88.8%), almost half the cohort were white (48.8%), and the mean age was 35.1 years, reported Dr. Hanly, of Dalhousie University, Halifax, N.S., and his associates.
The researchers used the American College of Rheumatology definition of psychosis: delusions or hallucinations without insight; (ii) causing clinical distress or impairment in social, occupational or other relevant areas of functioning; (iii) disturbance should not occur exclusively during delirium; (iv) not better accounted for by another mental disorder.
During study follow-up, 28 patients experienced 31 psychotic events (1.53%); 26 of these patients had one event, one patient had two, and one had three events, Dr. Hanly and his associates said.
Using two attribution models, the investigators found that most psychotic events were directly attributed to SLE, and (80%) had their first episode either in the year prior to or within 3 years following a diagnosis of SLE.
The factors positively associated with psychosis on multivariate analysis were African ancestry (hazard ratio, 4.59; 95% confidence interval, 1.79-11.76), previous SLE neuropsychiatric events (HR, 3.59; 95% CI, 1.16-11.14), male sex (HR 3, 95% CI, 1.20-7.50), and younger age at the time of SLE diagnosis (per 10 years, HR, 1.45; 95% CI. 1.01-2.07).
More than 80% of the psychotic events had resolved by the second annual assessment after onset of the event, the investigators reported.
In terms of impact on quality of life, all subscales of the 36-Item Short-Form Health Survey (SF-36) were negatively affected in patients with lupus psychosis.
However, the investigators said.
“Psychosis is an infrequent manifestation of [neuropsychiatric SLE]. Generally, it occurs early after SLE onset and has a significant negative impact on health status,” they concluded. “As determined by patient and physician report, the short- and long-term outlook is good for most patients, though careful follow-up is required.”
Dr. Hanly disclosed grant support from the Canadian Institutes of Health. His associates reported financial support from several entities, including the Basque Government, the Danish Rheumatism Association, the Hopkins Lupus Cohort, and the National Institute for Health Research/Wellcome Trust Birmingham Clinical Research Facility.
SOURCE: Hanly JG et al. Arthritis Rheumatol. 2018. doi: 10.1002/art.40764.
FROM ARTHRITIS & RHEUMATOLOGY
Key clinical point: Psychosis, a rare manifestation of systemic lupus erythematosus, is treatable with good short- and long-term outcomes.
Major finding: Twenty-eight patients experienced 31 psychotic events (1.53%); 80% had their first episode either in the year prior to or within 3 years of an SLE diagnosis.
Study details: Prospective study involving 1,826 patients from the Systemic Lupus International Collaborating Clinics network seen at 31 centers across 10 countries.
Disclosures: Dr. Hanly disclosed grant support from the Canadian Institutes of Health. His associates reported financial support from several entities, including the Basque Government, the Danish Rheumatism Association, the Hopkins Lupus Cohort, and the National Institute for Health Research/Wellcome Trust Birmingham Clinical Research Facility.Source: Hanly JG et al. Arthritis Rheumatol. 2018. doi: 10.1002/art.40764.
Fear of blindness hobbles hydroxychloroquine treatment of SLE
CHICAGO – The dosage of hydroxychloroquine (HCQ) for treating patients with systemic lupus erythematosus (SLE) is often overly influenced by fear that the drug could cause blindness, Michelle A. Petri, MD, said at the annual meeting of the American College of Rheumatology.
HCQ “is the most important drug we have to treat lupus. It’s the only treatment shown to improve survival of lupus patients. There is no reason to make patients afraid of this very important drug. I am very concerned that fear of blindness is causing our patients to be less adherent” or making them receive an inadequate dosage, said Dr. Petri, a professor of medicine and the director of the Lupus Center at Johns Hopkins University in Baltimore. “I have had no patients who went blind on HCQ. A few patients developed retinopathy, but none went blind.”
Dr. Petri spoke about experiences with some of her SLE patients who were frightened by what an ophthalmologist told them about the retinal effects of HCQ and had their dosage of the drug unilaterally cut by the ophthalmologist.
“The message we should give patients is that retinopathy is a real complication that can happen, but usually not until after 16 years of treatment with HCQ, and we will work together to make sure you are regularly screened so that, if retinopathy developed, we would pick it up early and you’ll remain asymptomatic,” she said. ”We need to put the risk into perspective for our patients.”
Reports differ on the incidence of retinopathy in SLE patients on long-term HCQ treatment. During the session in which Dr. Petri spoke, James T. Rosenbaum, MD, cited a seminal report from 2014 that tracked 2,361 U.S. patients treated with HCQ daily for at least 5 years with regular retinal follow-up. The results showed a steady, cumulative increase in patients who developed retinopathy, an increase that was also dose dependent. For example, patients who received daily dosage of 5-5.9 mg/kg and took the drug for 20 or more years had a cumulative retinopathy incidence of 30% (JAMA Opthalmol. 2014 Dec;132[12]:1453-60). For patients on higher dosages, the cumulative risk at 20 years or longer jumped above 50%.
The findings from this study led directly to the most recent recommendations from the American Academy of Ophthalmology for retinopathy screening for patients on chronic HCQ treatment, said Dr. Rosenbaum, a professor of medicine and opthalmology at Oregon Health & Science University in Portland. The recommendations called for a dosage cap of less than 5 mg/kg real weight, a baseline retinal examination, and then at least annual follow-up examinations starting after 5 years of daily HCQ use, ideally using both automated visual fields and spectral-domain optical coherence tomography (Ophthalmology. 2016 June;123[6]:1386-94). The recommendations also noted that the presence of retinopathy risk factors, including renal disease or concomitant tamoxifen use, warrant starting screening at 5 years or sooner on HCQ.
Clinicians have often exceeded recommended dosage guidelines. Dr. Rosenbaum cited a 2017 report from one U.S. health care system that reviewed the treatment of 554 patients on HCQ and found that roughly half were overdosed in their starting regimen based on prevailing treatment recommendations (Opthalmology. 2017 May;124[5]:604-8).
But Dr. Petri contended that concerns about excessive HCQ dosages are overblown. At the meeting, she reported data showing a different perspective on the retinopathy risk of patients on chronic HCQ treatment. In a prospective series of 477 SLE patients on chronic HCQ treatment and followed at Johns Hopkins, the incidence of retinopathy was 10% among patients on treatment for 16 or more years, she reported in a talk at the meeting (Arthritis Rheumatol. 2018;70[Suppl 10]: Abstract 2897).
A 10% retinopathy rate after 16 or more years on treatment “sounds a lot safer to patients” than rates as high as 30% or 50% that were reported in the JAMA Opthalmology report from 2014, Dr. Petri said. “There is a danger relying on one retrospective study,” she warned. In addition, the 10% risk for retinopathy is “manageable” when patients receive regular screening that produces early detection of retinal damage.
“There has been acceptance of suboptimal dosing of HCQ when discussion has only been about safety, not about efficacy. We need to put the risks into perspective and stop scaring patients.”
Dr. Petri presented her recommendations for treating SLE patients with HCQ: Treat with dosages as high as 6.5 mg/kg but without exceeding 400 mg/day, and cut the dosage for patients with renal insufficiency or failure, those with liver disease, or the elderly. In addition, Dr. Petri endorsed monitoring blood levels of HCQ. Data she reported at the meeting showed a roughly fourfold higher rate of retinopathy among patients who had a maximum HCQ blood level of 1,733 ng/mL or higher when compared with patients whose maximum level remained at 1,194 ng/mL or lower. Clinicians could use blood levels of HCQ to better focus screening and its intensity, she said. “We should embrace monitoring HCQ blood levels.”
Dr. Petri has been a consultant to Amgen, Exagen, GlaxoSmithKline, Inova Diagnostics, Janssen, Lilly, Merck, Novartis, Quintiles, and EMD Serono, and she has received research funding from AstraZeneca and Exagen. Dr. Rosenbaum has been a consultant to AbbVie, Eyevensys, Gilead, Janssen, Novartis, Regeneron, and Roche, and has received research funding from Pfizer.
CHICAGO – The dosage of hydroxychloroquine (HCQ) for treating patients with systemic lupus erythematosus (SLE) is often overly influenced by fear that the drug could cause blindness, Michelle A. Petri, MD, said at the annual meeting of the American College of Rheumatology.
HCQ “is the most important drug we have to treat lupus. It’s the only treatment shown to improve survival of lupus patients. There is no reason to make patients afraid of this very important drug. I am very concerned that fear of blindness is causing our patients to be less adherent” or making them receive an inadequate dosage, said Dr. Petri, a professor of medicine and the director of the Lupus Center at Johns Hopkins University in Baltimore. “I have had no patients who went blind on HCQ. A few patients developed retinopathy, but none went blind.”
Dr. Petri spoke about experiences with some of her SLE patients who were frightened by what an ophthalmologist told them about the retinal effects of HCQ and had their dosage of the drug unilaterally cut by the ophthalmologist.
“The message we should give patients is that retinopathy is a real complication that can happen, but usually not until after 16 years of treatment with HCQ, and we will work together to make sure you are regularly screened so that, if retinopathy developed, we would pick it up early and you’ll remain asymptomatic,” she said. ”We need to put the risk into perspective for our patients.”
Reports differ on the incidence of retinopathy in SLE patients on long-term HCQ treatment. During the session in which Dr. Petri spoke, James T. Rosenbaum, MD, cited a seminal report from 2014 that tracked 2,361 U.S. patients treated with HCQ daily for at least 5 years with regular retinal follow-up. The results showed a steady, cumulative increase in patients who developed retinopathy, an increase that was also dose dependent. For example, patients who received daily dosage of 5-5.9 mg/kg and took the drug for 20 or more years had a cumulative retinopathy incidence of 30% (JAMA Opthalmol. 2014 Dec;132[12]:1453-60). For patients on higher dosages, the cumulative risk at 20 years or longer jumped above 50%.
The findings from this study led directly to the most recent recommendations from the American Academy of Ophthalmology for retinopathy screening for patients on chronic HCQ treatment, said Dr. Rosenbaum, a professor of medicine and opthalmology at Oregon Health & Science University in Portland. The recommendations called for a dosage cap of less than 5 mg/kg real weight, a baseline retinal examination, and then at least annual follow-up examinations starting after 5 years of daily HCQ use, ideally using both automated visual fields and spectral-domain optical coherence tomography (Ophthalmology. 2016 June;123[6]:1386-94). The recommendations also noted that the presence of retinopathy risk factors, including renal disease or concomitant tamoxifen use, warrant starting screening at 5 years or sooner on HCQ.
Clinicians have often exceeded recommended dosage guidelines. Dr. Rosenbaum cited a 2017 report from one U.S. health care system that reviewed the treatment of 554 patients on HCQ and found that roughly half were overdosed in their starting regimen based on prevailing treatment recommendations (Opthalmology. 2017 May;124[5]:604-8).
But Dr. Petri contended that concerns about excessive HCQ dosages are overblown. At the meeting, she reported data showing a different perspective on the retinopathy risk of patients on chronic HCQ treatment. In a prospective series of 477 SLE patients on chronic HCQ treatment and followed at Johns Hopkins, the incidence of retinopathy was 10% among patients on treatment for 16 or more years, she reported in a talk at the meeting (Arthritis Rheumatol. 2018;70[Suppl 10]: Abstract 2897).
A 10% retinopathy rate after 16 or more years on treatment “sounds a lot safer to patients” than rates as high as 30% or 50% that were reported in the JAMA Opthalmology report from 2014, Dr. Petri said. “There is a danger relying on one retrospective study,” she warned. In addition, the 10% risk for retinopathy is “manageable” when patients receive regular screening that produces early detection of retinal damage.
“There has been acceptance of suboptimal dosing of HCQ when discussion has only been about safety, not about efficacy. We need to put the risks into perspective and stop scaring patients.”
Dr. Petri presented her recommendations for treating SLE patients with HCQ: Treat with dosages as high as 6.5 mg/kg but without exceeding 400 mg/day, and cut the dosage for patients with renal insufficiency or failure, those with liver disease, or the elderly. In addition, Dr. Petri endorsed monitoring blood levels of HCQ. Data she reported at the meeting showed a roughly fourfold higher rate of retinopathy among patients who had a maximum HCQ blood level of 1,733 ng/mL or higher when compared with patients whose maximum level remained at 1,194 ng/mL or lower. Clinicians could use blood levels of HCQ to better focus screening and its intensity, she said. “We should embrace monitoring HCQ blood levels.”
Dr. Petri has been a consultant to Amgen, Exagen, GlaxoSmithKline, Inova Diagnostics, Janssen, Lilly, Merck, Novartis, Quintiles, and EMD Serono, and she has received research funding from AstraZeneca and Exagen. Dr. Rosenbaum has been a consultant to AbbVie, Eyevensys, Gilead, Janssen, Novartis, Regeneron, and Roche, and has received research funding from Pfizer.
CHICAGO – The dosage of hydroxychloroquine (HCQ) for treating patients with systemic lupus erythematosus (SLE) is often overly influenced by fear that the drug could cause blindness, Michelle A. Petri, MD, said at the annual meeting of the American College of Rheumatology.
HCQ “is the most important drug we have to treat lupus. It’s the only treatment shown to improve survival of lupus patients. There is no reason to make patients afraid of this very important drug. I am very concerned that fear of blindness is causing our patients to be less adherent” or making them receive an inadequate dosage, said Dr. Petri, a professor of medicine and the director of the Lupus Center at Johns Hopkins University in Baltimore. “I have had no patients who went blind on HCQ. A few patients developed retinopathy, but none went blind.”
Dr. Petri spoke about experiences with some of her SLE patients who were frightened by what an ophthalmologist told them about the retinal effects of HCQ and had their dosage of the drug unilaterally cut by the ophthalmologist.
“The message we should give patients is that retinopathy is a real complication that can happen, but usually not until after 16 years of treatment with HCQ, and we will work together to make sure you are regularly screened so that, if retinopathy developed, we would pick it up early and you’ll remain asymptomatic,” she said. ”We need to put the risk into perspective for our patients.”
Reports differ on the incidence of retinopathy in SLE patients on long-term HCQ treatment. During the session in which Dr. Petri spoke, James T. Rosenbaum, MD, cited a seminal report from 2014 that tracked 2,361 U.S. patients treated with HCQ daily for at least 5 years with regular retinal follow-up. The results showed a steady, cumulative increase in patients who developed retinopathy, an increase that was also dose dependent. For example, patients who received daily dosage of 5-5.9 mg/kg and took the drug for 20 or more years had a cumulative retinopathy incidence of 30% (JAMA Opthalmol. 2014 Dec;132[12]:1453-60). For patients on higher dosages, the cumulative risk at 20 years or longer jumped above 50%.
The findings from this study led directly to the most recent recommendations from the American Academy of Ophthalmology for retinopathy screening for patients on chronic HCQ treatment, said Dr. Rosenbaum, a professor of medicine and opthalmology at Oregon Health & Science University in Portland. The recommendations called for a dosage cap of less than 5 mg/kg real weight, a baseline retinal examination, and then at least annual follow-up examinations starting after 5 years of daily HCQ use, ideally using both automated visual fields and spectral-domain optical coherence tomography (Ophthalmology. 2016 June;123[6]:1386-94). The recommendations also noted that the presence of retinopathy risk factors, including renal disease or concomitant tamoxifen use, warrant starting screening at 5 years or sooner on HCQ.
Clinicians have often exceeded recommended dosage guidelines. Dr. Rosenbaum cited a 2017 report from one U.S. health care system that reviewed the treatment of 554 patients on HCQ and found that roughly half were overdosed in their starting regimen based on prevailing treatment recommendations (Opthalmology. 2017 May;124[5]:604-8).
But Dr. Petri contended that concerns about excessive HCQ dosages are overblown. At the meeting, she reported data showing a different perspective on the retinopathy risk of patients on chronic HCQ treatment. In a prospective series of 477 SLE patients on chronic HCQ treatment and followed at Johns Hopkins, the incidence of retinopathy was 10% among patients on treatment for 16 or more years, she reported in a talk at the meeting (Arthritis Rheumatol. 2018;70[Suppl 10]: Abstract 2897).
A 10% retinopathy rate after 16 or more years on treatment “sounds a lot safer to patients” than rates as high as 30% or 50% that were reported in the JAMA Opthalmology report from 2014, Dr. Petri said. “There is a danger relying on one retrospective study,” she warned. In addition, the 10% risk for retinopathy is “manageable” when patients receive regular screening that produces early detection of retinal damage.
“There has been acceptance of suboptimal dosing of HCQ when discussion has only been about safety, not about efficacy. We need to put the risks into perspective and stop scaring patients.”
Dr. Petri presented her recommendations for treating SLE patients with HCQ: Treat with dosages as high as 6.5 mg/kg but without exceeding 400 mg/day, and cut the dosage for patients with renal insufficiency or failure, those with liver disease, or the elderly. In addition, Dr. Petri endorsed monitoring blood levels of HCQ. Data she reported at the meeting showed a roughly fourfold higher rate of retinopathy among patients who had a maximum HCQ blood level of 1,733 ng/mL or higher when compared with patients whose maximum level remained at 1,194 ng/mL or lower. Clinicians could use blood levels of HCQ to better focus screening and its intensity, she said. “We should embrace monitoring HCQ blood levels.”
Dr. Petri has been a consultant to Amgen, Exagen, GlaxoSmithKline, Inova Diagnostics, Janssen, Lilly, Merck, Novartis, Quintiles, and EMD Serono, and she has received research funding from AstraZeneca and Exagen. Dr. Rosenbaum has been a consultant to AbbVie, Eyevensys, Gilead, Janssen, Novartis, Regeneron, and Roche, and has received research funding from Pfizer.
REPORTING FROM THE ACR ANNUAL MEETING
Tofacitinib impresses in first trial for dermatomyositis
CHICAGO – Oral tofacitinib demonstrated strong clinical efficacy and good safety in the first-ever formal study of a Janus kinase inhibitor in patients with active, treatment-resistant dermatomyositis, Julie J. Paik, MD, reported at the annual meeting of the American College of Rheumatology.
Based upon the encouraging results of this small, open-label, proof-of-concept study, a larger randomized controlled trial is being planned, according to Dr. Paik, a rheumatologist at Johns Hopkins University in Baltimore.
The study included 10 dermatomyositis patients enrolled at the Johns Hopkins Myositis Clinic. All had previously failed at least two steroid-sparing drugs and/or high-dose steroids. After first going off all steroid-sparing agents and being limited to a maximum of 20 mg/day of prednisone, the participants were placed on 11 mg of open-label, extended-release tofacitinib (Xeljanz XR) once daily. Dr. Paik only reported results in 9 patients because the 10th hadn’t yet reached the 12-week mark.
The primary outcome was the rate of achievement of significant improvement at week 12 as defined using the validated International Myositis Assessment and Clinical Studies (IMACS) criteria, which require at least a 20% improvement in three of six core set measures coupled with no more than two measures worsening by 25% or more. By this standard, all nine patients met the primary endpoint. Five were rated as showing moderate improvement, and the other four demonstrated minimal improvement, based on the Total Improvement Score of the Myositis Response criteria. The median Total Improvement Score was 40, indicative of at least moderate improvement.
The mean CDASI (Cutaneous Dermatomyositis Disease Area and Severity Index) activity score – a key secondary endpoint – improved from 28 at baseline to 9.5 at week 12, which translates to a shift from moderate or severe disease to mild disease.
Levels of the alpha-chemokines CXCL9 and CXCL10, which are expressed in muscle affected by idiopathic inflammatory myopathies such as dermatomyositis, declined strongly over the course of 12 weeks of treatment to an extent that was just shy of statistical significance.
Myositis antibody titers didn’t change in response to tofacitinib therapy. Of note, six patients were positive for antitranscriptional intermediary factor 1-gamma, and five of the six were moderate responders to JAK inhibitor therapy.
Four patients were on 20 mg/day of prednisone at baseline; three of the four were able to go off steroids altogether over the course of 12 weeks.
The treatment was well tolerated, with no serious adverse events.
Asked if she thought 11 mg/day of tofacitinib was the right dose for this population of refractory dermatomyositis patients, Dr. Paik replied, “We’re not sure we have the right dose. We had one patient who didn’t have as robust a response, and I really wonder, if we gave her a higher dose, it would have made a difference.”
Extended-release tofacitinib at 11 mg/day is the approved dose for rheumatoid arthritis and psoriatic arthritis. However, 20 mg/day is approved for patients with ulcerative colitis, and Dr. Paik is lobbying for inclusion of a higher-dose arm in the randomized, controlled trial.
Prior to this formal proof-of-concept study, which was funded by Pfizer, the experience with tofacitinib in refractory dermatomyositis was limited to anecdotal case reports.
Dr. Paik reported having no financial conflicts.
SOURCE: Paik JJ et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract L02.
CHICAGO – Oral tofacitinib demonstrated strong clinical efficacy and good safety in the first-ever formal study of a Janus kinase inhibitor in patients with active, treatment-resistant dermatomyositis, Julie J. Paik, MD, reported at the annual meeting of the American College of Rheumatology.
Based upon the encouraging results of this small, open-label, proof-of-concept study, a larger randomized controlled trial is being planned, according to Dr. Paik, a rheumatologist at Johns Hopkins University in Baltimore.
The study included 10 dermatomyositis patients enrolled at the Johns Hopkins Myositis Clinic. All had previously failed at least two steroid-sparing drugs and/or high-dose steroids. After first going off all steroid-sparing agents and being limited to a maximum of 20 mg/day of prednisone, the participants were placed on 11 mg of open-label, extended-release tofacitinib (Xeljanz XR) once daily. Dr. Paik only reported results in 9 patients because the 10th hadn’t yet reached the 12-week mark.
The primary outcome was the rate of achievement of significant improvement at week 12 as defined using the validated International Myositis Assessment and Clinical Studies (IMACS) criteria, which require at least a 20% improvement in three of six core set measures coupled with no more than two measures worsening by 25% or more. By this standard, all nine patients met the primary endpoint. Five were rated as showing moderate improvement, and the other four demonstrated minimal improvement, based on the Total Improvement Score of the Myositis Response criteria. The median Total Improvement Score was 40, indicative of at least moderate improvement.
The mean CDASI (Cutaneous Dermatomyositis Disease Area and Severity Index) activity score – a key secondary endpoint – improved from 28 at baseline to 9.5 at week 12, which translates to a shift from moderate or severe disease to mild disease.
Levels of the alpha-chemokines CXCL9 and CXCL10, which are expressed in muscle affected by idiopathic inflammatory myopathies such as dermatomyositis, declined strongly over the course of 12 weeks of treatment to an extent that was just shy of statistical significance.
Myositis antibody titers didn’t change in response to tofacitinib therapy. Of note, six patients were positive for antitranscriptional intermediary factor 1-gamma, and five of the six were moderate responders to JAK inhibitor therapy.
Four patients were on 20 mg/day of prednisone at baseline; three of the four were able to go off steroids altogether over the course of 12 weeks.
The treatment was well tolerated, with no serious adverse events.
Asked if she thought 11 mg/day of tofacitinib was the right dose for this population of refractory dermatomyositis patients, Dr. Paik replied, “We’re not sure we have the right dose. We had one patient who didn’t have as robust a response, and I really wonder, if we gave her a higher dose, it would have made a difference.”
Extended-release tofacitinib at 11 mg/day is the approved dose for rheumatoid arthritis and psoriatic arthritis. However, 20 mg/day is approved for patients with ulcerative colitis, and Dr. Paik is lobbying for inclusion of a higher-dose arm in the randomized, controlled trial.
Prior to this formal proof-of-concept study, which was funded by Pfizer, the experience with tofacitinib in refractory dermatomyositis was limited to anecdotal case reports.
Dr. Paik reported having no financial conflicts.
SOURCE: Paik JJ et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract L02.
CHICAGO – Oral tofacitinib demonstrated strong clinical efficacy and good safety in the first-ever formal study of a Janus kinase inhibitor in patients with active, treatment-resistant dermatomyositis, Julie J. Paik, MD, reported at the annual meeting of the American College of Rheumatology.
Based upon the encouraging results of this small, open-label, proof-of-concept study, a larger randomized controlled trial is being planned, according to Dr. Paik, a rheumatologist at Johns Hopkins University in Baltimore.
The study included 10 dermatomyositis patients enrolled at the Johns Hopkins Myositis Clinic. All had previously failed at least two steroid-sparing drugs and/or high-dose steroids. After first going off all steroid-sparing agents and being limited to a maximum of 20 mg/day of prednisone, the participants were placed on 11 mg of open-label, extended-release tofacitinib (Xeljanz XR) once daily. Dr. Paik only reported results in 9 patients because the 10th hadn’t yet reached the 12-week mark.
The primary outcome was the rate of achievement of significant improvement at week 12 as defined using the validated International Myositis Assessment and Clinical Studies (IMACS) criteria, which require at least a 20% improvement in three of six core set measures coupled with no more than two measures worsening by 25% or more. By this standard, all nine patients met the primary endpoint. Five were rated as showing moderate improvement, and the other four demonstrated minimal improvement, based on the Total Improvement Score of the Myositis Response criteria. The median Total Improvement Score was 40, indicative of at least moderate improvement.
The mean CDASI (Cutaneous Dermatomyositis Disease Area and Severity Index) activity score – a key secondary endpoint – improved from 28 at baseline to 9.5 at week 12, which translates to a shift from moderate or severe disease to mild disease.
Levels of the alpha-chemokines CXCL9 and CXCL10, which are expressed in muscle affected by idiopathic inflammatory myopathies such as dermatomyositis, declined strongly over the course of 12 weeks of treatment to an extent that was just shy of statistical significance.
Myositis antibody titers didn’t change in response to tofacitinib therapy. Of note, six patients were positive for antitranscriptional intermediary factor 1-gamma, and five of the six were moderate responders to JAK inhibitor therapy.
Four patients were on 20 mg/day of prednisone at baseline; three of the four were able to go off steroids altogether over the course of 12 weeks.
The treatment was well tolerated, with no serious adverse events.
Asked if she thought 11 mg/day of tofacitinib was the right dose for this population of refractory dermatomyositis patients, Dr. Paik replied, “We’re not sure we have the right dose. We had one patient who didn’t have as robust a response, and I really wonder, if we gave her a higher dose, it would have made a difference.”
Extended-release tofacitinib at 11 mg/day is the approved dose for rheumatoid arthritis and psoriatic arthritis. However, 20 mg/day is approved for patients with ulcerative colitis, and Dr. Paik is lobbying for inclusion of a higher-dose arm in the randomized, controlled trial.
Prior to this formal proof-of-concept study, which was funded by Pfizer, the experience with tofacitinib in refractory dermatomyositis was limited to anecdotal case reports.
Dr. Paik reported having no financial conflicts.
SOURCE: Paik JJ et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract L02.
REPORTING FROM THE ACR ANNUAL MEETING
Key clinical point:
Major finding: Among patients with refractory dermatomyositis, the mean Cutaneous Dermatomyositis Disease Area and Severity Index activity score improved from 28 at baseline to 9.5 after 12 weeks on oral tofacitinib.
Study details: This first-in-class, open-label, 12-week study included 10 patients with refractory dermatomyositis placed on extended-release tofacitinib at 11 mg once daily.
Disclosures: The presenter reported having no financial conflicts regarding the study, sponsored by Pfizer.
Source: Paik JJ et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract L02
Scleroderma SCOT trial findings hold similar in lung disease
CHICAGO – Changes in quantitative lung CT scores for scleroderma-related interstitial lung disease independently validate the superiority of hematopoietic stem cell transplantation versus cyclophosphamide for severe systemic sclerosis, according to findings in a subset of patients from the SCOT (Scleroderma: Cyclophosphamide or Transplantation) trial.
The recently published findings from the SCOT trial showed that myeloablation followed by autologous hematopoietic stem cell transplant (HSCT) significantly improved event-free and overall survival of systemic sclerosis patients at 54 months, compared with 12 monthly treatments with intravenous cyclophosphamide (N Engl J Med. 2018;378:35-47).
In a subset of 75 patients from the SCOT trial, the investigators analyzed changes in lung parenchymal abnormalities on high-resolution CT scans between baseline and serial follow-up exams performed yearly for up to 5 years. Follow-up scans at 14, 26, 48, and 54 months in available patients at each time point showed that whole-lung quantitative interstitial lung disease (QILD) scores – a validated measure that combines various CT texture-based characteristics to determine disease extent – decreased significantly by 7% at 54 months in patients who underwent HSCT, compared with no change in those who received cyclophosphamide (CYC; P = .024), Keith M. Sullivan, MD, reported at the annual meeting of the American College of Rheumatology.
Additionally, whole-lung quantitative lung fibrosis (QLF) scores were stable (–1%) in the HSCT patients, but increased 3% in the CYC patients (P = .047), said Dr. Sullivan, a professor of medicine at Duke University, Durham, N.C.
Dr. Sullivan was the first author on the SCOT trial, and he reported the current study results on behalf of lead investigator Jonathan Goldin, MD, PhD, of the department of radiologic sciences at the University of California, Los Angeles.
“These are really kind of meaningful associations, especially since the worst of the [CYC] treatment group didn’t make it to month 54,” Dr. Sullivan said.
Quantitative scores of scleroderma-related interstitial lung disease were measured using computer-based quantitative image analysis of standardized, noncontrast, volumetric, thin-section, thoracic, high-resolution CT. The same CT machine was used for all time points (except for one subject) with careful attention to breath hold reproducibility and image quality. Baseline characteristics were not different between the HSCT and CYC groups, he noted, stressing the rigorous study design.
CT assessments were also compared for the most severe lobe in each patient and showed similar findings, with both QILD and QLF scores for that lobe improving in the HSCT patients relative to the CYC patients (P = .004 and P = .002, respectively), Dr. Sullivan said, adding that the direction of change in structural measures of QILD and QLF for both whole lung and most severe lobe CTs tracked with physiological pulmonary function tests, including forced vital capacity (FVC), forced expiratory volume in 1 second, and diffusing capacity of the lungs for carbon monoxide.
“The FVC improved while QILD decreased, and that’s what you would expect to see,” he said. “So for each of these ways of displaying data, there was an expected and sensible inverse correlation.”
Scleroderma-related interstitial lung disease is a major cause of morbidity and mortality in severe systemic sclerosis. In the wake of the SCOT trial findings, questions remained with respect to correlation between those findings and pulmonary function; if the improvements with HSCT are real and meaningful, they should have meaningful correlation with pulmonary function, and these findings demonstrate those correlates, he said.
“Changes in quantitative lung CT scoring of scleroderma lung disease provide an objective radiologic validation of the long-term benefits of transplant compared to cyclophosphamide in individuals with severe scleroderma and lung involvement. Improvement in imaging after transplant continues for up to 54 months after randomization, giving radiologic confirmation of a durable treatment benefit,” Dr. Sullivan concluded.
The investigators reported having no relevant disclosures.
SOURCE: Goldin J et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 901.
CHICAGO – Changes in quantitative lung CT scores for scleroderma-related interstitial lung disease independently validate the superiority of hematopoietic stem cell transplantation versus cyclophosphamide for severe systemic sclerosis, according to findings in a subset of patients from the SCOT (Scleroderma: Cyclophosphamide or Transplantation) trial.
The recently published findings from the SCOT trial showed that myeloablation followed by autologous hematopoietic stem cell transplant (HSCT) significantly improved event-free and overall survival of systemic sclerosis patients at 54 months, compared with 12 monthly treatments with intravenous cyclophosphamide (N Engl J Med. 2018;378:35-47).
In a subset of 75 patients from the SCOT trial, the investigators analyzed changes in lung parenchymal abnormalities on high-resolution CT scans between baseline and serial follow-up exams performed yearly for up to 5 years. Follow-up scans at 14, 26, 48, and 54 months in available patients at each time point showed that whole-lung quantitative interstitial lung disease (QILD) scores – a validated measure that combines various CT texture-based characteristics to determine disease extent – decreased significantly by 7% at 54 months in patients who underwent HSCT, compared with no change in those who received cyclophosphamide (CYC; P = .024), Keith M. Sullivan, MD, reported at the annual meeting of the American College of Rheumatology.
Additionally, whole-lung quantitative lung fibrosis (QLF) scores were stable (–1%) in the HSCT patients, but increased 3% in the CYC patients (P = .047), said Dr. Sullivan, a professor of medicine at Duke University, Durham, N.C.
Dr. Sullivan was the first author on the SCOT trial, and he reported the current study results on behalf of lead investigator Jonathan Goldin, MD, PhD, of the department of radiologic sciences at the University of California, Los Angeles.
“These are really kind of meaningful associations, especially since the worst of the [CYC] treatment group didn’t make it to month 54,” Dr. Sullivan said.
Quantitative scores of scleroderma-related interstitial lung disease were measured using computer-based quantitative image analysis of standardized, noncontrast, volumetric, thin-section, thoracic, high-resolution CT. The same CT machine was used for all time points (except for one subject) with careful attention to breath hold reproducibility and image quality. Baseline characteristics were not different between the HSCT and CYC groups, he noted, stressing the rigorous study design.
CT assessments were also compared for the most severe lobe in each patient and showed similar findings, with both QILD and QLF scores for that lobe improving in the HSCT patients relative to the CYC patients (P = .004 and P = .002, respectively), Dr. Sullivan said, adding that the direction of change in structural measures of QILD and QLF for both whole lung and most severe lobe CTs tracked with physiological pulmonary function tests, including forced vital capacity (FVC), forced expiratory volume in 1 second, and diffusing capacity of the lungs for carbon monoxide.
“The FVC improved while QILD decreased, and that’s what you would expect to see,” he said. “So for each of these ways of displaying data, there was an expected and sensible inverse correlation.”
Scleroderma-related interstitial lung disease is a major cause of morbidity and mortality in severe systemic sclerosis. In the wake of the SCOT trial findings, questions remained with respect to correlation between those findings and pulmonary function; if the improvements with HSCT are real and meaningful, they should have meaningful correlation with pulmonary function, and these findings demonstrate those correlates, he said.
“Changes in quantitative lung CT scoring of scleroderma lung disease provide an objective radiologic validation of the long-term benefits of transplant compared to cyclophosphamide in individuals with severe scleroderma and lung involvement. Improvement in imaging after transplant continues for up to 54 months after randomization, giving radiologic confirmation of a durable treatment benefit,” Dr. Sullivan concluded.
The investigators reported having no relevant disclosures.
SOURCE: Goldin J et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 901.
CHICAGO – Changes in quantitative lung CT scores for scleroderma-related interstitial lung disease independently validate the superiority of hematopoietic stem cell transplantation versus cyclophosphamide for severe systemic sclerosis, according to findings in a subset of patients from the SCOT (Scleroderma: Cyclophosphamide or Transplantation) trial.
The recently published findings from the SCOT trial showed that myeloablation followed by autologous hematopoietic stem cell transplant (HSCT) significantly improved event-free and overall survival of systemic sclerosis patients at 54 months, compared with 12 monthly treatments with intravenous cyclophosphamide (N Engl J Med. 2018;378:35-47).
In a subset of 75 patients from the SCOT trial, the investigators analyzed changes in lung parenchymal abnormalities on high-resolution CT scans between baseline and serial follow-up exams performed yearly for up to 5 years. Follow-up scans at 14, 26, 48, and 54 months in available patients at each time point showed that whole-lung quantitative interstitial lung disease (QILD) scores – a validated measure that combines various CT texture-based characteristics to determine disease extent – decreased significantly by 7% at 54 months in patients who underwent HSCT, compared with no change in those who received cyclophosphamide (CYC; P = .024), Keith M. Sullivan, MD, reported at the annual meeting of the American College of Rheumatology.
Additionally, whole-lung quantitative lung fibrosis (QLF) scores were stable (–1%) in the HSCT patients, but increased 3% in the CYC patients (P = .047), said Dr. Sullivan, a professor of medicine at Duke University, Durham, N.C.
Dr. Sullivan was the first author on the SCOT trial, and he reported the current study results on behalf of lead investigator Jonathan Goldin, MD, PhD, of the department of radiologic sciences at the University of California, Los Angeles.
“These are really kind of meaningful associations, especially since the worst of the [CYC] treatment group didn’t make it to month 54,” Dr. Sullivan said.
Quantitative scores of scleroderma-related interstitial lung disease were measured using computer-based quantitative image analysis of standardized, noncontrast, volumetric, thin-section, thoracic, high-resolution CT. The same CT machine was used for all time points (except for one subject) with careful attention to breath hold reproducibility and image quality. Baseline characteristics were not different between the HSCT and CYC groups, he noted, stressing the rigorous study design.
CT assessments were also compared for the most severe lobe in each patient and showed similar findings, with both QILD and QLF scores for that lobe improving in the HSCT patients relative to the CYC patients (P = .004 and P = .002, respectively), Dr. Sullivan said, adding that the direction of change in structural measures of QILD and QLF for both whole lung and most severe lobe CTs tracked with physiological pulmonary function tests, including forced vital capacity (FVC), forced expiratory volume in 1 second, and diffusing capacity of the lungs for carbon monoxide.
“The FVC improved while QILD decreased, and that’s what you would expect to see,” he said. “So for each of these ways of displaying data, there was an expected and sensible inverse correlation.”
Scleroderma-related interstitial lung disease is a major cause of morbidity and mortality in severe systemic sclerosis. In the wake of the SCOT trial findings, questions remained with respect to correlation between those findings and pulmonary function; if the improvements with HSCT are real and meaningful, they should have meaningful correlation with pulmonary function, and these findings demonstrate those correlates, he said.
“Changes in quantitative lung CT scoring of scleroderma lung disease provide an objective radiologic validation of the long-term benefits of transplant compared to cyclophosphamide in individuals with severe scleroderma and lung involvement. Improvement in imaging after transplant continues for up to 54 months after randomization, giving radiologic confirmation of a durable treatment benefit,” Dr. Sullivan concluded.
The investigators reported having no relevant disclosures.
SOURCE: Goldin J et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 901.
REPORTING FROM THE ACR ANNUAL MEETING
Key clinical point: Lung CT scores remain stable or improve following hematopoietic stem cell transplantation in patients with scleroderma-related interstitial lung disease when compared against monthly cyclophosphamide treatments.
Major finding: Quantitative interstitial lung disease scores decreased by 7% at 54 months in hematopoietic stem cell transplant patients versus no change in those who received cyclophosphamide (P = .024).
Study details: A study of 75 patients from the SCOT trial.
Disclosures: The investigators reported having no relevant disclosures.
Source: Goldin J et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 901.
Rituximab shines in pediatric vasculitis
CHICAGO – Rituximab demonstrated a high degree of effectiveness with no safety surprises in the first-ever major clinical trial of the potent B-cell inhibitor conducted in pediatric patients with newly diagnosed or relapsing granulomatosis with polyangiitis or microscopic polyangiitis, Jennifer Cooper, MD, PharmD, said at the annual meeting of the American College of Rheumatology.
“This is exciting news. We know that rituximab is very effective in treating adults with GPA and MPA, both in terms of inducing remission and even for maintenance therapy for this rare and severe disease. A lot of pediatric rheumatologists would like to have access to rituximab. Some are even using it for this condition. But until now there were no data in children. I hope this study improves access to rituximab for pediatric patients with ANCA-associated vasculitis,” said Dr. Cooper, a pediatric rheumatologist at the University of Colorado, Denver.
She presented the results of the PePRS (Pediatric Polyangiitis and Rituximab Study), a phase 2a, single-arm, open-label, long-term study of 25 patients in six countries. She anticipates the results will be practice changing, given that pediatric GPA and MPA are recognized as severe systemic autoimmune disorders with a high unmet need for new therapies.
“I don’t believe there are plans for a randomized, controlled trial. Since we now have the pharmacokinetic and safety data in children, we’ll hopefully be able to use extrapolation and our exploratory efficacy endpoints to gain a pediatric indication, or at least a label update for these patients based on this study,” Dr. Cooper continued.
A total of 19 patients had GPA and 6 had MPA, with a median disease duration of 6 months at study entry. All received three pulsed doses of methylprednisolone during the screening period. Then for induction remission they got four once-weekly intravenous infusions of rituximab (Rituxan) at 375 mg/m2 as well as oral corticosteroids, which were tapered from 1 mg/kg per day to 0.2 mg/kg per day over the course of the first 6 months. After that, two-thirds of patients received additional rituximab at their provider’s discretion.
The remission rate by 6 months as defined by Pediatric Vasculitis Activity Score (PVAS) criteria was 56%. At 12 months, the rate was 92%, and at 18 months the rate of remission and sustained disease control was 100%. The mean and median durations of remission were 72 and 56 weeks, respectively.
These results in pediatric patients are comparable to those seen in adults in the landmark RAVE (Rituximab in ANCA-Associated Vasculitis) trial (N Engl J Med. 2013 Aug 1;369[5]:417-27), where 64% of patients reached remission at 6 months, Dr. Cooper noted.
All 25 patients were able to tolerate the four rituximab infusions for remission induction. The main side effect was infusion-related reactions. Overall, 32% of patients experienced such reactions in response to their first infusion, 20% with the second, 12% with the third, and only 8% with the fourth.
Eight patients withdrew from the study after 18 months, mostly because of transfer to adult care. The remaining participants were followed for as long as 4.5 years.
F. Hoffmann-La Roche and Genentech sponsored the PePRS study. Dr. Cooper was a Genentech clinical research fellow at the time.
SOURCE: Brogan P at al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract L04.
CHICAGO – Rituximab demonstrated a high degree of effectiveness with no safety surprises in the first-ever major clinical trial of the potent B-cell inhibitor conducted in pediatric patients with newly diagnosed or relapsing granulomatosis with polyangiitis or microscopic polyangiitis, Jennifer Cooper, MD, PharmD, said at the annual meeting of the American College of Rheumatology.
“This is exciting news. We know that rituximab is very effective in treating adults with GPA and MPA, both in terms of inducing remission and even for maintenance therapy for this rare and severe disease. A lot of pediatric rheumatologists would like to have access to rituximab. Some are even using it for this condition. But until now there were no data in children. I hope this study improves access to rituximab for pediatric patients with ANCA-associated vasculitis,” said Dr. Cooper, a pediatric rheumatologist at the University of Colorado, Denver.
She presented the results of the PePRS (Pediatric Polyangiitis and Rituximab Study), a phase 2a, single-arm, open-label, long-term study of 25 patients in six countries. She anticipates the results will be practice changing, given that pediatric GPA and MPA are recognized as severe systemic autoimmune disorders with a high unmet need for new therapies.
“I don’t believe there are plans for a randomized, controlled trial. Since we now have the pharmacokinetic and safety data in children, we’ll hopefully be able to use extrapolation and our exploratory efficacy endpoints to gain a pediatric indication, or at least a label update for these patients based on this study,” Dr. Cooper continued.
A total of 19 patients had GPA and 6 had MPA, with a median disease duration of 6 months at study entry. All received three pulsed doses of methylprednisolone during the screening period. Then for induction remission they got four once-weekly intravenous infusions of rituximab (Rituxan) at 375 mg/m2 as well as oral corticosteroids, which were tapered from 1 mg/kg per day to 0.2 mg/kg per day over the course of the first 6 months. After that, two-thirds of patients received additional rituximab at their provider’s discretion.
The remission rate by 6 months as defined by Pediatric Vasculitis Activity Score (PVAS) criteria was 56%. At 12 months, the rate was 92%, and at 18 months the rate of remission and sustained disease control was 100%. The mean and median durations of remission were 72 and 56 weeks, respectively.
These results in pediatric patients are comparable to those seen in adults in the landmark RAVE (Rituximab in ANCA-Associated Vasculitis) trial (N Engl J Med. 2013 Aug 1;369[5]:417-27), where 64% of patients reached remission at 6 months, Dr. Cooper noted.
All 25 patients were able to tolerate the four rituximab infusions for remission induction. The main side effect was infusion-related reactions. Overall, 32% of patients experienced such reactions in response to their first infusion, 20% with the second, 12% with the third, and only 8% with the fourth.
Eight patients withdrew from the study after 18 months, mostly because of transfer to adult care. The remaining participants were followed for as long as 4.5 years.
F. Hoffmann-La Roche and Genentech sponsored the PePRS study. Dr. Cooper was a Genentech clinical research fellow at the time.
SOURCE: Brogan P at al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract L04.
CHICAGO – Rituximab demonstrated a high degree of effectiveness with no safety surprises in the first-ever major clinical trial of the potent B-cell inhibitor conducted in pediatric patients with newly diagnosed or relapsing granulomatosis with polyangiitis or microscopic polyangiitis, Jennifer Cooper, MD, PharmD, said at the annual meeting of the American College of Rheumatology.
“This is exciting news. We know that rituximab is very effective in treating adults with GPA and MPA, both in terms of inducing remission and even for maintenance therapy for this rare and severe disease. A lot of pediatric rheumatologists would like to have access to rituximab. Some are even using it for this condition. But until now there were no data in children. I hope this study improves access to rituximab for pediatric patients with ANCA-associated vasculitis,” said Dr. Cooper, a pediatric rheumatologist at the University of Colorado, Denver.
She presented the results of the PePRS (Pediatric Polyangiitis and Rituximab Study), a phase 2a, single-arm, open-label, long-term study of 25 patients in six countries. She anticipates the results will be practice changing, given that pediatric GPA and MPA are recognized as severe systemic autoimmune disorders with a high unmet need for new therapies.
“I don’t believe there are plans for a randomized, controlled trial. Since we now have the pharmacokinetic and safety data in children, we’ll hopefully be able to use extrapolation and our exploratory efficacy endpoints to gain a pediatric indication, or at least a label update for these patients based on this study,” Dr. Cooper continued.
A total of 19 patients had GPA and 6 had MPA, with a median disease duration of 6 months at study entry. All received three pulsed doses of methylprednisolone during the screening period. Then for induction remission they got four once-weekly intravenous infusions of rituximab (Rituxan) at 375 mg/m2 as well as oral corticosteroids, which were tapered from 1 mg/kg per day to 0.2 mg/kg per day over the course of the first 6 months. After that, two-thirds of patients received additional rituximab at their provider’s discretion.
The remission rate by 6 months as defined by Pediatric Vasculitis Activity Score (PVAS) criteria was 56%. At 12 months, the rate was 92%, and at 18 months the rate of remission and sustained disease control was 100%. The mean and median durations of remission were 72 and 56 weeks, respectively.
These results in pediatric patients are comparable to those seen in adults in the landmark RAVE (Rituximab in ANCA-Associated Vasculitis) trial (N Engl J Med. 2013 Aug 1;369[5]:417-27), where 64% of patients reached remission at 6 months, Dr. Cooper noted.
All 25 patients were able to tolerate the four rituximab infusions for remission induction. The main side effect was infusion-related reactions. Overall, 32% of patients experienced such reactions in response to their first infusion, 20% with the second, 12% with the third, and only 8% with the fourth.
Eight patients withdrew from the study after 18 months, mostly because of transfer to adult care. The remaining participants were followed for as long as 4.5 years.
F. Hoffmann-La Roche and Genentech sponsored the PePRS study. Dr. Cooper was a Genentech clinical research fellow at the time.
SOURCE: Brogan P at al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract L04.
REPORTING FROM THE ACR ANNUAL MEETING
Key clinical point:
Major finding: The first clinical trial of rituximab for newly diagnosed or relapsing GPA or MPA in pediatric patients showed remission rates of 56%, 92%, and 100% by months 6, 12, and 18, respectively.
Study details: The PePRS study was a phase 2a, single-arm, open-label, long-term study of 25 patients in six countries.
Disclosures: F. Hoffmann-La Roche and Genentech sponsored the study. The presenter was a Genentech clinical research fellow at the time.
Source: Brogan P at al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract L04.