User login
Down syndrome arthritis: Distinct from JIA and missed in the clinic
ATLANTA – Pediatric Down syndrome arthritis is more aggressive and severe than juvenile idiopathic arthritis (JIA), but it’s underrecognized and undertreated, according to reports at the annual meeting of the American College of Rheumatology.
“The vast majority of parents don’t know their kids are at risk for arthritis,” and a lot of doctors don’t realize it, either. Meanwhile, children show up in the clinic a year or more into the process with irreversible joint damage, said pediatric rheumatologist Jordan Jones, DO, an assistant professor at the University of Missouri, Kansas City, and the lead investigator on a review of 36 children with Down syndrome (DS) in the national Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry.
One solution is to add routine musculoskeletal exams to American Academy of Pediatrics DS guidelines, something Dr. Jones said he and his colleagues are hoping to do.
Part of the problem is that children with DS have a hard time articulating and localizing pain, and it’s easy to attribute functional issues to DS itself. Charlene Foley, MD, PhD, from the National Centre for Paediatric Rheumatology in Dublin, said she’s seen “loads of cases” in which parents were told that their children were acting up, probably because of the DS, when they didn’t want to walk down stairs anymore or hold their parent’s hand.
She was the lead investigator on an Irish program that screened 503 DS children, about one-third of the country’s pediatric DS population, for arthritis; 33 cases were identified, including 18 new ones. Most of the children had polyarticular, rheumatoid factor–negative arthritis, and all of them were antinuclear antibody negative.
A key take-home from the work is that DS arthritis preferentially attacks the hands and wrists and was present exclusively in the hands and wrists of about one-third of the Irish cohort. “So, if you only have a second to examine a child or you can’t get them to sit still, just go straight for the hands, and have a low threshold for imaging,” Dr. Foley said.
DS arthritis is often considered a subtype of JIA, but findings from the studies call that into question and suggest the need for novel therapeutic targets, the investigators said.
The Irish team found that 42% of their subjects (14 of 33) had joint erosions, far more than the 14% of JIA children (3 of 21) who served as controls, and Dr. Foley and colleagues didn’t think that was solely because of delayed diagnosis. Also, at about 20 cases per 1,000, they estimated that arthritis was far more prevalent in DS than was JIA in the general pediatrics population.
Disease onset was at a mean of 7.1 years in Dr. Jones’ CARRA registry review, and mean delay to diagnosis was 11.5 months. The 36 children presented with an average of four affected joints. Only 22% (8 of 36) had elevated inflammatory markers; just one-third were positive for antinuclear antibody, and 17% for human leukocyte antigen B27. It means that “these kids can present with normal labs, even with very aggressive disease. The threshold of concern for arthritis has to be very high when you evaluate these children,” Dr. Jones said.
Treatment was initiated with disease-modifying antirheumatic drugs (DMARDs) in two-thirds of the registry children, often with a concomitant biologic, most commonly etanercept. Over half had at least one switch during a mean follow-up of 4.5 years; methotrexate was a leading culprit, frequently discontinued because of nausea and other problems, and biologics were changed for lack of effect. Active joint counts and physician assessments improved, but there were no significant changes in limited joint counts and health assessments.
In short, “the current therapies for JIA appear to be poorly tolerated, more toxic, and less effective in patients with Down syndrome. These kids don’t respond the same. They have a very high disease burden despite being treated aggressively,” Dr. Jones said.
That finding adds additional weight to the idea that DS arthritis is a distinct disease entity, with unique therapeutic targets. “Down syndrome has a lot of immunologic issues associated with it; maybe that’s it. I think in the next few years, we will be able to show that this is a different disease,” Dr. Jones said.
There was a boost in that direction from benchwork, also led and presented by Dr. Foley, that found significant immunologic, histologic, and genetic differences between JIA and DS arthritis, including lower CD19- and CD20-positive B-cell counts in DS arthritis and higher interferon-gamma and tumor necrosis factor–alpha production, greater synovial lining hyperplasia, and different minor allele frequencies.
There was no industry funding for the studies, and the investigators didn’t have any industry disclosures.
SOURCES: Jones J et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 2722; Foley C et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1817; and Foley C et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 781
ATLANTA – Pediatric Down syndrome arthritis is more aggressive and severe than juvenile idiopathic arthritis (JIA), but it’s underrecognized and undertreated, according to reports at the annual meeting of the American College of Rheumatology.
“The vast majority of parents don’t know their kids are at risk for arthritis,” and a lot of doctors don’t realize it, either. Meanwhile, children show up in the clinic a year or more into the process with irreversible joint damage, said pediatric rheumatologist Jordan Jones, DO, an assistant professor at the University of Missouri, Kansas City, and the lead investigator on a review of 36 children with Down syndrome (DS) in the national Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry.
One solution is to add routine musculoskeletal exams to American Academy of Pediatrics DS guidelines, something Dr. Jones said he and his colleagues are hoping to do.
Part of the problem is that children with DS have a hard time articulating and localizing pain, and it’s easy to attribute functional issues to DS itself. Charlene Foley, MD, PhD, from the National Centre for Paediatric Rheumatology in Dublin, said she’s seen “loads of cases” in which parents were told that their children were acting up, probably because of the DS, when they didn’t want to walk down stairs anymore or hold their parent’s hand.
She was the lead investigator on an Irish program that screened 503 DS children, about one-third of the country’s pediatric DS population, for arthritis; 33 cases were identified, including 18 new ones. Most of the children had polyarticular, rheumatoid factor–negative arthritis, and all of them were antinuclear antibody negative.
A key take-home from the work is that DS arthritis preferentially attacks the hands and wrists and was present exclusively in the hands and wrists of about one-third of the Irish cohort. “So, if you only have a second to examine a child or you can’t get them to sit still, just go straight for the hands, and have a low threshold for imaging,” Dr. Foley said.
DS arthritis is often considered a subtype of JIA, but findings from the studies call that into question and suggest the need for novel therapeutic targets, the investigators said.
The Irish team found that 42% of their subjects (14 of 33) had joint erosions, far more than the 14% of JIA children (3 of 21) who served as controls, and Dr. Foley and colleagues didn’t think that was solely because of delayed diagnosis. Also, at about 20 cases per 1,000, they estimated that arthritis was far more prevalent in DS than was JIA in the general pediatrics population.
Disease onset was at a mean of 7.1 years in Dr. Jones’ CARRA registry review, and mean delay to diagnosis was 11.5 months. The 36 children presented with an average of four affected joints. Only 22% (8 of 36) had elevated inflammatory markers; just one-third were positive for antinuclear antibody, and 17% for human leukocyte antigen B27. It means that “these kids can present with normal labs, even with very aggressive disease. The threshold of concern for arthritis has to be very high when you evaluate these children,” Dr. Jones said.
Treatment was initiated with disease-modifying antirheumatic drugs (DMARDs) in two-thirds of the registry children, often with a concomitant biologic, most commonly etanercept. Over half had at least one switch during a mean follow-up of 4.5 years; methotrexate was a leading culprit, frequently discontinued because of nausea and other problems, and biologics were changed for lack of effect. Active joint counts and physician assessments improved, but there were no significant changes in limited joint counts and health assessments.
In short, “the current therapies for JIA appear to be poorly tolerated, more toxic, and less effective in patients with Down syndrome. These kids don’t respond the same. They have a very high disease burden despite being treated aggressively,” Dr. Jones said.
That finding adds additional weight to the idea that DS arthritis is a distinct disease entity, with unique therapeutic targets. “Down syndrome has a lot of immunologic issues associated with it; maybe that’s it. I think in the next few years, we will be able to show that this is a different disease,” Dr. Jones said.
There was a boost in that direction from benchwork, also led and presented by Dr. Foley, that found significant immunologic, histologic, and genetic differences between JIA and DS arthritis, including lower CD19- and CD20-positive B-cell counts in DS arthritis and higher interferon-gamma and tumor necrosis factor–alpha production, greater synovial lining hyperplasia, and different minor allele frequencies.
There was no industry funding for the studies, and the investigators didn’t have any industry disclosures.
SOURCES: Jones J et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 2722; Foley C et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1817; and Foley C et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 781
ATLANTA – Pediatric Down syndrome arthritis is more aggressive and severe than juvenile idiopathic arthritis (JIA), but it’s underrecognized and undertreated, according to reports at the annual meeting of the American College of Rheumatology.
“The vast majority of parents don’t know their kids are at risk for arthritis,” and a lot of doctors don’t realize it, either. Meanwhile, children show up in the clinic a year or more into the process with irreversible joint damage, said pediatric rheumatologist Jordan Jones, DO, an assistant professor at the University of Missouri, Kansas City, and the lead investigator on a review of 36 children with Down syndrome (DS) in the national Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry.
One solution is to add routine musculoskeletal exams to American Academy of Pediatrics DS guidelines, something Dr. Jones said he and his colleagues are hoping to do.
Part of the problem is that children with DS have a hard time articulating and localizing pain, and it’s easy to attribute functional issues to DS itself. Charlene Foley, MD, PhD, from the National Centre for Paediatric Rheumatology in Dublin, said she’s seen “loads of cases” in which parents were told that their children were acting up, probably because of the DS, when they didn’t want to walk down stairs anymore or hold their parent’s hand.
She was the lead investigator on an Irish program that screened 503 DS children, about one-third of the country’s pediatric DS population, for arthritis; 33 cases were identified, including 18 new ones. Most of the children had polyarticular, rheumatoid factor–negative arthritis, and all of them were antinuclear antibody negative.
A key take-home from the work is that DS arthritis preferentially attacks the hands and wrists and was present exclusively in the hands and wrists of about one-third of the Irish cohort. “So, if you only have a second to examine a child or you can’t get them to sit still, just go straight for the hands, and have a low threshold for imaging,” Dr. Foley said.
DS arthritis is often considered a subtype of JIA, but findings from the studies call that into question and suggest the need for novel therapeutic targets, the investigators said.
The Irish team found that 42% of their subjects (14 of 33) had joint erosions, far more than the 14% of JIA children (3 of 21) who served as controls, and Dr. Foley and colleagues didn’t think that was solely because of delayed diagnosis. Also, at about 20 cases per 1,000, they estimated that arthritis was far more prevalent in DS than was JIA in the general pediatrics population.
Disease onset was at a mean of 7.1 years in Dr. Jones’ CARRA registry review, and mean delay to diagnosis was 11.5 months. The 36 children presented with an average of four affected joints. Only 22% (8 of 36) had elevated inflammatory markers; just one-third were positive for antinuclear antibody, and 17% for human leukocyte antigen B27. It means that “these kids can present with normal labs, even with very aggressive disease. The threshold of concern for arthritis has to be very high when you evaluate these children,” Dr. Jones said.
Treatment was initiated with disease-modifying antirheumatic drugs (DMARDs) in two-thirds of the registry children, often with a concomitant biologic, most commonly etanercept. Over half had at least one switch during a mean follow-up of 4.5 years; methotrexate was a leading culprit, frequently discontinued because of nausea and other problems, and biologics were changed for lack of effect. Active joint counts and physician assessments improved, but there were no significant changes in limited joint counts and health assessments.
In short, “the current therapies for JIA appear to be poorly tolerated, more toxic, and less effective in patients with Down syndrome. These kids don’t respond the same. They have a very high disease burden despite being treated aggressively,” Dr. Jones said.
That finding adds additional weight to the idea that DS arthritis is a distinct disease entity, with unique therapeutic targets. “Down syndrome has a lot of immunologic issues associated with it; maybe that’s it. I think in the next few years, we will be able to show that this is a different disease,” Dr. Jones said.
There was a boost in that direction from benchwork, also led and presented by Dr. Foley, that found significant immunologic, histologic, and genetic differences between JIA and DS arthritis, including lower CD19- and CD20-positive B-cell counts in DS arthritis and higher interferon-gamma and tumor necrosis factor–alpha production, greater synovial lining hyperplasia, and different minor allele frequencies.
There was no industry funding for the studies, and the investigators didn’t have any industry disclosures.
SOURCES: Jones J et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 2722; Foley C et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1817; and Foley C et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 781
REPORTING FROM ACR 2019
Adult atopic dermatitis brings increased osteoporosis risk
MADRID – – even if they’ve never taken systemic corticosteroids, according to a large observational Danish national registry study.
A key study finding was that these elevated risks were concentrated in the patients who used potent or superpotent topical corticosteroids. Adult AD patients who used mild- or moderate-potency topical steroids were not at significantly increased risk. Neither were patients on topical calcineurin inhibitors, Jacob P. Thyssen, MD, PhD, reported at a meeting of the European Task Force on Atopic Dermatitis held in conjunction with the annual congress of the European Academy of Dermatology and Venereology.
“The absolute risk is low, but it’s real,” commented Dr. Thyssen, professor of dermatology at the University of Copenhagen.
His advice to colleagues: “Dermatologists should consider alternative treatments in the chronic excessive users of topical corticosteroids, or use them in combination with prophylactic treatment to preserve bone homeostasis in such patients.”
He presented the results of a retrospective case-control study of 10,636 Danish adults with AD and 87,989 matched controls. At baseline in this study, which featured a maximum of 20 years of follow-up starting in 1997, participants had no history of osteoporosis.
Dr. Thyssen expressed the absolute risk of being diagnosed with osteoporosis in the study as follows: If 10,000 adult AD patients were followed for 1 year, on average 23.5 of them would be diagnosed with osteoporosis, a rate more than double the 10.3 per 10,000 in the general population. Moreover, on average, 42.6 out of 10,000 adult AD patients would incur a major osteoporotic fracture during a year of follow-up, compared with 32.3 individuals in the general population.
In the subgroup of patients who never used systemic corticosteroids, the risk of being diagnosed with osteoporosis was 12.8 per 10,000 per year, significantly higher than the 7.4 per 10,000 rate in the general population. Similarly, the 1-year rate of major osteoporotic fractures was 33.1 per 10,000 among the AD group and 29.6 in matched controls.
In a Cox regression analysis adjusted for age, sex, socioeconomic status, body mass index, asthma, and the use of a variety of medications thought to potentially have a negative effect upon bone metabolism, the risk of osteoporosis in the entire group of 10,636 adult AD patients was 51% greater than in matched controls, and their risk of major osteoporotic fractures was 18% greater. In the subgroup of AD patients who never used systemic steroids, the risks of osteoporosis and major osteoporotic fractures were 82% and 14% greater than in controls. The medications adjusted for in the regression analysis included proton pump inhibitors, thiazide diuretics, H2 receptor blockers, statins, cyclosporine, hormone therapy, contraceptives, and psychotropic medications.
Scoring Atopic Dermatitis (SCORAD) ratings were available on roughly 4,000 of the adult AD patients. In an analysis of this large subgroup, disease severity as reflected in SCORAD scores did not explain the increased osteoporosis and fracture risks. However, the use of potent or superpotent topical corticosteroids did. Patients who used potent topical steroids had a statistically significant 16% increased risk of being diagnosed with osteoporosis than nonusers, as well as a 7% increased risk of major osteoporotic fractures. Patients who applied superpotent topical steroids had 42% and 18% increased risks of those two adverse outcomes.
In contrast, neither the use of topical calcineurin inhibitors nor mild- or mid-potency topical steroids was associated with increased risk of bone events in a Cox regression analysis adjusted for potential confounders.
A relationship between the use of high-potency topical corticosteroids and adverse bone events is biologically plausible, according to Dr. Thyssen. He and his coinvestigators have previously documented a 100%-400% increased rate of chemical penetration through atopic skin, which is notoriously barrier damaged.
“We find it very likely that, if you put topical steroids on atopic skin in high amounts and for a very long time, you may have systemic effects,” he said.
A great many adult AD patients do exactly that. When Dr. Thyssen and coworkers analyzed Danish national prescription drug registry data for their patient cohort, they found that roughly one-third of the elderly subgroup had filled prescriptions totaling greater than 2 kg of mometasone or other similar-potency steroids over the previous 10 years.
“So we know that a significant proportion of our atopic dermatitis patients are really high users of topical corticosteroids,” the dermatologist noted.
Dr. Thyssen’s national osteoporosis and fracture study was funded with a government research grant. He reported serving as an advisor to and/or recipient of research grants from AbbVie, Pfizer, Leo Pharma, Eli Lilly, Regeneron, Sanofi Genzyme, and Union Therapeutics.
MADRID – – even if they’ve never taken systemic corticosteroids, according to a large observational Danish national registry study.
A key study finding was that these elevated risks were concentrated in the patients who used potent or superpotent topical corticosteroids. Adult AD patients who used mild- or moderate-potency topical steroids were not at significantly increased risk. Neither were patients on topical calcineurin inhibitors, Jacob P. Thyssen, MD, PhD, reported at a meeting of the European Task Force on Atopic Dermatitis held in conjunction with the annual congress of the European Academy of Dermatology and Venereology.
“The absolute risk is low, but it’s real,” commented Dr. Thyssen, professor of dermatology at the University of Copenhagen.
His advice to colleagues: “Dermatologists should consider alternative treatments in the chronic excessive users of topical corticosteroids, or use them in combination with prophylactic treatment to preserve bone homeostasis in such patients.”
He presented the results of a retrospective case-control study of 10,636 Danish adults with AD and 87,989 matched controls. At baseline in this study, which featured a maximum of 20 years of follow-up starting in 1997, participants had no history of osteoporosis.
Dr. Thyssen expressed the absolute risk of being diagnosed with osteoporosis in the study as follows: If 10,000 adult AD patients were followed for 1 year, on average 23.5 of them would be diagnosed with osteoporosis, a rate more than double the 10.3 per 10,000 in the general population. Moreover, on average, 42.6 out of 10,000 adult AD patients would incur a major osteoporotic fracture during a year of follow-up, compared with 32.3 individuals in the general population.
In the subgroup of patients who never used systemic corticosteroids, the risk of being diagnosed with osteoporosis was 12.8 per 10,000 per year, significantly higher than the 7.4 per 10,000 rate in the general population. Similarly, the 1-year rate of major osteoporotic fractures was 33.1 per 10,000 among the AD group and 29.6 in matched controls.
In a Cox regression analysis adjusted for age, sex, socioeconomic status, body mass index, asthma, and the use of a variety of medications thought to potentially have a negative effect upon bone metabolism, the risk of osteoporosis in the entire group of 10,636 adult AD patients was 51% greater than in matched controls, and their risk of major osteoporotic fractures was 18% greater. In the subgroup of AD patients who never used systemic steroids, the risks of osteoporosis and major osteoporotic fractures were 82% and 14% greater than in controls. The medications adjusted for in the regression analysis included proton pump inhibitors, thiazide diuretics, H2 receptor blockers, statins, cyclosporine, hormone therapy, contraceptives, and psychotropic medications.
Scoring Atopic Dermatitis (SCORAD) ratings were available on roughly 4,000 of the adult AD patients. In an analysis of this large subgroup, disease severity as reflected in SCORAD scores did not explain the increased osteoporosis and fracture risks. However, the use of potent or superpotent topical corticosteroids did. Patients who used potent topical steroids had a statistically significant 16% increased risk of being diagnosed with osteoporosis than nonusers, as well as a 7% increased risk of major osteoporotic fractures. Patients who applied superpotent topical steroids had 42% and 18% increased risks of those two adverse outcomes.
In contrast, neither the use of topical calcineurin inhibitors nor mild- or mid-potency topical steroids was associated with increased risk of bone events in a Cox regression analysis adjusted for potential confounders.
A relationship between the use of high-potency topical corticosteroids and adverse bone events is biologically plausible, according to Dr. Thyssen. He and his coinvestigators have previously documented a 100%-400% increased rate of chemical penetration through atopic skin, which is notoriously barrier damaged.
“We find it very likely that, if you put topical steroids on atopic skin in high amounts and for a very long time, you may have systemic effects,” he said.
A great many adult AD patients do exactly that. When Dr. Thyssen and coworkers analyzed Danish national prescription drug registry data for their patient cohort, they found that roughly one-third of the elderly subgroup had filled prescriptions totaling greater than 2 kg of mometasone or other similar-potency steroids over the previous 10 years.
“So we know that a significant proportion of our atopic dermatitis patients are really high users of topical corticosteroids,” the dermatologist noted.
Dr. Thyssen’s national osteoporosis and fracture study was funded with a government research grant. He reported serving as an advisor to and/or recipient of research grants from AbbVie, Pfizer, Leo Pharma, Eli Lilly, Regeneron, Sanofi Genzyme, and Union Therapeutics.
MADRID – – even if they’ve never taken systemic corticosteroids, according to a large observational Danish national registry study.
A key study finding was that these elevated risks were concentrated in the patients who used potent or superpotent topical corticosteroids. Adult AD patients who used mild- or moderate-potency topical steroids were not at significantly increased risk. Neither were patients on topical calcineurin inhibitors, Jacob P. Thyssen, MD, PhD, reported at a meeting of the European Task Force on Atopic Dermatitis held in conjunction with the annual congress of the European Academy of Dermatology and Venereology.
“The absolute risk is low, but it’s real,” commented Dr. Thyssen, professor of dermatology at the University of Copenhagen.
His advice to colleagues: “Dermatologists should consider alternative treatments in the chronic excessive users of topical corticosteroids, or use them in combination with prophylactic treatment to preserve bone homeostasis in such patients.”
He presented the results of a retrospective case-control study of 10,636 Danish adults with AD and 87,989 matched controls. At baseline in this study, which featured a maximum of 20 years of follow-up starting in 1997, participants had no history of osteoporosis.
Dr. Thyssen expressed the absolute risk of being diagnosed with osteoporosis in the study as follows: If 10,000 adult AD patients were followed for 1 year, on average 23.5 of them would be diagnosed with osteoporosis, a rate more than double the 10.3 per 10,000 in the general population. Moreover, on average, 42.6 out of 10,000 adult AD patients would incur a major osteoporotic fracture during a year of follow-up, compared with 32.3 individuals in the general population.
In the subgroup of patients who never used systemic corticosteroids, the risk of being diagnosed with osteoporosis was 12.8 per 10,000 per year, significantly higher than the 7.4 per 10,000 rate in the general population. Similarly, the 1-year rate of major osteoporotic fractures was 33.1 per 10,000 among the AD group and 29.6 in matched controls.
In a Cox regression analysis adjusted for age, sex, socioeconomic status, body mass index, asthma, and the use of a variety of medications thought to potentially have a negative effect upon bone metabolism, the risk of osteoporosis in the entire group of 10,636 adult AD patients was 51% greater than in matched controls, and their risk of major osteoporotic fractures was 18% greater. In the subgroup of AD patients who never used systemic steroids, the risks of osteoporosis and major osteoporotic fractures were 82% and 14% greater than in controls. The medications adjusted for in the regression analysis included proton pump inhibitors, thiazide diuretics, H2 receptor blockers, statins, cyclosporine, hormone therapy, contraceptives, and psychotropic medications.
Scoring Atopic Dermatitis (SCORAD) ratings were available on roughly 4,000 of the adult AD patients. In an analysis of this large subgroup, disease severity as reflected in SCORAD scores did not explain the increased osteoporosis and fracture risks. However, the use of potent or superpotent topical corticosteroids did. Patients who used potent topical steroids had a statistically significant 16% increased risk of being diagnosed with osteoporosis than nonusers, as well as a 7% increased risk of major osteoporotic fractures. Patients who applied superpotent topical steroids had 42% and 18% increased risks of those two adverse outcomes.
In contrast, neither the use of topical calcineurin inhibitors nor mild- or mid-potency topical steroids was associated with increased risk of bone events in a Cox regression analysis adjusted for potential confounders.
A relationship between the use of high-potency topical corticosteroids and adverse bone events is biologically plausible, according to Dr. Thyssen. He and his coinvestigators have previously documented a 100%-400% increased rate of chemical penetration through atopic skin, which is notoriously barrier damaged.
“We find it very likely that, if you put topical steroids on atopic skin in high amounts and for a very long time, you may have systemic effects,” he said.
A great many adult AD patients do exactly that. When Dr. Thyssen and coworkers analyzed Danish national prescription drug registry data for their patient cohort, they found that roughly one-third of the elderly subgroup had filled prescriptions totaling greater than 2 kg of mometasone or other similar-potency steroids over the previous 10 years.
“So we know that a significant proportion of our atopic dermatitis patients are really high users of topical corticosteroids,” the dermatologist noted.
Dr. Thyssen’s national osteoporosis and fracture study was funded with a government research grant. He reported serving as an advisor to and/or recipient of research grants from AbbVie, Pfizer, Leo Pharma, Eli Lilly, Regeneron, Sanofi Genzyme, and Union Therapeutics.
REPORTING FROM EADV 2019
Tofacitinib improves disease activity in patients with polyarticular-course JIA
ATLANTA – Treatment of polyarticular-course juvenile idiopathic arthritis with tofacitinib led to significantly fewer disease flares and greater improvement in disease activity than with placebo in a phase 3, multinational, randomized, double-blind, controlled withdrawal study presented at the annual meeting of the American College of Rheumatology.
Hermine I. Brunner, MD, director of the division of rheumatology at Cincinnati Children’s Hospital Medical Center, and colleagues conducted the study in 225 patients between 2 and less than 18 years old with polyarticular-course juvenile idiopathic arthritis (pJIA; n = 184), psoriatic arthritis (PsA; n = 20), or enthesitis-related arthritis (ERA; n = 21). Patients were included if they had an inadequate response or intolerance to a disease-modifying antirheumatic drug and active disease with five or more active joints in the case of pJIA and three or more active joints in PsA or ERA.
Dr. Brunner presented results only for pJIA patients; the results for PsA and ERA patients will be assessed and presented separately.
The researchers divided their study into two sections. In the open-label portion of the study, patients received twice-daily tofacitinib (Xeljanz) at a dose of 5 mg or a weight-based lower dose in patients under 40 kg for 18 weeks. A total of 173 patients met JIA ACR30 response criteria, defined as 30% or greater improvement in three of six JIA core set variables and worsening in no more than one of the core set variables, and then were randomized in part 2 of the study to continue the same dose of tofacitinib or receive placebo until 44 weeks. Dr. Brunner noted that most patients who discontinued treatment in parts 1 and 2 did so because of insufficient clinical response rather than from adverse events.
Disease flare occurrence between 18 and 44 weeks was measured as a primary endpoint, and key secondary endpoints included JIA ACR30/50/70 response and change in Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI) scores from part 2 baseline. The researchers used a “gatekeeping approach” that sequenced outcome measures in their statistical analysis to control for false positives in primary and secondary outcomes, where statistical significance could be achieved only if the previous outcome in the sequence was statistically significant.
Patients had a median age of 13 years, and most were female, white (about 87%), and between one-third and one-half of patients were based in North America. JIA disease duration was a median of about 2.5 years, C-reactive protein was about 0.3 mg/dL, and median CHAQ-DI scores were about 0.9 across tofacitinib and placebo groups. Other baseline characteristics were balanced between the two groups, Dr. Brunner said.
“Patients with polyarticular-course JIA in the open-label study experienced a rapid improvement of their disease activity from very high to moderate within 18 weeks,” Dr. Brunner said in her presentation. “[T]ofacitinib demonstrated significantly greater efficacy versus placebo in patients with polyarticular-course JIA based on occurrence of fewer flares in part 2.”
Specifically, disease flare occurred in 29.2% of patients by 44 weeks in the tofacitinib group, compared with 52.9% of patients in the placebo group (P = .0031), for an overall 54% lower risk of flare among patients receiving tofacitinib (hazard ratio, 0.459; 95% confidence interval, 0.268-0.785; P = .0037). The response rate was higher for patients receiving tofacitinib at 44 weeks when measured by JIA ACR30 (70.8% vs. 47.1% with placebo; P = .0031) or by JIA ACR50 (66.7% vs. 47.1%; P = .0166) and JIA ACR70 criteria (54.2% vs. 37.1%; P = .0387). The change in CHAQ-DI score also improved at 44 weeks to a significantly greater extent in the tofacitinib group than with placebo (–0.09 vs. 0.03; P = .0292).
“The safety profile of tofacitinib in children with JIA was comparable to what you have seen or known in the [rheumatoid arthritis] population, and no new safety risks were identified in this pediatric population,” Dr. Brunner said.
The researchers reported ties with Pfizer, which funded the study, and more than two dozen other pharmaceutical companies.
SOURCE: Brunner HI et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract L22.
ATLANTA – Treatment of polyarticular-course juvenile idiopathic arthritis with tofacitinib led to significantly fewer disease flares and greater improvement in disease activity than with placebo in a phase 3, multinational, randomized, double-blind, controlled withdrawal study presented at the annual meeting of the American College of Rheumatology.
Hermine I. Brunner, MD, director of the division of rheumatology at Cincinnati Children’s Hospital Medical Center, and colleagues conducted the study in 225 patients between 2 and less than 18 years old with polyarticular-course juvenile idiopathic arthritis (pJIA; n = 184), psoriatic arthritis (PsA; n = 20), or enthesitis-related arthritis (ERA; n = 21). Patients were included if they had an inadequate response or intolerance to a disease-modifying antirheumatic drug and active disease with five or more active joints in the case of pJIA and three or more active joints in PsA or ERA.
Dr. Brunner presented results only for pJIA patients; the results for PsA and ERA patients will be assessed and presented separately.
The researchers divided their study into two sections. In the open-label portion of the study, patients received twice-daily tofacitinib (Xeljanz) at a dose of 5 mg or a weight-based lower dose in patients under 40 kg for 18 weeks. A total of 173 patients met JIA ACR30 response criteria, defined as 30% or greater improvement in three of six JIA core set variables and worsening in no more than one of the core set variables, and then were randomized in part 2 of the study to continue the same dose of tofacitinib or receive placebo until 44 weeks. Dr. Brunner noted that most patients who discontinued treatment in parts 1 and 2 did so because of insufficient clinical response rather than from adverse events.
Disease flare occurrence between 18 and 44 weeks was measured as a primary endpoint, and key secondary endpoints included JIA ACR30/50/70 response and change in Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI) scores from part 2 baseline. The researchers used a “gatekeeping approach” that sequenced outcome measures in their statistical analysis to control for false positives in primary and secondary outcomes, where statistical significance could be achieved only if the previous outcome in the sequence was statistically significant.
Patients had a median age of 13 years, and most were female, white (about 87%), and between one-third and one-half of patients were based in North America. JIA disease duration was a median of about 2.5 years, C-reactive protein was about 0.3 mg/dL, and median CHAQ-DI scores were about 0.9 across tofacitinib and placebo groups. Other baseline characteristics were balanced between the two groups, Dr. Brunner said.
“Patients with polyarticular-course JIA in the open-label study experienced a rapid improvement of their disease activity from very high to moderate within 18 weeks,” Dr. Brunner said in her presentation. “[T]ofacitinib demonstrated significantly greater efficacy versus placebo in patients with polyarticular-course JIA based on occurrence of fewer flares in part 2.”
Specifically, disease flare occurred in 29.2% of patients by 44 weeks in the tofacitinib group, compared with 52.9% of patients in the placebo group (P = .0031), for an overall 54% lower risk of flare among patients receiving tofacitinib (hazard ratio, 0.459; 95% confidence interval, 0.268-0.785; P = .0037). The response rate was higher for patients receiving tofacitinib at 44 weeks when measured by JIA ACR30 (70.8% vs. 47.1% with placebo; P = .0031) or by JIA ACR50 (66.7% vs. 47.1%; P = .0166) and JIA ACR70 criteria (54.2% vs. 37.1%; P = .0387). The change in CHAQ-DI score also improved at 44 weeks to a significantly greater extent in the tofacitinib group than with placebo (–0.09 vs. 0.03; P = .0292).
“The safety profile of tofacitinib in children with JIA was comparable to what you have seen or known in the [rheumatoid arthritis] population, and no new safety risks were identified in this pediatric population,” Dr. Brunner said.
The researchers reported ties with Pfizer, which funded the study, and more than two dozen other pharmaceutical companies.
SOURCE: Brunner HI et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract L22.
ATLANTA – Treatment of polyarticular-course juvenile idiopathic arthritis with tofacitinib led to significantly fewer disease flares and greater improvement in disease activity than with placebo in a phase 3, multinational, randomized, double-blind, controlled withdrawal study presented at the annual meeting of the American College of Rheumatology.
Hermine I. Brunner, MD, director of the division of rheumatology at Cincinnati Children’s Hospital Medical Center, and colleagues conducted the study in 225 patients between 2 and less than 18 years old with polyarticular-course juvenile idiopathic arthritis (pJIA; n = 184), psoriatic arthritis (PsA; n = 20), or enthesitis-related arthritis (ERA; n = 21). Patients were included if they had an inadequate response or intolerance to a disease-modifying antirheumatic drug and active disease with five or more active joints in the case of pJIA and three or more active joints in PsA or ERA.
Dr. Brunner presented results only for pJIA patients; the results for PsA and ERA patients will be assessed and presented separately.
The researchers divided their study into two sections. In the open-label portion of the study, patients received twice-daily tofacitinib (Xeljanz) at a dose of 5 mg or a weight-based lower dose in patients under 40 kg for 18 weeks. A total of 173 patients met JIA ACR30 response criteria, defined as 30% or greater improvement in three of six JIA core set variables and worsening in no more than one of the core set variables, and then were randomized in part 2 of the study to continue the same dose of tofacitinib or receive placebo until 44 weeks. Dr. Brunner noted that most patients who discontinued treatment in parts 1 and 2 did so because of insufficient clinical response rather than from adverse events.
Disease flare occurrence between 18 and 44 weeks was measured as a primary endpoint, and key secondary endpoints included JIA ACR30/50/70 response and change in Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI) scores from part 2 baseline. The researchers used a “gatekeeping approach” that sequenced outcome measures in their statistical analysis to control for false positives in primary and secondary outcomes, where statistical significance could be achieved only if the previous outcome in the sequence was statistically significant.
Patients had a median age of 13 years, and most were female, white (about 87%), and between one-third and one-half of patients were based in North America. JIA disease duration was a median of about 2.5 years, C-reactive protein was about 0.3 mg/dL, and median CHAQ-DI scores were about 0.9 across tofacitinib and placebo groups. Other baseline characteristics were balanced between the two groups, Dr. Brunner said.
“Patients with polyarticular-course JIA in the open-label study experienced a rapid improvement of their disease activity from very high to moderate within 18 weeks,” Dr. Brunner said in her presentation. “[T]ofacitinib demonstrated significantly greater efficacy versus placebo in patients with polyarticular-course JIA based on occurrence of fewer flares in part 2.”
Specifically, disease flare occurred in 29.2% of patients by 44 weeks in the tofacitinib group, compared with 52.9% of patients in the placebo group (P = .0031), for an overall 54% lower risk of flare among patients receiving tofacitinib (hazard ratio, 0.459; 95% confidence interval, 0.268-0.785; P = .0037). The response rate was higher for patients receiving tofacitinib at 44 weeks when measured by JIA ACR30 (70.8% vs. 47.1% with placebo; P = .0031) or by JIA ACR50 (66.7% vs. 47.1%; P = .0166) and JIA ACR70 criteria (54.2% vs. 37.1%; P = .0387). The change in CHAQ-DI score also improved at 44 weeks to a significantly greater extent in the tofacitinib group than with placebo (–0.09 vs. 0.03; P = .0292).
“The safety profile of tofacitinib in children with JIA was comparable to what you have seen or known in the [rheumatoid arthritis] population, and no new safety risks were identified in this pediatric population,” Dr. Brunner said.
The researchers reported ties with Pfizer, which funded the study, and more than two dozen other pharmaceutical companies.
SOURCE: Brunner HI et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract L22.
REPORTING FROM ACR 2019
Patient-Reported Outcomes in Multiple Sclerosis: An Overview
From the Dartmouth Institute for Health Policy & Clinical Practice, Geisel School of Medicine, Hanover, NH (Ms. Manohar and Dr. Oliver), the Department of Community & Family Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH (Ms. Perkins, Ms. Laurion, and Dr. Oliver), and the Multiple Sclerosis Specialty Care Program, Concord Hospital, Concord, NH (Dr. Oliver).
Abstract
- Background: Patient-reported outcomes (PROs), including patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs), can be used to assess perceived health status, functioning, quality of life, and experience of care. Complex chronic illnesses such as multiple sclerosis (MS) affect multiple aspects of health, and PROs can be applied in assessment and decision-making in MS care as well as in research pertaining to MS.
- Objective: To provide a general review of PROs, with a specific focus on implications for MS care.
- Methods: Evidence synthesis of available literature on PROs in MS care.
- Results: PROs (including PROMs and PREMs) have historically been utilized in research and are now being applied in clinical, improvement, and population health settings using learning health system approaches in many disease populations, including MS. Many challenges complicate the use of PROs in MS care, including reliability, validity, and interpretability of PROMs, as well as feasibility barriers due to time and financial constraints in clinical settings.
- Conclusion: PROs have the potential to better inform clinical care, empower patient-centered care, inform health care improvement efforts, and create the conditions for coproduction of health care services.
Keywords: PRO; PROM; patient-reported outcome measure; patient-reported experience measure; quality of life; patient-centered care.
Multiple sclerosis (MS) is a disabling, complex, chronic, immune-mediated disorder of the central nervous system (CNS). MS causes inflammatory and degenerative damage in the CNS, which disrupts signaling pathways.1 It is most commonly diagnosed in young adults and affects 2.3 million people worldwide.2 People with MS experience very different disease courses and a wide range of neurological symptoms, including visual, somatic, mental health, sensory, motor, and cognitive problems.1-3 Relapsing-remitting MS, the most common form, affects 85% of those with MS and is characterized by periods of relapse (exacerbation) and remission.1 Other forms of MS (primary progressive and secondary progressive MS) are characterized by progressive deterioration and worsening symptom severity without exacerbations. Disease-modifying therapies (DMTs) can reduce the frequency of exacerbations and disability progression, but unfortunately there is no cure for MS. Treatment is focused on increasing quality of life, minimizing disability, and maximizing wellness.
Patient-reported outcomes (PROs) describe the perceived health status, function, and/or experience of a person as obtained by direct self-report. Patient-reported outcome measures (PROMs) are validated PROs that can be used to inform clinical care,4 and have demonstrated effectiveness in improving patient-provider communication and decision-making.5-7 PROMs are currently used in some MS clinical trials to determine the impact of experimental interventions,8-10 and are also being used to inform and improve clinical care in some settings. Especially for persons with MS, they can provide individualized perspectives about health experience and outcomes.11 In more advanced applications, PROMs can be used to improve face-to-face collaborations between clinicians and patients and to inform patient-centered systems of care.12-14 PROMs can also be used to inform systems-level improvement for entire patient populations.15,16
In this article, we review current applications of PROs and PROMs in the care of persons with MS, as well as current limitations and barriers to their use.
At a recent visit to her neurologist, Marion reviews her health diary, in which she has been tracking her fatigue levels throughout the day and when she has to visit the bathroom. The PRO diary also helps her remember details that she might not otherwise be able to recall at the time of her clinic visit. They review the diary entrees together to develop a shared understanding of what Marion has been experiencing and identify trends in the PRO data. They discuss symptom management and use the PRO information from the diary to help guide adjustments to her physical therapy routine and medication regimen.
Part of Marion’s “PRO package” includes the Center for Epidemiologic Studies Depression Scale (CES-D), a validated depression screening and symptom severity questionnaire that she completes every 3 months. Although she denies being depressed, she has noticed that her CES-D scores in recent months have been consistently increasing. This prompts a discussion about mental health in MS and a referral to work on depression with the MS mental health specialist. Marion and the mental health specialist use CES-D measures at baseline and during treatment to set a remission target and to track progress during treatment. Marion finds this helpful because she says it is hard for her to “wrap my hands around depression… it’s not something that there is a blood test or a MRI for.” Marion is encouraged by being able to see her CES-D scores change as her depression severity decreases, and this helps motivate her to keep engaged in treatment.
PROs and PROMs: General Applications
PROs are measures obtained directly from an individual without a priori interpretation by a clinician.9,17 PROs capture individual perspectives on symptoms, capability, disability, and health-related quality of life.9 With increasing emphasis on patient-centered care,18 individual perspectives and preferences elicited using PROMs may be able to inform better quality of care and patient-centered disease treatment and management.19-21
PROMs are standardized, validated questionnaires used to assess PROs and can be generic or condition-specific. Generic PROMs can be used in any patient population. The SF-3622 is a set of quality of life measures that assess perceived ability to complete physical tasks and routine activities, general health status, fatigue, social functioning, pain, and emotional and mental health.23 Condition-specific PROMs can be used for particular patient populations and are helpful in identifying changes in health status for a specific disease, disability, or surgery. For example, the PDQ-39 assesses 8 dimensions of daily living, functioning, and well-being for people with Parkinson’s disease.24
PROMs have been used in some MS clinical trials and research studies to determine the effectiveness of experimental treatments from the viewpoint of study participants.9,25,26 PROs can also be utilized in clinical care to facilitate communication of needs and track health outcomes,27 and can inform improvement in outcomes for health systems and populations. They can also be used to assess experience of care,28 encouraging a focus on high-quality outcomes through PRO-connected reimbursement mechanisms,29 and provide aggregate data to evaluate clinical practice, population health outcomes, and the effectiveness of public policies.27
Patient-reported experience measures (PREMs) assess patient satisfaction and experience of health care.30,31 CollaboRATE32 is a PREM that assesses the degree of shared decision-making occurring between patients and clinicians during clinical care. PREMs are currently used for assessing self-efficacy and in shared decision-making and health care improvement applications. PREMs have yet to be developed specifically for persons with MS.
PROMs in MS Care
Generic PROMs have shown that persons with MS are disproportionately burdened by poor quality of life.33-35 Other generic PROMs, like the SF-36,36 the Sickness Impact Profile,37 and versions of the Health Utilities Index,38 can be used to gather information on dysfunction and to determine quality and duration of life modified by MS-related dysfunction and disability. MS-specific PROMs are used to assess MS impairments, including pain, fatigue, cognition, sexual dysfunction, and depression.12,39-42 PROMs have also been used in MS clinical trials, including the Multiple Sclerosis Impact Scale-29 (MSIS-29),43,44 the Leeds MS QoL (LMSQoL),45,46 the Functional Assessment of MS (FAMS),47 the Hamburg Quality of Life Questionnaire in MS (HAQUAMS),48 the MS Quality of Life-54 (MSQoL-54),49 the MS International QoL (MUSIQoL),50 and the Patient-Reported Indices for MS Activity Limitations Scale (PRIMUS).51
Condition-specific PROMs are more sensitive to changes in health status and functioning for persons with MS compared to generic PROMs. They are also more reliable during MS remission and relapse periods.44,52 For example, the SF-36 has floor and ceiling effects in MS populations—a high proportion of persons with MS are scored at the maximum or minimum levels of the scale, limiting discriminant capability.22 As a result, a “combined approach” using both generic and MS-specific measures is often recommended.53 Some MS PROMs (eg, MSQoL-54) include generic questions found in the SF-36 as well as additional MS-specific questions or scales.
The variety of PROMs available (see Table for a selected listing) introduces a significant challenge to using them—limited generalizability and difficulty comparing PROs across MS studies. Efforts to establish common PROMs have been undertaken to address this problem.54 The National Institute of Neurologicical Disorders and Stroke (NINDS) sponsored the development of a neurological quality of life battery, the Neuro-QOL.55 Neuro-QOL measures the physical, mental, and social effects of neurological conditions in adults and children with neurological disorders and has the capability to facilitate comparisons across different neurological conditions. Additionally, the Patient-Reported Outcomes Measure Information System (PROMIS) has been developed to assess physical, mental, and social effects of chronic disease. PROMIS has a hybrid design that includes generic and MS-specific measures (such as PROMIS FatigueMS).56 PROMIS can be used to assess persons with MS as well as to compare the MS population with other populations with chronic illness.
PROMs have varying levels of reliability and validity. The Evaluating the Measure of Patient-Reported Outcomes57 study evaluated the development process of MS PROMs,43 and found that the MSIS-29 and LMSQoL had the highest overall reliability among the most common MS PROMs. However, both scored poorly on validity due to lack of patient involvement during development. This questions the overall capability of existing MS PROMs to accurately and consistently assess PROs in persons with MS.
“Feed-Forward” PROMs
Oliver and colleagues16 have described “feed-forward” PROM applications in MS care in a community hospital setting using a learning health system approach. This MS clinic uses feed-forward PROs to inform clinical care—PRO data are gathered before the clinic visit and analyzed ahead of or during the clinic visit by the clinician. Patients are asked to arrive early and complete a questionnaire comprised of PROMs measuring disability, functioning, quality of life, cognitive ability, pain, fatigue, sleep quality, anxiety, and depression. Clinicians score the PROMs and input scores into the electronic health record before the clinical encounter. During the clinic visit, PROM data is visually displayed so that the clinician and patient can discuss results and use the data to better inform decision-making. The visual data display contains longitudinal information, displaying trends in health status across multiple domains, and includes specified thresholds for clinically active symptom levels (Figure).16 Longitudinal monitoring of PROM data allows for real-time assessment of goal-related progress throughout treatment. As illustrated previously by Marion’s case study, the use of real-time feed-forward PROM data can strengthen the partnership between patient and clinician as well as improve empowerment, engagement, self-monitoring, and adherence.
PRO Dashboards
Performance dashboards are increasingly used in health care to visually display clinical and PRO data for individual patients, systems, and populations over time. Dashboards display a parsimonious group of critically important measures to give clinicians and patients a longitudinal view of PRO status. They can inform decision-making in clinical care, operations, health care improvement efforts, and population health initiatives.58 Effective dashboards allow for user customization with meaningful measures, knowledge discovery for analysis of health problems, accessibility of health information, clear visualization, alerts for unexpected data values, and system connectivity.59,60 Appropriate development of PRO dashboards requires meaningful patient and clinician involvement via focus groups and key informant interviews, Delphi process approaches to prioritize and finalize selection of priority measures, iterative building of the interface with design input from key informants and stakeholders (co-design), and pilot testing to assess feasibility and acceptability of use.61-63
Other Applications of PROs/PROMs in MS
Learning Health Systems
The National Quality Forum (NQF) and the Centers for Medicaid and Medicare Services have adopted PROs for use in quality measurement.64-66 This includes a movement towards the use of LHS, defined as a health system in which information from patients and clinicians is systematically collected and synthesized with external evidence to inform clinical care, improvement, and research.67-70 Often a LHS is undertaken as a collaborative effort between multiple health care centers to improve quality and outcomes of care.70 The MS Continuous Quality Improvement Collaborative (MS-CQI), the first multi-center systems-level health care improvement research collaborative for MS,71 as well as IBD Qorus and the Cystic Fibrosis Care Center Network utilize LHS approaches.72-77
IBD Qorus is a LHS developed by the Crohn’s and Colitis Foundation that uses performance dashboards to better inform clinical care for people with inflammatory bowel disease. It also employs system-level dashboards for performance benchmarking in quality improvement initiatives and aggregate-level dashboards to assess population health status.78,79 MS-CQI uses a LHS approach to inform the improvement of MS care across multiple centers using a comprehensive dashboard, including PROMs, for benchmarking and to monitor system and population health status. MS-CQI collects PROMs using a secure online platform that can be accessed by persons with MS and their clinicians and also includes a journaling feature for collecting qualitative information and for reference and self-monitoring.71
MS Research
PROMs are used in clinical and epidemiological research to evaluate many aspects of MS, including the FAMS, the PDSS, the Fatigue Impact Scale (FIS), and others.80-82 For example, the PROMIS FatigueMS and the Fatigue Performance Scale have been used to assess the impact of MS-related fatigue on social participation.83 Generic and MS-specific PROMs have been used to assess pain levels for people with MS,84-87 and multiple MS-specific PROMs, like PRIMUS and MSQoL-54,43 as well as the SF-3639 include pain assessment scales. PROMs have also been used to assess MS-related bladder, bowel, and sexual dysfunction. Urgency, frequency, and incontinence affect up to 75% of patients with MS,88 and many PROMs, such as the LMSQoL, MUSIQoL, and the MSQoL-54, are able to evaluate bladder control and sexual functioning.43,89
PROMs are employed in MS clinical trials to help assess the tolerability and effectiveness of DMTs.90,91 PROs have been used as secondary endpoints to understand the global experience of a DMT from the patient perspective.92-94 There are 15 FDA-approved DMTs for MS, and clinical trials for 6 of these have used PROMs as an effectiveness end point.54,91,95,96 However, most DMT clinical trials are powered for MRI, relapse rate, or disease progression primary outcomes rather than PROMs, often resulting in underpowered PROM analyses.97 In addition, many PROMs are not appropriate for use in DMT clinical trials.98,99
In order to bridge the gap between clinical research and practice, some industry entities are championing “patient-focused drug development” approaches. The Accelerated Cure Project for MS has launched iConquerMS, which collects PROMs from persons with MS to further PRO research in MS and follows 4700 individuals with MS worldwide.100 In 2018, the American College of Physicians announced a collaboration with an industry partner to share data to inform DMT clinical trials and develop and validate PROMs specifically designed for DMT clinical trials.101
Population Health
Registries following large cohorts of people with MS have the potential to develop knowledge about disease progression, treatment patterns, and outcomes.102 The Swedish EIMS study has identified associations between pre-disease body mass index and MS prognosis,102 alcohol and tobacco consumption affecting MS risk,103,104 and exposure to shift work at a young age and increased MS risk.105 The North American Research Committee on MS83,106,107 and iConquerMS registries are “PROM-driven” and have been useful in identifying reductions in disease progression in people using DMTs.107,108 The New York State MS Consortium has identified important demographic characteristics that influence MS progression.109,110 PROs can also be used to determine risk of MS-related mortality111 and decline in quality of life.112,113 Limitations of these approaches include use of different PROMs, inconsistencies in data collection processes, and different follow-up intervals used across registries.102
Patient-Centered Care
The Institute of Medicine defines patient-centeredness as “care that is respectful and responsive to individual patient preferences, needs, and values and ensures that patient values guide all clinical decisions.”114 PROs are useful for identifying a patient’s individual health concerns and preferences, something that is needed when treating a highly variable chronic health condition like MS. The use of PROs can help clinicicans visualize the lived experience of persons with MS and identify personal preferences,115 as well as improve self-monitoring, self-management, self-efficacy, adherence, wellness, and coping ability.116 At the system level, PROs can inform improvement initiatives and patient-centered care design efforts.117-120
Selecting PROMs
Initiatives from groups like the COnsensus-based Standards for the Selection of health Measurement INstruments (COSMIN)121 and the International Society for Quality of Life Research (ISOQOL)108 offer guidance on selecting PROs. The NINDS has promoted common data collection between clinical studies of the brain and nervous system.122 General guidance from these sources recommends first considering the outcome and target population, selecting PROMs to measure the outcome through a synthesis of the available evidence, assessing validity and reliability of selected PROMs, and using standard measures that can be compared across studies or populations.108,121 Other factors include feasibility, acceptability, and burden of use for patients, clinicians, and systems, as well as literacy, cultural, and linguistic factors.123
The NQF recommends that consideration be given to individual patient needs, insurance factors, clinical setting constraints, and available resources when selecting PROMs.124 To maximize response rate, PROMs that are sensitive, reliable, valid, and developed in a comparative demographic of patients are advised.125 ISOQOL has released a User’s Guide and several companion guides on implementing and utilizing PROMs.108,126,127 Finally, PRO-Performance Measures (PRO-PMs) are sometimes used to assess whether PROMs are appropriately contributing to performance improvement and accountability.124
The Cons of PROs
PROs can disrupt busy clinical care environments and overextend clinical staff.125 Online collection of PROs outside of clinical encounters can relieve PRO-related burden, but this requires finding and funding appropriate secure online networks to effectively collect PROs.128 In 2015, only 60% of people seen for primary care visits could access or view their records online, and of those, only 57% used messaging for medical questions or concerns.129 Ideally, online patient portal or mobile health apps could synchronize directly to electronic health records or virtual scribes to transfer patient communications into clinical documentation.130 There has been limited success with this approach in European countries131 and with some chronic illness conditions in the United States.74
Electronic health technologies, including mobile health (mHealth) solutions, have improved the self-monitoring and self-management capability of patients with MS via information sharing in patient networks, assistive technologies, smartphone applications, and wearable devices.132,133 A recent study found that communication modes included secure online patient portal use (29%) and email use (21%), and among those who owned tablets or smartphones, 46% used mHealth apps.134 Social media use has been associated with increased peer/social/emotional support and increased access to health information, as well as clinical monitoring and behavior change.134,135 Individuals using mHealth apps are younger, have comorbidities, and have higher socioeconomic and education levels,135,136 suggesting that inequities in mHealth access exist.
Questionnaires can be time-consuming and cause mental distress if not appropriately facilitated.137 Decreasing questionnaire length and providing the option for PROMs to be delivered and completed online or outside of the clinic context can reduce burden.138 Additionally, while some people are consistent in sharing their PROs, others struggle with using computers, especially while experiencing severe symptoms, forget to complete PROMs, or simply do not have internet access due to financial or geographic constraints.139 A group of disabled and elderly persons with MS reported barriers to internet use due to visual deficits, small website font sizes, and distracting color schemes.140
Interpretability
Interpreting PROMs and displays of longitudinal PROM data can be a challenge for persons with MS and their clinicians. There is little standardization in how PROMs are scored and presented, and there is often confusion about thresholds for clinical significance and how PROM scores can be compared to other PROMs.141,142 While guidelines exist for implementing PRO scores in clinical settings,126,143 there are few that aid PROM interpretation. As a result, clinicians often seek research evidence for PROMs used in other similar patient populations as a benchmark,142-144 or compare them to other patients seen in their clinical practice.
Longitudinal PRO data are usually displayed in simple line graphs.145,146 Overall, line graphs have been found to have the highest ease of understanding by both patients and clinicians, but sometimes can be confusing.147 For example, upward trending lines are usually viewed as improvement and downward trending lines as decline; however, upward trending scores on a PROM can indicate decline, such as increasing fatigue severity. Annotation of visual displays can help. Patients and clinicians find that employing thresholds and color coding is useful, and better than “stoplight” red-yellow-green shading schemes or red-circle formats to indicate data that warrant attention.142
PROs are not free of risk for error, especially if they are used independently of other information sources, such as clinical interview, examination, and diagnostic testing, or if they are utilized too frequently, too infrequently, or are duplicated in practice. If a PRO instrument is employed too frequently, score changes may reflect learning effects rather than actual clinical status. Conversely, if used too infrequently, PRO information will not be timely enough to inform real-time clinical practice. Duplication of PRO assessments (eg, multiple measures of the same PRO for the same patient on the same day) or use of multiple PRO measures to assess the same aspect (eg, 2 measures used to assess fatigue) could introduce unnecessary complexity and confusion to interpretation of PRO results.
PRO measures also can be biased or modified by clinical status and/or perceptions of people with MS at the time of assessment. For example, cognitive impairment, whether at baseline state or due to a cognitive MS relapse event, could impact patients’ ability to understand and respond to PRO assessments, producing erroneous results. However, when used appropriately, PROs targeting cognitive dysfunction may be able to detect onset of cognitive events or help to measure recovery from them. Finally, PROs measure perceived (self-reported) status, which may not be an accurate depiction of actual status.
All of these potential pitfalls support the argument that PROs should be utilized to augment the clinical interview, examination, and diagnostic (objective) testing aspects of comprehensive MS care. In this way, PROs can be correlated with other information sources to deepen the shared understanding of health status between a person with MS and her clinician, increasing the potential to make better treatment decisions and care plans together in partnership.
Value and Cost
National groups such as the Patient-Centered Outcomes Research Institute (PCORI) are working with regulatory bodies, funding agencies, insurance providers, patient advocacy groups, researchers, providers, and specialty groups to investigate how PROMs can be implemented into value-based health care reforms, including value-based reimbursement.148 However, practical PRO implementation requires considerable time and resources, and many methodological and operational questions must be addressed before widespread adoption and reimbursement for PROMs will be feasible.148,149
Summary
PROs can generate valuable information about perceived health status, function, quality of life, and experience of care using self-reported sources. Validated PRO assessment tools include PROMs and PREMs. PROs are currently utilized in research settings (especially PROMs) but are also being used in clinical practice, quality improvement initiatives, and population health applications using LHS approaches. PROs have the advantages of empowering and informing persons with MS and clinicians to optimize patient-centered care, improve systems of care, and study population health outcomes. Barriers include PROM validity, reliability, comparability, specificity, interpretability, equity, time, and cost. Generic PROMs and PREMs, and some MS-specific PROMs, can be used for persons with MS. Unfortunately, no PREMs have been developed specifically for persons with MS, and this is an area for future research. With appropriate development and utilization in LHS applications, PROs can inform patient-centered clinical care, system-level improvement initiatives, and population health research, and have the potential to help facilitate coproduction of health care services.
Acknowledgments: The authors thank Ann Cabot, DO, of the MS Specialty Care Program at Concord Hospital and (especially) peer mentors from a peer outreach wellness program for people with MS (who have asked to remain anonymous) for interviews conducted with their permission to inform the case study described in this article. The case study used in this manuscript has been de-identified, with some aspects modified from actual, and the person in the case study is fictitiously named.
Corresponding author: Brant Oliver, PhD, MS, MPH, APRN-BC, Department of Community & Family Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756; [email protected].
Financial disclosures: None.
1. Goldenberg MM. Multiple sclerosis review. PT. 2012;37:175-184.
2. Doshi A, Chataway J. Multiple sclerosis, a treatable disease. Clin Med. 2016;16(Suppl 6):s53-s9.
3. Perrin Ross A. Management of multiple sclerosis. Am J Managed Care. 2013;19(16 Suppl):s301-s306.
4. Batalden M, Batalden P, Margolis P, et al. Coproduction of healthcare service. BMJ Qual Saf. 2016;25:509-517.
5. Chen J, Ou L, Hollis SJ. A systematic review of the impact of routine collection of patient reported outcome measures on patients, providers and health organisations in an oncologic setting. BMC Health Serv Res. 2013;13:211.
6. Knaup C, Koesters M, Schoefer D, et al. Effect of feedback of treatment outcome in specialist mental healthcare: meta-analysis. Br J Psychiatr. 2009;195:15-22.
7. Dudgeon D. The impact of measuring patient-reported outcome measures on quality of and access to palliative care. J Palliat Med. 2018;21(S1):S76-s80.
8. Snyder CF, Herman JM, White SM, et al. When using patient-reported outcomes in clinical practice, the measure matters: a randomized controlled trial. J Oncol Pract. 2014;10:e299-e306.
9. Guidance for industry: patient-reported outcome measures: use in medical product development to support labeling claims: draft guidance. Health Qual Life Outcomes. 2006;4:79.
10. de Jong MJ, Huibregtse R, Masclee AAM, et al. Patient-reported outcome measures for use in clinical trials and clinical practice in inflammatory bowel diseases: a systematic review. Clin Gastroenterol Hepatol. 2018;16:648-663.
11. Roman D, Osborne-Stafsnes J, Amy CH, et al. Early lessons from four ‘aligning forces for quality’ communities bolster the case for patient-centered care. Health Affairs. 2013;32:232-241.
12. Ehde DM, Alschuler KN, Sullivan MD, et al. Improving the quality of depression and pain care in multiple sclerosis using collaborative care: The MS-care trial protocol. Contemporary Clinical Trials. 2018;64:219-229.
13. Lavallee DC, Chenok KE, Love RM, et al. Incorporating patient-reported outcomes into health care to engage patients and enhance care. Health Affairs. 2016;35:575-582.
14. Schick-Makaroff K, Thummapol O, Thompson S, et al. Strategies for incorporating patient-reported outcomes in the care of people with chronic kidney disease (PRO kidney): a protocol for a realist synthesis. Clin Gastroenterol Hepatol. 2018;16:648-663.
15. Nelson EC, Dixon-Woods M, Batalden PB, et al. Patient focused registries can improve health, care, and science. BMJ. 2016;354:i3319.
16. Oliver BJ, Nelson EC, Kerrigan CL. Turning feed-forward and feedback processes on patient-reported data into intelligent action and informed decision-making: case studies and principles. Med Care. 2019;57 Suppl 1:S31-s37.
17. Deshpande PR, Rajan S, Sudeepthi BL, Abdul Nazir CP. Patient-reported outcomes: A new era in clinical research. Perspect Clin Res. 2011;2:137-144.
18. Epstein RM, Street RL, Jr. The values and value of patient-centered care. Ann Fam Med. 2011;9:100-103.
19. Payne SA. A study of quality of life in cancer patients receiving palliative chemotherapy. Soc Sci Med. 1992;35:1505-1509.
20. Borgaonkar MR, Irvine EJ. Quality of life measurement in gastrointestinal and liver disorders. Gut. 2000;47:444-454.
21. Macdonell R, Nagels G, Laplaud DA, et al. Improved patient-reported health impact of multiple sclerosis: The ENABLE study of PR-fampridine. Multiple Sclerosis. 2016;22:944-954.
22. Hobart J, Freeman J, Lamping D, et al. The SF-36 in multiple sclerosis: why basic assumptions must be tested. J Neurol Neurosurg Psychiatry. 2001;71:363-370.
23. Lins L, Carvalho FM. SF-36 total score as a single measure of health-related quality of life: Scoping review. SAGE Open Med. 2016;4:2050312116671725.
24. Parkinson’s Disease Society of the United Kingdom. The Parkinson’s Disease Questionnaire (PDQ-39). https://www.parkinsons.org.uk/professionals/resources/parkinsons-disease-questionnaire-pdq-39. Accessed October 20, 2019.
25. Basch E. The missing voice of patients in drug-safety reporting. N Engl J Med. 2010;362:865-869.
26. Calvert M, Brundage M, Jacobsen PB, et al. The CONSORT Patient-Reported Outcome (PRO) extension: implications for clinical trials and practice. Health Qual Life Outcomes. 2013;11:184.
27. Black N. Patient reported outcome measures could help transform healthcare. BMJ. 2013;346:f167.
28. Franks P, Fiscella K, Shields CG, et al. Are patients’ ratings of their physicians related to health outcomes? Ann Fam Med. 2005;3:229-234.
29. Hostetter M, Klein S. Using patient-reported outcomes to improve health care quality. The Commonwealth Fund 2019. www.commonwealthfund.org/publications/newsletter-article/using-patient-reported-outcomes-improve-health-care-quality. Accessed October 24, 2019.
30. Charlotte Kingsley SP. Patient-reported outcome measures and patient-reported experience measures. BJA Education. 2017;17:137-144.
31. Weldring T, Smith SM. Patient-Reported outcomes (PROs) and patient-reported outcome measures (PROMs). Health Services Insights. 2013;6:61-68.
32. Elwyn G, Barr PJ, Grande SW, et al. Developing CollaboRATE: A fast and frugal patient-reported measure of shared decision making in clinical encounters. Patient Educ Couns. 2013;93:102-107.
33. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:1444-1452.
34. Rudick RA, Miller D, Clough JD, et al. Quality of life in multiple sclerosis. Comparison with inflammatory bowel disease and rheumatoid arthritis. Arch Neurol. 1992;49:1237-1242.
35. Benito-Leon J, Morales JM, Rivera-Navarro J, Mitchell A. A review about the impact of multiple sclerosis on health-related quality of life. Disabil Rehabil. 2003;25:1291-1303.
36. RAND Corporation. 36-Item Short Form Survey (SF-36). [https://www.rand.org/health-care/surveys_tools/mos/36-item-short-form.html. Accessed October 20, 2019.
37. Bergner M, Bobbitt RA, Carter WB, Gilson BS. The sickness impact profile: development and final revision of a health status measure. Medical Care. 1981;19:787-805.
38. Horsman J, Furlong W, Feeny D, Torrance G. The Health Utilities Index (HUI): concepts, measurement properties and applications. Health Qual Life Outcomes. 2003;1:54.
39. Kinkel RP, Laforet G, You X. Disease-related determinants of quality of life 10 years after clinically isolated syndrome. Int J MS Care. 2015;17:26-34.
40. Baumstarck-Barrau K, Simeoni MC, Reuter F, et al. Cognitive function and quality of life in multiple sclerosis patients: a cross-sectional study. BMC Neurology. 2011;11:17.
41. Samartzis L, Gavala E, Zoukos Y, et al. Perceived cognitive decline in multiple sclerosis impacts quality of life independently of depression. Rehabil Res Pract. 2014;2014:128751.
42. Vitkova M, Rosenberger J, Krokavcova M, et al. Health-related quality of life in multiple sclerosis patients with bladder, bowel and sexual dysfunction. Disabil Rehabil. 2014;36:987-992.
43. Khurana V, Sharma H, Afroz N, et al. Patient-reported outcomes in multiple sclerosis: a systematic comparison of available measures. Eur J Neurol. 2017;24:1099-1107.
44. Hobart J, Lamping D, Fitzpatrick R, et al. The Multiple Sclerosis Impact Scale (MSIS-29): a new patient-based outcome measure. Brain. 2001;124(Pt 5):962-973.
45. Lily O, McFadden E, Hensor E, et al. Disease-specific quality of life in multiple sclerosis: the effect of disease modifying treatment. Multiple Sclerosis. 2006;12:808-813.
46. Ford HL, Gerry E, Tennant A, et al. Developing a disease-specific quality of life measure for people with multiple sclerosis. Clin Rehabil. 2001;15:247-258.
47. Cella DF, Dineen K, Arnason B, et al. Validation of the functional assessment of multiple sclerosis quality of life instrument. Neurology. 1996;47:129-139.
48. Gold SM, Heesen C, Schulz H, et al. Disease specific quality of life instruments in multiple sclerosis: validation of the Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS). Multiple Sclerosis. 2001;7:119-130.
49. Vickrey BG, Hays RD, Harooni R, et al. A health-related quality of life measure for multiple sclerosis. Qual Life Res. 1995;4:187-206.
50. Simeoni M, Auquier P, Fernandez O, et al. Validation of the Multiple Sclerosis International Quality of Life questionnaire. Multiple Sclerosis. 2008;14:219-230.
51. Doward LC, McKenna SP, Meads DM, et al. The development of patient-reported outcome indices for multiple sclerosis (PRIMUS). Multiple Sclerosis. 2009;15:1092-1102.
52. Ozakbas S, Akdede BB, Kosehasanogullari G, et al. Difference between generic and multiple sclerosis-specific quality of life instruments regarding the assessment of treatment efficacy. J Neurol Sci. 2007;256:30-34.
53. Cella DF, Wiklund I, Shumaker SA, Aaronson NK. Integrating health-related quality of life into cross-national clinical trials. Qual Life Res. 1993;2:433-440.
54. Nowinski CJ, Miller DM, Cella D. Evolution of patient-reported outcomes and their role in multiple sclerosis clinical trials. Neurotherapeutics. 2017;14:934-944.
55. Cella D, Nowinski C, Peterman A, et al. The neurology quality-of-life measurement initiative. Arch Phys Med Rehabil. 2011;92(10 Suppl):S28-S36.
56. HealthMeasures: PROMIS. http://www.healthmeasures.net/explore-measurement-systems/promis. Accessed October 20, 2019.
57. Valderas JM, Ferrer M, Mendivil J, et al. Development of EMPRO: a tool for the standardized assessment of patient-reported outcome measures. Value Health. 2008;11:700-708.
58. Bach K, Martling C, Mork PJ, et al. Design of a clinician dashboard to facilitate co-decision making in the management of non-specific low back pain. J Intelligent Helath Syst. 2019;52:269-284.
59. Karami M, Safdari R, Rahimi A. Effective radiology dashboards: key research findings. Radiology Management. 2013;35:42-45.
60. Dowding D, Randell R, Gardner P, et al. Dashboards for improving patient care: review of the literature. Int J Med Informatic. 2015;84:87-100.
61. Mlaver E, Schnipper JL, Boxer RB, et al. User-centered collaborative design and development of an inpatient safety dashboard. Jt Comm J Qual Patient Saf. 2017;43:676-685.
62. Dowding D, Merrill J, Russell D. Using feedback intervention theory to guide clinical dashboard design. AMIA Annu Symp Proc. 2018;2018:395-403.
63. Hartzler AL, Izard JP, Dalkin BL, et al. Design and feasibility of integrating personalized PRO dashboards into prostate cancer care. J Am Med Inform Assoc. 2016;23:38-47.
64. Lavallee DC, Chenok KE, Love RM, et al. Incorporating patient-reported outcomes into health care to engage patients and enhance care. Health Affairs. 2016;35:575-582.
65. U.S. Centers for Medicare & Medicaid Services. Comprehensive Care for Joint Replacement Model. https://innovation.cms.gov/initiatives/CJR. Accessed August 3, 2019.
66. National Quality Forum. Patient-reported outcomes: Accessed August 3, 2019. http://www.qualityforum.org/Patient-Reported_Outcomes.aspx. Accessed October 20, 2019.
67. Institute of Medicine Roundtable on Evidence-Based Medicine. The National Academies Collection: Reports funded by National Institutes of Health. In: Olsen LA, Aisner D, McGinnis JM, eds. The Learning Healthcare System: Workshop Summary. Washington (DC): National Academies Press (US).National Academy of Sciences; 2007.
68. About Learning Health Systems: Agency for Healthcare Research and Quality. https://www.ahrq.gov/learning-health-systems/about.html. Accessed August 3, 2019.
69. Best Care at Lower Cost: The Path to Continuously Learning Health Care in America. Washington (DC): National Academies Press; 2013.
70. Committee on Quality of Health Care in America. Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, DC: National Academies Press; 2001.
71. Oliver BJ, for the MS-CQI Investigators. The Multiple Sclerosis Continuous improvement collaborative: the first coproduction learning health system improvement science research collaborative for multiple sclerosis. The International Society for Quality in Health Care (ISQua) Annual International Conference; October 2019; Cape Town, South Africa.
72. Britto MT, Fuller SC, Kaplan HC, et al. Using a network organisational architecture to support the development of Learning Healthcare Systems. BMJ Qual Saf. 2018;27:937-946.
73. Care Centers: Cystic Fibrosis Foundation. https://www.cff.org/Care/Care-Centers/. Accessed August 3, 2019.
74. Schechter MS, Fink AK, Homa K, Goss CH. The Cystic Fibrosis Foundation patient registry as a tool for use in quality improvement. BMJ Qual Saf. 2014;23(Suppl 1):i9-i14.
75. Mogayzel PJ, Dunitz J, Marrow LC, Hazle LA. Improving chronic care delivery and outcomes: the impact of the cystic fibrosis Care Center Network. BMJ Qual Saf. 2014;23(Suppl 1):i3-i8.
76. Godfrey MM, Oliver BJ. Accelerating the rate of improvement in cystic fibrosis care: contributions and insights of the learning and leadership collaborative. BMJ Qual Saf. 2014;23(Suppl 1):i23-i32.
77. Nelson EC, Godfrey MM. Quality by Design: A Clinical Microsystems Approach. San Francisco, California: Jossey-Bass; 2007.
78. Crohn’s & Colitis Foundation.Quality of Care: IBD Qorus: https://www.crohnscolitisfoundation.org/research/ibd-qorus. Accessed October 23, 2019.
79. Johnson LC, Melmed GY, Nelson EC, et al. Fostering collaboration through creation of an ibd learning health system. Am J Gastroenterol. 2017;112:406-468.
80. Fernandez-Munoz JJ, Moron-Verdasco A, Cigaran-Mendez M, et al. Disability, quality of life, personality, cognitive and psychological variables associated with fatigue in patients with multiple sclerosis. Acta Neurologica Scandinavica. 2015;132:118-124.
81. Flachenecker P, Kumpfel T, Kallmann B, et al. Fatigue in multiple sclerosis: a comparison of different rating scales and correlation to clinical parameters. Multiple Sclerosis. 2002;8:523-526.
82. Tellez N, Rio J, Tintore M, et al. Does the Modified Fatigue Impact Scale offer a more comprehensive assessment of fatigue in MS? Multiple Sclerosis. 2005;11:198-202.
83. Salter A, Fox RJ, Tyry T, et al. The association of fatigue and social participation in multiple sclerosis as assessed using two different instruments. Mult Scler Relat Disord. 2019;31:165-72.
84. Solaro C, Trabucco E, Messmer Uccelli M. Pain and multiple sclerosis: pathophysiology and treatment. Curr Neurol Neurosci Rep. 2013;13:320.
85. Jawahar R, Oh U, Yang S, Lapane KL. A systematic review of pharmacological pain management in multiple sclerosis. Drugs. 2013;73:1711-1722.
86. Rintala A, Hakkinen A, Paltamaa J. Ten-year follow-up of health-related quality of life among ambulatory persons with multiple sclerosis at baseline. Qual Life Res. 2016;25:3119-3127.
87. Tepavcevic DK, Pekmezovic T, Stojsavljevic N, et al. Change in quality of life and predictors of change among patients with multiple sclerosis: a prospective cohort study. Qual Life Res. 2014;23:1027-1037.
88. DasGupta R, Fowler CJ. Bladder, bowel and sexual dysfunction in multiple sclerosis: management strategies. Drugs. 2003;63:153-166.
89. Marck CH, Jelinek PL, Weiland TJ, et al. Sexual function in multiple sclerosis and associations with demographic, disease and lifestyle characteristics: an international cross-sectional study. BMC Neurology. 2016;16:210.
90. Gajofatto A, Benedetti MD. Treatment strategies for multiple sclerosis: When to start, when to change, when to stop? World J Clinical Cases. 2015;3:545-555.
91. National Multiple Sclerosis Society. Disease-modifying therapies for MS. 2018.
92. Rudick RA, Panzara MA. Natalizumab for the treatment of relapsing multiple sclerosis. Biologics. 2008;2:189-199.
93. Cohen JA, Cutter GR, Fischer JS, et al. Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology. 2002;59:679-687.
94. Patti F, Pappalardo A, Montanari E, et al. Interferon-beta-1a treatment has a positive effect on quality of life of relapsing-remitting multiple sclerosis: results from a longitudinal study. J Neurol Sci. 2014;337:180-185.
95. Novartis. Exploring the efficacy and safety of Siponimod in patients with secondary progressive multiple sclerosis (EXPAND). Available from clinicaltrials.gov/ct2/show/NCT01665144. NLM identifier: NCT01665144.
96. Singal AG, Higgins PD, Waljee AK. A primer on effectiveness and efficacy trials. Clin Transl Gastroenterol. 2014;5:e45.
97. Jongen PJ. Health-related quality of life in patients with multiple sclerosis: impact of disease-modifying drugs. CNS Drugs. 2017;31:585-602.
98. Coretti S, Ruggeri M, McNamee P. The minimum clinically important difference for EQ-5D index: a critical review. Expert Rev Pharmacoecon Outcomes Res. 2014;14:221-233.
99. Clinical Review Report: Ocrelizumab (Ocrevus). CADTH Common Drug Review. 2018:Appendix 4, Validity of Outcome Measures.
100. iCounquer MS; Empowering patients: how individuals with ms are contributing to the fight to find a cure: 2018. https://www.iconquerms.org/empowering-patients-how-individuals-ms-are-contributing-fight-find-cure. Accessed October 23, 2019.
101. K M. Accelerated Cure Project Announces Collaboration with EMD Serono to Advance Patient-Focused Drug Development in Multiple Sclerosis2018. https://www.iconquerms.org/accelerated-cure-project-announces-collaboration-emd-serono-advance-patient-focused-drug-development. Accessed October 24, 2019.
102. Bebo BF Jr, Fox RJ, Lee K, et al. Landscape of MS patient cohorts and registries: Recommendations for maximizing impact. Multiple Sclerosis. 2018;24:579-586.
103. Hedstrom AK, Hillert J, Olsson T, Alfredsson L. Alcohol as a modifiable lifestyle factor affecting multiple sclerosis risk. JAMA Neurology. 2014;71:300-305.
104. Hedstrom AK, Baarnhielm M, Olsson T, Alfredsson L. Tobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis. Neurology. 2009;73:696-701.
105. Hedstrom AK, Akerstedt T, Hillert J, et al. Shift work at young age is associated with increased risk for multiple sclerosis. Ann Neurol. 2011;70:733-741.
106. Hadjimichael O, Vollmer T, Oleen-Burkey M. Fatigue characteristics in multiple sclerosis: the North American Research Committee on Multiple Sclerosis (NARCOMS) survey. Health Qual Life Outcomes. 2008;6:100.
107. Fox RJ, Salter AR, Tyry T, et al. Treatment discontinuation and disease progression with injectable disease-modifying therapies: findings from the North American research committee on multiple sclerosis database. Int J MS Care. 2013;15:194-201.
108. Reeve BB, Wyrwich KW, Wu AW, et al. ISOQOL recommends minimum standards for patient-reported outcome measures used in patient-centered outcomes and comparative effectiveness research. Qual Life Res. 2013;22:1889-1905.
109. Jacobs LD, Wende KE, Brownscheidle CM, et al. A profile of multiple sclerosis: the New York State Multiple Sclerosis Consortium. Multiple Sclerosis. 1999;5:369-376.
110. Weinstock-Guttman B, Jacobs LD, Brownscheidle CM, et al. Multiple sclerosis characteristics in African American patients in the New York State Multiple Sclerosis Consortium. Multiple Sclerosis. 2003;9:293-298.
111. Raffel J, Wallace A, Gveric D, et al. Patient-reported outcomes and survival in multiple sclerosis: A 10-year retrospective cohort study using the Multiple Sclerosis Impact Scale-29. PLoS Med. 2017;14:e1002346.
112. Vaughn CB, Kavak KS, Dwyer MG, et al. Fatigue at enrollment predicts EDSS worsening in the New York State Multiple Sclerosis Consortium. Multiple Sclerosis. 2018:1352458518816619.
113. Alroughani RA, Akhtar S, Ahmed SF, Al-Hashel JY. Clinical predictors of disease progression in multiple sclerosis patients with relapsing onset in a nation-wide cohort. Int J Neuroscience. 2015;125:831-837.
114. Dolan JG, Veazie PJ, Russ AJ. Development and initial evaluation of a treatment decision dashboard. BMC Med Inform Decision Mak. 2013;13:51.
115. Stuifbergen AK, Becker H, Blozis S, et al. A randomized clinical trial of a wellness intervention for women with multiple sclerosis. Arch Phys Med Rehabil. 2003;84:467-476.
116. Finkelstein J, Martin C, Bhushan A, et al. Feasibility of computer-assisted education in patients with multiple sclerosis. In: Proceedings of the IEEE Symposium on Computer-Based Medical Systems. Bethesda, MD; 2004.
117. Batalden P. Getting more health from healthcare: quality improvement must acknowledge patient coproduction—an essay by Paul Batalden. BMJ. 2018;362:k3617.
118. Batalden PB, Davidoff F. What is “quality improvement” and how can it transform healthcare? Qual Saf Health Care. 2007;16:2-3.
119. Ovretveit J, Zubkoff L, Nelson EC, et al. Using patient-reported outcome measurement to improve patient care. Int J Qual Health Care. 2017;29:874-879.
120. Prodinger B, Taylor P. Improving quality of care through patient-reported outcome measures (PROMs): expert interviews using the NHS PROMs Programme and the Swedish quality registers for knee and hip arthroplasty as examples. BMC Health Services Res. 2018;18:87.
121. Prinsen CA, Vohra S, Rose MR, et al. How to select outcome measurement instruments for outcomes included in a “Core Outcome Set” – a practical guideline. Trials. 2016;17:449.
122. NINDS. NINDS Common Data Elements: Streamline Your Neuroscience Clinical Research National Institute of Health. https://www.commondataelements.ninds.nih.gov/#page=Default. Accessed October 23, 2019.
123. Francis DO, McPheeters ML, Noud M, et al. Checklist to operationalize measurement characteristics of patient-reported outcome measures. Systematic Rev. 2016;5:129.
124. National Quality Forum. Patient-reported outcomes (PROs) in performance measurement. 2013. https://www.qualityforum.org/Publications/2012/12/Patient-Reported_Outcomes_in_Performance_Measurement.aspx. Accessed October 15, 2019.
125. Dawson J, Doll H, Fitzpatrick R, et al. The routine use of patient reported outcome measures in healthcare settings. BMJ. 2010;340:c186.
126. Aaronson N ET, Greenlhalgh J, Halyard M, et al. User’s guide to implementation of patient reported outcomes assessment in clinical practice. International Society for Quality of Life. 2015.
127. Chan EKH, Edwards TC, Haywood K, et al. Implementing patient-reported outcomes mesaures in clinical practice: a companion guide to the ISOQOL user’s guide. Qual Life Res. 2018;28:621-627.
128. Snyder CF, Wu AW, Miller RS, et al. The role of informatics in promoting patient-centered care. Cancer J. 2011;17:211-218
129. Osborn R, Moulds D, Schneider EC, et al. Primary care physicians in ten countries report challenges caring for patients with complex health needs. Health Affairs. 2015;34:2104-2112.
130. Wu AW, Kharrazi H, Boulware LE, Snyder CF. Measure once, cut 0wice--adding patient-reported outcome measures to the electronic health record for comparative effectiveness research. J Clin Epidemiol. 2013;66(8 Suppl):S12-S20.
131. Trojano M, Bergamaschi R, Amato MP, et al. The Italian multiple sclerosis register. Neurol Sci. 2019;40:155-165.
132. Moorhead SA, Hazlett DE, Harrison L, et al. A new dimension of health care: systematic review of the uses, benefits, and limitations of social media for health communication. J Med Internet Res. 2013;15:e85.
133. Luigi L, Francesco B, Marcello M, et al. e-Health and multiple sclerosis: An update. Multiple Sclerosis J. 2018;24:1657-1664.
134. Marrie RA, Leung S, Tyry T, et al. Use of eHealth and mHealth technology by persons with multiple sclerosis. Mult Scler Relat Dis. 2019;27:13-19.
135. Giunti G, Kool J, Rivera Romero O, Dorronzoro Zubiete E. Exploring the specific needs of persons with multiple sclerosis for mhealth solutions for physical activity: mixed-methods study. JMIR Mhealth Uhealth. 2018;6:e37.
136. Spooner KK, Salemi JL, Salihu HM, Zoorob RJ. eHealth patient-provider communication in the United States: interest, inequalities, and predictors. J Am Med Inform Assoc. 2017;24(e1):e18-e27.
137. Safdar N, Abbo LM, Knobloch MJ, Seo SK. Research methods in healthcare epidemiology: survey and qualitative research. Infect Control Hosp Epidemiol. 2016;37:1272-1277.
138. Rolstad S, Adler J, Rydén A. Response burden and questionnaire length: is shorter better? A review and meta-analysis. Value Health. 2011;14:1101-1108.
139. Chiu C, Bishop M, Pionke JJ, et al. Barriers to the accessibility and continuity of health-care services in people with multiple sclerosis: a literature review. Int J MS Care. 2017;19:313-321.
140. Atreja A, Mehta N, Miller D, et al. One size does not fit all: using qualitative methods to inform the development of an Internet portal for multiple sclerosis patients. AMIA Annu Symp Proc Symp. 2005:16-20.
141. Snyder CF, Blackford AL, Brahmer JR, et al. Needs assessments can identify scores on HRQOL questionnaires that represent problems for patients: an illustration with the Supportive Care Needs Survey and the QLQ-C30. Qual Life Res. 2010;19:837-845.
142. de Vet HC, Terwee CB. The minimal detectable change should not replace the minimal important difference. J Clin Epidemiol. 2010;63:804-805.
143. Snyder CF, Aaronson NK, Choucair AK, et al. Implementing patient-reported outcomes assessment in clinical practice: a review of the options and considerations. Qual Life. 2012;21:1305-1314.
144. Myla DG, Melanie DW, Robert WM, et al. Identification and validation of clinically meaningful benchmarks in the 12-item Multiple Sclerosis Walking Scale. Multiple Sclerosis J. 2017;23:1405-1414.
145. van Munster CEP, Uitdehaag BMJ. Outcome measures in clinical trials for multiple sclerosis. CNS Drugs. 2017;31:217-236.
146. Snyder CF, Jensen R, Courtin SO, Wu AW. PatientViewpoint: a website for patient-reported outcomes assessment. Quality Life Res. 2009;18:793-800.
147. Snyder CF, Smith KC, Bantug ET, et al. What do these scores mean? Presenting patient-reported outcomes data to patients and clinicians to improve interpretability. Cancer. 2017;123:1848-1859.
148. Squitieri L, Bozic KJ, Pusic AL. The role of patient-reported outcome measures in value-based payment reform. Value Health. 2017;20:834-836.
149. Boyce MB, Browne JP. The effectiveness of providing peer benchmarked feedback to hip replacement surgeons based on patient-reported outcome measures—results from the PROFILE trial: a cluster randomised controlled study. BMJ Open. 2015;5:e008325.
From the Dartmouth Institute for Health Policy & Clinical Practice, Geisel School of Medicine, Hanover, NH (Ms. Manohar and Dr. Oliver), the Department of Community & Family Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH (Ms. Perkins, Ms. Laurion, and Dr. Oliver), and the Multiple Sclerosis Specialty Care Program, Concord Hospital, Concord, NH (Dr. Oliver).
Abstract
- Background: Patient-reported outcomes (PROs), including patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs), can be used to assess perceived health status, functioning, quality of life, and experience of care. Complex chronic illnesses such as multiple sclerosis (MS) affect multiple aspects of health, and PROs can be applied in assessment and decision-making in MS care as well as in research pertaining to MS.
- Objective: To provide a general review of PROs, with a specific focus on implications for MS care.
- Methods: Evidence synthesis of available literature on PROs in MS care.
- Results: PROs (including PROMs and PREMs) have historically been utilized in research and are now being applied in clinical, improvement, and population health settings using learning health system approaches in many disease populations, including MS. Many challenges complicate the use of PROs in MS care, including reliability, validity, and interpretability of PROMs, as well as feasibility barriers due to time and financial constraints in clinical settings.
- Conclusion: PROs have the potential to better inform clinical care, empower patient-centered care, inform health care improvement efforts, and create the conditions for coproduction of health care services.
Keywords: PRO; PROM; patient-reported outcome measure; patient-reported experience measure; quality of life; patient-centered care.
Multiple sclerosis (MS) is a disabling, complex, chronic, immune-mediated disorder of the central nervous system (CNS). MS causes inflammatory and degenerative damage in the CNS, which disrupts signaling pathways.1 It is most commonly diagnosed in young adults and affects 2.3 million people worldwide.2 People with MS experience very different disease courses and a wide range of neurological symptoms, including visual, somatic, mental health, sensory, motor, and cognitive problems.1-3 Relapsing-remitting MS, the most common form, affects 85% of those with MS and is characterized by periods of relapse (exacerbation) and remission.1 Other forms of MS (primary progressive and secondary progressive MS) are characterized by progressive deterioration and worsening symptom severity without exacerbations. Disease-modifying therapies (DMTs) can reduce the frequency of exacerbations and disability progression, but unfortunately there is no cure for MS. Treatment is focused on increasing quality of life, minimizing disability, and maximizing wellness.
Patient-reported outcomes (PROs) describe the perceived health status, function, and/or experience of a person as obtained by direct self-report. Patient-reported outcome measures (PROMs) are validated PROs that can be used to inform clinical care,4 and have demonstrated effectiveness in improving patient-provider communication and decision-making.5-7 PROMs are currently used in some MS clinical trials to determine the impact of experimental interventions,8-10 and are also being used to inform and improve clinical care in some settings. Especially for persons with MS, they can provide individualized perspectives about health experience and outcomes.11 In more advanced applications, PROMs can be used to improve face-to-face collaborations between clinicians and patients and to inform patient-centered systems of care.12-14 PROMs can also be used to inform systems-level improvement for entire patient populations.15,16
In this article, we review current applications of PROs and PROMs in the care of persons with MS, as well as current limitations and barriers to their use.
At a recent visit to her neurologist, Marion reviews her health diary, in which she has been tracking her fatigue levels throughout the day and when she has to visit the bathroom. The PRO diary also helps her remember details that she might not otherwise be able to recall at the time of her clinic visit. They review the diary entrees together to develop a shared understanding of what Marion has been experiencing and identify trends in the PRO data. They discuss symptom management and use the PRO information from the diary to help guide adjustments to her physical therapy routine and medication regimen.
Part of Marion’s “PRO package” includes the Center for Epidemiologic Studies Depression Scale (CES-D), a validated depression screening and symptom severity questionnaire that she completes every 3 months. Although she denies being depressed, she has noticed that her CES-D scores in recent months have been consistently increasing. This prompts a discussion about mental health in MS and a referral to work on depression with the MS mental health specialist. Marion and the mental health specialist use CES-D measures at baseline and during treatment to set a remission target and to track progress during treatment. Marion finds this helpful because she says it is hard for her to “wrap my hands around depression… it’s not something that there is a blood test or a MRI for.” Marion is encouraged by being able to see her CES-D scores change as her depression severity decreases, and this helps motivate her to keep engaged in treatment.
PROs and PROMs: General Applications
PROs are measures obtained directly from an individual without a priori interpretation by a clinician.9,17 PROs capture individual perspectives on symptoms, capability, disability, and health-related quality of life.9 With increasing emphasis on patient-centered care,18 individual perspectives and preferences elicited using PROMs may be able to inform better quality of care and patient-centered disease treatment and management.19-21
PROMs are standardized, validated questionnaires used to assess PROs and can be generic or condition-specific. Generic PROMs can be used in any patient population. The SF-3622 is a set of quality of life measures that assess perceived ability to complete physical tasks and routine activities, general health status, fatigue, social functioning, pain, and emotional and mental health.23 Condition-specific PROMs can be used for particular patient populations and are helpful in identifying changes in health status for a specific disease, disability, or surgery. For example, the PDQ-39 assesses 8 dimensions of daily living, functioning, and well-being for people with Parkinson’s disease.24
PROMs have been used in some MS clinical trials and research studies to determine the effectiveness of experimental treatments from the viewpoint of study participants.9,25,26 PROs can also be utilized in clinical care to facilitate communication of needs and track health outcomes,27 and can inform improvement in outcomes for health systems and populations. They can also be used to assess experience of care,28 encouraging a focus on high-quality outcomes through PRO-connected reimbursement mechanisms,29 and provide aggregate data to evaluate clinical practice, population health outcomes, and the effectiveness of public policies.27
Patient-reported experience measures (PREMs) assess patient satisfaction and experience of health care.30,31 CollaboRATE32 is a PREM that assesses the degree of shared decision-making occurring between patients and clinicians during clinical care. PREMs are currently used for assessing self-efficacy and in shared decision-making and health care improvement applications. PREMs have yet to be developed specifically for persons with MS.
PROMs in MS Care
Generic PROMs have shown that persons with MS are disproportionately burdened by poor quality of life.33-35 Other generic PROMs, like the SF-36,36 the Sickness Impact Profile,37 and versions of the Health Utilities Index,38 can be used to gather information on dysfunction and to determine quality and duration of life modified by MS-related dysfunction and disability. MS-specific PROMs are used to assess MS impairments, including pain, fatigue, cognition, sexual dysfunction, and depression.12,39-42 PROMs have also been used in MS clinical trials, including the Multiple Sclerosis Impact Scale-29 (MSIS-29),43,44 the Leeds MS QoL (LMSQoL),45,46 the Functional Assessment of MS (FAMS),47 the Hamburg Quality of Life Questionnaire in MS (HAQUAMS),48 the MS Quality of Life-54 (MSQoL-54),49 the MS International QoL (MUSIQoL),50 and the Patient-Reported Indices for MS Activity Limitations Scale (PRIMUS).51
Condition-specific PROMs are more sensitive to changes in health status and functioning for persons with MS compared to generic PROMs. They are also more reliable during MS remission and relapse periods.44,52 For example, the SF-36 has floor and ceiling effects in MS populations—a high proportion of persons with MS are scored at the maximum or minimum levels of the scale, limiting discriminant capability.22 As a result, a “combined approach” using both generic and MS-specific measures is often recommended.53 Some MS PROMs (eg, MSQoL-54) include generic questions found in the SF-36 as well as additional MS-specific questions or scales.
The variety of PROMs available (see Table for a selected listing) introduces a significant challenge to using them—limited generalizability and difficulty comparing PROs across MS studies. Efforts to establish common PROMs have been undertaken to address this problem.54 The National Institute of Neurologicical Disorders and Stroke (NINDS) sponsored the development of a neurological quality of life battery, the Neuro-QOL.55 Neuro-QOL measures the physical, mental, and social effects of neurological conditions in adults and children with neurological disorders and has the capability to facilitate comparisons across different neurological conditions. Additionally, the Patient-Reported Outcomes Measure Information System (PROMIS) has been developed to assess physical, mental, and social effects of chronic disease. PROMIS has a hybrid design that includes generic and MS-specific measures (such as PROMIS FatigueMS).56 PROMIS can be used to assess persons with MS as well as to compare the MS population with other populations with chronic illness.
PROMs have varying levels of reliability and validity. The Evaluating the Measure of Patient-Reported Outcomes57 study evaluated the development process of MS PROMs,43 and found that the MSIS-29 and LMSQoL had the highest overall reliability among the most common MS PROMs. However, both scored poorly on validity due to lack of patient involvement during development. This questions the overall capability of existing MS PROMs to accurately and consistently assess PROs in persons with MS.
“Feed-Forward” PROMs
Oliver and colleagues16 have described “feed-forward” PROM applications in MS care in a community hospital setting using a learning health system approach. This MS clinic uses feed-forward PROs to inform clinical care—PRO data are gathered before the clinic visit and analyzed ahead of or during the clinic visit by the clinician. Patients are asked to arrive early and complete a questionnaire comprised of PROMs measuring disability, functioning, quality of life, cognitive ability, pain, fatigue, sleep quality, anxiety, and depression. Clinicians score the PROMs and input scores into the electronic health record before the clinical encounter. During the clinic visit, PROM data is visually displayed so that the clinician and patient can discuss results and use the data to better inform decision-making. The visual data display contains longitudinal information, displaying trends in health status across multiple domains, and includes specified thresholds for clinically active symptom levels (Figure).16 Longitudinal monitoring of PROM data allows for real-time assessment of goal-related progress throughout treatment. As illustrated previously by Marion’s case study, the use of real-time feed-forward PROM data can strengthen the partnership between patient and clinician as well as improve empowerment, engagement, self-monitoring, and adherence.
PRO Dashboards
Performance dashboards are increasingly used in health care to visually display clinical and PRO data for individual patients, systems, and populations over time. Dashboards display a parsimonious group of critically important measures to give clinicians and patients a longitudinal view of PRO status. They can inform decision-making in clinical care, operations, health care improvement efforts, and population health initiatives.58 Effective dashboards allow for user customization with meaningful measures, knowledge discovery for analysis of health problems, accessibility of health information, clear visualization, alerts for unexpected data values, and system connectivity.59,60 Appropriate development of PRO dashboards requires meaningful patient and clinician involvement via focus groups and key informant interviews, Delphi process approaches to prioritize and finalize selection of priority measures, iterative building of the interface with design input from key informants and stakeholders (co-design), and pilot testing to assess feasibility and acceptability of use.61-63
Other Applications of PROs/PROMs in MS
Learning Health Systems
The National Quality Forum (NQF) and the Centers for Medicaid and Medicare Services have adopted PROs for use in quality measurement.64-66 This includes a movement towards the use of LHS, defined as a health system in which information from patients and clinicians is systematically collected and synthesized with external evidence to inform clinical care, improvement, and research.67-70 Often a LHS is undertaken as a collaborative effort between multiple health care centers to improve quality and outcomes of care.70 The MS Continuous Quality Improvement Collaborative (MS-CQI), the first multi-center systems-level health care improvement research collaborative for MS,71 as well as IBD Qorus and the Cystic Fibrosis Care Center Network utilize LHS approaches.72-77
IBD Qorus is a LHS developed by the Crohn’s and Colitis Foundation that uses performance dashboards to better inform clinical care for people with inflammatory bowel disease. It also employs system-level dashboards for performance benchmarking in quality improvement initiatives and aggregate-level dashboards to assess population health status.78,79 MS-CQI uses a LHS approach to inform the improvement of MS care across multiple centers using a comprehensive dashboard, including PROMs, for benchmarking and to monitor system and population health status. MS-CQI collects PROMs using a secure online platform that can be accessed by persons with MS and their clinicians and also includes a journaling feature for collecting qualitative information and for reference and self-monitoring.71
MS Research
PROMs are used in clinical and epidemiological research to evaluate many aspects of MS, including the FAMS, the PDSS, the Fatigue Impact Scale (FIS), and others.80-82 For example, the PROMIS FatigueMS and the Fatigue Performance Scale have been used to assess the impact of MS-related fatigue on social participation.83 Generic and MS-specific PROMs have been used to assess pain levels for people with MS,84-87 and multiple MS-specific PROMs, like PRIMUS and MSQoL-54,43 as well as the SF-3639 include pain assessment scales. PROMs have also been used to assess MS-related bladder, bowel, and sexual dysfunction. Urgency, frequency, and incontinence affect up to 75% of patients with MS,88 and many PROMs, such as the LMSQoL, MUSIQoL, and the MSQoL-54, are able to evaluate bladder control and sexual functioning.43,89
PROMs are employed in MS clinical trials to help assess the tolerability and effectiveness of DMTs.90,91 PROs have been used as secondary endpoints to understand the global experience of a DMT from the patient perspective.92-94 There are 15 FDA-approved DMTs for MS, and clinical trials for 6 of these have used PROMs as an effectiveness end point.54,91,95,96 However, most DMT clinical trials are powered for MRI, relapse rate, or disease progression primary outcomes rather than PROMs, often resulting in underpowered PROM analyses.97 In addition, many PROMs are not appropriate for use in DMT clinical trials.98,99
In order to bridge the gap between clinical research and practice, some industry entities are championing “patient-focused drug development” approaches. The Accelerated Cure Project for MS has launched iConquerMS, which collects PROMs from persons with MS to further PRO research in MS and follows 4700 individuals with MS worldwide.100 In 2018, the American College of Physicians announced a collaboration with an industry partner to share data to inform DMT clinical trials and develop and validate PROMs specifically designed for DMT clinical trials.101
Population Health
Registries following large cohorts of people with MS have the potential to develop knowledge about disease progression, treatment patterns, and outcomes.102 The Swedish EIMS study has identified associations between pre-disease body mass index and MS prognosis,102 alcohol and tobacco consumption affecting MS risk,103,104 and exposure to shift work at a young age and increased MS risk.105 The North American Research Committee on MS83,106,107 and iConquerMS registries are “PROM-driven” and have been useful in identifying reductions in disease progression in people using DMTs.107,108 The New York State MS Consortium has identified important demographic characteristics that influence MS progression.109,110 PROs can also be used to determine risk of MS-related mortality111 and decline in quality of life.112,113 Limitations of these approaches include use of different PROMs, inconsistencies in data collection processes, and different follow-up intervals used across registries.102
Patient-Centered Care
The Institute of Medicine defines patient-centeredness as “care that is respectful and responsive to individual patient preferences, needs, and values and ensures that patient values guide all clinical decisions.”114 PROs are useful for identifying a patient’s individual health concerns and preferences, something that is needed when treating a highly variable chronic health condition like MS. The use of PROs can help clinicicans visualize the lived experience of persons with MS and identify personal preferences,115 as well as improve self-monitoring, self-management, self-efficacy, adherence, wellness, and coping ability.116 At the system level, PROs can inform improvement initiatives and patient-centered care design efforts.117-120
Selecting PROMs
Initiatives from groups like the COnsensus-based Standards for the Selection of health Measurement INstruments (COSMIN)121 and the International Society for Quality of Life Research (ISOQOL)108 offer guidance on selecting PROs. The NINDS has promoted common data collection between clinical studies of the brain and nervous system.122 General guidance from these sources recommends first considering the outcome and target population, selecting PROMs to measure the outcome through a synthesis of the available evidence, assessing validity and reliability of selected PROMs, and using standard measures that can be compared across studies or populations.108,121 Other factors include feasibility, acceptability, and burden of use for patients, clinicians, and systems, as well as literacy, cultural, and linguistic factors.123
The NQF recommends that consideration be given to individual patient needs, insurance factors, clinical setting constraints, and available resources when selecting PROMs.124 To maximize response rate, PROMs that are sensitive, reliable, valid, and developed in a comparative demographic of patients are advised.125 ISOQOL has released a User’s Guide and several companion guides on implementing and utilizing PROMs.108,126,127 Finally, PRO-Performance Measures (PRO-PMs) are sometimes used to assess whether PROMs are appropriately contributing to performance improvement and accountability.124
The Cons of PROs
PROs can disrupt busy clinical care environments and overextend clinical staff.125 Online collection of PROs outside of clinical encounters can relieve PRO-related burden, but this requires finding and funding appropriate secure online networks to effectively collect PROs.128 In 2015, only 60% of people seen for primary care visits could access or view their records online, and of those, only 57% used messaging for medical questions or concerns.129 Ideally, online patient portal or mobile health apps could synchronize directly to electronic health records or virtual scribes to transfer patient communications into clinical documentation.130 There has been limited success with this approach in European countries131 and with some chronic illness conditions in the United States.74
Electronic health technologies, including mobile health (mHealth) solutions, have improved the self-monitoring and self-management capability of patients with MS via information sharing in patient networks, assistive technologies, smartphone applications, and wearable devices.132,133 A recent study found that communication modes included secure online patient portal use (29%) and email use (21%), and among those who owned tablets or smartphones, 46% used mHealth apps.134 Social media use has been associated with increased peer/social/emotional support and increased access to health information, as well as clinical monitoring and behavior change.134,135 Individuals using mHealth apps are younger, have comorbidities, and have higher socioeconomic and education levels,135,136 suggesting that inequities in mHealth access exist.
Questionnaires can be time-consuming and cause mental distress if not appropriately facilitated.137 Decreasing questionnaire length and providing the option for PROMs to be delivered and completed online or outside of the clinic context can reduce burden.138 Additionally, while some people are consistent in sharing their PROs, others struggle with using computers, especially while experiencing severe symptoms, forget to complete PROMs, or simply do not have internet access due to financial or geographic constraints.139 A group of disabled and elderly persons with MS reported barriers to internet use due to visual deficits, small website font sizes, and distracting color schemes.140
Interpretability
Interpreting PROMs and displays of longitudinal PROM data can be a challenge for persons with MS and their clinicians. There is little standardization in how PROMs are scored and presented, and there is often confusion about thresholds for clinical significance and how PROM scores can be compared to other PROMs.141,142 While guidelines exist for implementing PRO scores in clinical settings,126,143 there are few that aid PROM interpretation. As a result, clinicians often seek research evidence for PROMs used in other similar patient populations as a benchmark,142-144 or compare them to other patients seen in their clinical practice.
Longitudinal PRO data are usually displayed in simple line graphs.145,146 Overall, line graphs have been found to have the highest ease of understanding by both patients and clinicians, but sometimes can be confusing.147 For example, upward trending lines are usually viewed as improvement and downward trending lines as decline; however, upward trending scores on a PROM can indicate decline, such as increasing fatigue severity. Annotation of visual displays can help. Patients and clinicians find that employing thresholds and color coding is useful, and better than “stoplight” red-yellow-green shading schemes or red-circle formats to indicate data that warrant attention.142
PROs are not free of risk for error, especially if they are used independently of other information sources, such as clinical interview, examination, and diagnostic testing, or if they are utilized too frequently, too infrequently, or are duplicated in practice. If a PRO instrument is employed too frequently, score changes may reflect learning effects rather than actual clinical status. Conversely, if used too infrequently, PRO information will not be timely enough to inform real-time clinical practice. Duplication of PRO assessments (eg, multiple measures of the same PRO for the same patient on the same day) or use of multiple PRO measures to assess the same aspect (eg, 2 measures used to assess fatigue) could introduce unnecessary complexity and confusion to interpretation of PRO results.
PRO measures also can be biased or modified by clinical status and/or perceptions of people with MS at the time of assessment. For example, cognitive impairment, whether at baseline state or due to a cognitive MS relapse event, could impact patients’ ability to understand and respond to PRO assessments, producing erroneous results. However, when used appropriately, PROs targeting cognitive dysfunction may be able to detect onset of cognitive events or help to measure recovery from them. Finally, PROs measure perceived (self-reported) status, which may not be an accurate depiction of actual status.
All of these potential pitfalls support the argument that PROs should be utilized to augment the clinical interview, examination, and diagnostic (objective) testing aspects of comprehensive MS care. In this way, PROs can be correlated with other information sources to deepen the shared understanding of health status between a person with MS and her clinician, increasing the potential to make better treatment decisions and care plans together in partnership.
Value and Cost
National groups such as the Patient-Centered Outcomes Research Institute (PCORI) are working with regulatory bodies, funding agencies, insurance providers, patient advocacy groups, researchers, providers, and specialty groups to investigate how PROMs can be implemented into value-based health care reforms, including value-based reimbursement.148 However, practical PRO implementation requires considerable time and resources, and many methodological and operational questions must be addressed before widespread adoption and reimbursement for PROMs will be feasible.148,149
Summary
PROs can generate valuable information about perceived health status, function, quality of life, and experience of care using self-reported sources. Validated PRO assessment tools include PROMs and PREMs. PROs are currently utilized in research settings (especially PROMs) but are also being used in clinical practice, quality improvement initiatives, and population health applications using LHS approaches. PROs have the advantages of empowering and informing persons with MS and clinicians to optimize patient-centered care, improve systems of care, and study population health outcomes. Barriers include PROM validity, reliability, comparability, specificity, interpretability, equity, time, and cost. Generic PROMs and PREMs, and some MS-specific PROMs, can be used for persons with MS. Unfortunately, no PREMs have been developed specifically for persons with MS, and this is an area for future research. With appropriate development and utilization in LHS applications, PROs can inform patient-centered clinical care, system-level improvement initiatives, and population health research, and have the potential to help facilitate coproduction of health care services.
Acknowledgments: The authors thank Ann Cabot, DO, of the MS Specialty Care Program at Concord Hospital and (especially) peer mentors from a peer outreach wellness program for people with MS (who have asked to remain anonymous) for interviews conducted with their permission to inform the case study described in this article. The case study used in this manuscript has been de-identified, with some aspects modified from actual, and the person in the case study is fictitiously named.
Corresponding author: Brant Oliver, PhD, MS, MPH, APRN-BC, Department of Community & Family Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756; [email protected].
Financial disclosures: None.
From the Dartmouth Institute for Health Policy & Clinical Practice, Geisel School of Medicine, Hanover, NH (Ms. Manohar and Dr. Oliver), the Department of Community & Family Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH (Ms. Perkins, Ms. Laurion, and Dr. Oliver), and the Multiple Sclerosis Specialty Care Program, Concord Hospital, Concord, NH (Dr. Oliver).
Abstract
- Background: Patient-reported outcomes (PROs), including patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs), can be used to assess perceived health status, functioning, quality of life, and experience of care. Complex chronic illnesses such as multiple sclerosis (MS) affect multiple aspects of health, and PROs can be applied in assessment and decision-making in MS care as well as in research pertaining to MS.
- Objective: To provide a general review of PROs, with a specific focus on implications for MS care.
- Methods: Evidence synthesis of available literature on PROs in MS care.
- Results: PROs (including PROMs and PREMs) have historically been utilized in research and are now being applied in clinical, improvement, and population health settings using learning health system approaches in many disease populations, including MS. Many challenges complicate the use of PROs in MS care, including reliability, validity, and interpretability of PROMs, as well as feasibility barriers due to time and financial constraints in clinical settings.
- Conclusion: PROs have the potential to better inform clinical care, empower patient-centered care, inform health care improvement efforts, and create the conditions for coproduction of health care services.
Keywords: PRO; PROM; patient-reported outcome measure; patient-reported experience measure; quality of life; patient-centered care.
Multiple sclerosis (MS) is a disabling, complex, chronic, immune-mediated disorder of the central nervous system (CNS). MS causes inflammatory and degenerative damage in the CNS, which disrupts signaling pathways.1 It is most commonly diagnosed in young adults and affects 2.3 million people worldwide.2 People with MS experience very different disease courses and a wide range of neurological symptoms, including visual, somatic, mental health, sensory, motor, and cognitive problems.1-3 Relapsing-remitting MS, the most common form, affects 85% of those with MS and is characterized by periods of relapse (exacerbation) and remission.1 Other forms of MS (primary progressive and secondary progressive MS) are characterized by progressive deterioration and worsening symptom severity without exacerbations. Disease-modifying therapies (DMTs) can reduce the frequency of exacerbations and disability progression, but unfortunately there is no cure for MS. Treatment is focused on increasing quality of life, minimizing disability, and maximizing wellness.
Patient-reported outcomes (PROs) describe the perceived health status, function, and/or experience of a person as obtained by direct self-report. Patient-reported outcome measures (PROMs) are validated PROs that can be used to inform clinical care,4 and have demonstrated effectiveness in improving patient-provider communication and decision-making.5-7 PROMs are currently used in some MS clinical trials to determine the impact of experimental interventions,8-10 and are also being used to inform and improve clinical care in some settings. Especially for persons with MS, they can provide individualized perspectives about health experience and outcomes.11 In more advanced applications, PROMs can be used to improve face-to-face collaborations between clinicians and patients and to inform patient-centered systems of care.12-14 PROMs can also be used to inform systems-level improvement for entire patient populations.15,16
In this article, we review current applications of PROs and PROMs in the care of persons with MS, as well as current limitations and barriers to their use.
At a recent visit to her neurologist, Marion reviews her health diary, in which she has been tracking her fatigue levels throughout the day and when she has to visit the bathroom. The PRO diary also helps her remember details that she might not otherwise be able to recall at the time of her clinic visit. They review the diary entrees together to develop a shared understanding of what Marion has been experiencing and identify trends in the PRO data. They discuss symptom management and use the PRO information from the diary to help guide adjustments to her physical therapy routine and medication regimen.
Part of Marion’s “PRO package” includes the Center for Epidemiologic Studies Depression Scale (CES-D), a validated depression screening and symptom severity questionnaire that she completes every 3 months. Although she denies being depressed, she has noticed that her CES-D scores in recent months have been consistently increasing. This prompts a discussion about mental health in MS and a referral to work on depression with the MS mental health specialist. Marion and the mental health specialist use CES-D measures at baseline and during treatment to set a remission target and to track progress during treatment. Marion finds this helpful because she says it is hard for her to “wrap my hands around depression… it’s not something that there is a blood test or a MRI for.” Marion is encouraged by being able to see her CES-D scores change as her depression severity decreases, and this helps motivate her to keep engaged in treatment.
PROs and PROMs: General Applications
PROs are measures obtained directly from an individual without a priori interpretation by a clinician.9,17 PROs capture individual perspectives on symptoms, capability, disability, and health-related quality of life.9 With increasing emphasis on patient-centered care,18 individual perspectives and preferences elicited using PROMs may be able to inform better quality of care and patient-centered disease treatment and management.19-21
PROMs are standardized, validated questionnaires used to assess PROs and can be generic or condition-specific. Generic PROMs can be used in any patient population. The SF-3622 is a set of quality of life measures that assess perceived ability to complete physical tasks and routine activities, general health status, fatigue, social functioning, pain, and emotional and mental health.23 Condition-specific PROMs can be used for particular patient populations and are helpful in identifying changes in health status for a specific disease, disability, or surgery. For example, the PDQ-39 assesses 8 dimensions of daily living, functioning, and well-being for people with Parkinson’s disease.24
PROMs have been used in some MS clinical trials and research studies to determine the effectiveness of experimental treatments from the viewpoint of study participants.9,25,26 PROs can also be utilized in clinical care to facilitate communication of needs and track health outcomes,27 and can inform improvement in outcomes for health systems and populations. They can also be used to assess experience of care,28 encouraging a focus on high-quality outcomes through PRO-connected reimbursement mechanisms,29 and provide aggregate data to evaluate clinical practice, population health outcomes, and the effectiveness of public policies.27
Patient-reported experience measures (PREMs) assess patient satisfaction and experience of health care.30,31 CollaboRATE32 is a PREM that assesses the degree of shared decision-making occurring between patients and clinicians during clinical care. PREMs are currently used for assessing self-efficacy and in shared decision-making and health care improvement applications. PREMs have yet to be developed specifically for persons with MS.
PROMs in MS Care
Generic PROMs have shown that persons with MS are disproportionately burdened by poor quality of life.33-35 Other generic PROMs, like the SF-36,36 the Sickness Impact Profile,37 and versions of the Health Utilities Index,38 can be used to gather information on dysfunction and to determine quality and duration of life modified by MS-related dysfunction and disability. MS-specific PROMs are used to assess MS impairments, including pain, fatigue, cognition, sexual dysfunction, and depression.12,39-42 PROMs have also been used in MS clinical trials, including the Multiple Sclerosis Impact Scale-29 (MSIS-29),43,44 the Leeds MS QoL (LMSQoL),45,46 the Functional Assessment of MS (FAMS),47 the Hamburg Quality of Life Questionnaire in MS (HAQUAMS),48 the MS Quality of Life-54 (MSQoL-54),49 the MS International QoL (MUSIQoL),50 and the Patient-Reported Indices for MS Activity Limitations Scale (PRIMUS).51
Condition-specific PROMs are more sensitive to changes in health status and functioning for persons with MS compared to generic PROMs. They are also more reliable during MS remission and relapse periods.44,52 For example, the SF-36 has floor and ceiling effects in MS populations—a high proportion of persons with MS are scored at the maximum or minimum levels of the scale, limiting discriminant capability.22 As a result, a “combined approach” using both generic and MS-specific measures is often recommended.53 Some MS PROMs (eg, MSQoL-54) include generic questions found in the SF-36 as well as additional MS-specific questions or scales.
The variety of PROMs available (see Table for a selected listing) introduces a significant challenge to using them—limited generalizability and difficulty comparing PROs across MS studies. Efforts to establish common PROMs have been undertaken to address this problem.54 The National Institute of Neurologicical Disorders and Stroke (NINDS) sponsored the development of a neurological quality of life battery, the Neuro-QOL.55 Neuro-QOL measures the physical, mental, and social effects of neurological conditions in adults and children with neurological disorders and has the capability to facilitate comparisons across different neurological conditions. Additionally, the Patient-Reported Outcomes Measure Information System (PROMIS) has been developed to assess physical, mental, and social effects of chronic disease. PROMIS has a hybrid design that includes generic and MS-specific measures (such as PROMIS FatigueMS).56 PROMIS can be used to assess persons with MS as well as to compare the MS population with other populations with chronic illness.
PROMs have varying levels of reliability and validity. The Evaluating the Measure of Patient-Reported Outcomes57 study evaluated the development process of MS PROMs,43 and found that the MSIS-29 and LMSQoL had the highest overall reliability among the most common MS PROMs. However, both scored poorly on validity due to lack of patient involvement during development. This questions the overall capability of existing MS PROMs to accurately and consistently assess PROs in persons with MS.
“Feed-Forward” PROMs
Oliver and colleagues16 have described “feed-forward” PROM applications in MS care in a community hospital setting using a learning health system approach. This MS clinic uses feed-forward PROs to inform clinical care—PRO data are gathered before the clinic visit and analyzed ahead of or during the clinic visit by the clinician. Patients are asked to arrive early and complete a questionnaire comprised of PROMs measuring disability, functioning, quality of life, cognitive ability, pain, fatigue, sleep quality, anxiety, and depression. Clinicians score the PROMs and input scores into the electronic health record before the clinical encounter. During the clinic visit, PROM data is visually displayed so that the clinician and patient can discuss results and use the data to better inform decision-making. The visual data display contains longitudinal information, displaying trends in health status across multiple domains, and includes specified thresholds for clinically active symptom levels (Figure).16 Longitudinal monitoring of PROM data allows for real-time assessment of goal-related progress throughout treatment. As illustrated previously by Marion’s case study, the use of real-time feed-forward PROM data can strengthen the partnership between patient and clinician as well as improve empowerment, engagement, self-monitoring, and adherence.
PRO Dashboards
Performance dashboards are increasingly used in health care to visually display clinical and PRO data for individual patients, systems, and populations over time. Dashboards display a parsimonious group of critically important measures to give clinicians and patients a longitudinal view of PRO status. They can inform decision-making in clinical care, operations, health care improvement efforts, and population health initiatives.58 Effective dashboards allow for user customization with meaningful measures, knowledge discovery for analysis of health problems, accessibility of health information, clear visualization, alerts for unexpected data values, and system connectivity.59,60 Appropriate development of PRO dashboards requires meaningful patient and clinician involvement via focus groups and key informant interviews, Delphi process approaches to prioritize and finalize selection of priority measures, iterative building of the interface with design input from key informants and stakeholders (co-design), and pilot testing to assess feasibility and acceptability of use.61-63
Other Applications of PROs/PROMs in MS
Learning Health Systems
The National Quality Forum (NQF) and the Centers for Medicaid and Medicare Services have adopted PROs for use in quality measurement.64-66 This includes a movement towards the use of LHS, defined as a health system in which information from patients and clinicians is systematically collected and synthesized with external evidence to inform clinical care, improvement, and research.67-70 Often a LHS is undertaken as a collaborative effort between multiple health care centers to improve quality and outcomes of care.70 The MS Continuous Quality Improvement Collaborative (MS-CQI), the first multi-center systems-level health care improvement research collaborative for MS,71 as well as IBD Qorus and the Cystic Fibrosis Care Center Network utilize LHS approaches.72-77
IBD Qorus is a LHS developed by the Crohn’s and Colitis Foundation that uses performance dashboards to better inform clinical care for people with inflammatory bowel disease. It also employs system-level dashboards for performance benchmarking in quality improvement initiatives and aggregate-level dashboards to assess population health status.78,79 MS-CQI uses a LHS approach to inform the improvement of MS care across multiple centers using a comprehensive dashboard, including PROMs, for benchmarking and to monitor system and population health status. MS-CQI collects PROMs using a secure online platform that can be accessed by persons with MS and their clinicians and also includes a journaling feature for collecting qualitative information and for reference and self-monitoring.71
MS Research
PROMs are used in clinical and epidemiological research to evaluate many aspects of MS, including the FAMS, the PDSS, the Fatigue Impact Scale (FIS), and others.80-82 For example, the PROMIS FatigueMS and the Fatigue Performance Scale have been used to assess the impact of MS-related fatigue on social participation.83 Generic and MS-specific PROMs have been used to assess pain levels for people with MS,84-87 and multiple MS-specific PROMs, like PRIMUS and MSQoL-54,43 as well as the SF-3639 include pain assessment scales. PROMs have also been used to assess MS-related bladder, bowel, and sexual dysfunction. Urgency, frequency, and incontinence affect up to 75% of patients with MS,88 and many PROMs, such as the LMSQoL, MUSIQoL, and the MSQoL-54, are able to evaluate bladder control and sexual functioning.43,89
PROMs are employed in MS clinical trials to help assess the tolerability and effectiveness of DMTs.90,91 PROs have been used as secondary endpoints to understand the global experience of a DMT from the patient perspective.92-94 There are 15 FDA-approved DMTs for MS, and clinical trials for 6 of these have used PROMs as an effectiveness end point.54,91,95,96 However, most DMT clinical trials are powered for MRI, relapse rate, or disease progression primary outcomes rather than PROMs, often resulting in underpowered PROM analyses.97 In addition, many PROMs are not appropriate for use in DMT clinical trials.98,99
In order to bridge the gap between clinical research and practice, some industry entities are championing “patient-focused drug development” approaches. The Accelerated Cure Project for MS has launched iConquerMS, which collects PROMs from persons with MS to further PRO research in MS and follows 4700 individuals with MS worldwide.100 In 2018, the American College of Physicians announced a collaboration with an industry partner to share data to inform DMT clinical trials and develop and validate PROMs specifically designed for DMT clinical trials.101
Population Health
Registries following large cohorts of people with MS have the potential to develop knowledge about disease progression, treatment patterns, and outcomes.102 The Swedish EIMS study has identified associations between pre-disease body mass index and MS prognosis,102 alcohol and tobacco consumption affecting MS risk,103,104 and exposure to shift work at a young age and increased MS risk.105 The North American Research Committee on MS83,106,107 and iConquerMS registries are “PROM-driven” and have been useful in identifying reductions in disease progression in people using DMTs.107,108 The New York State MS Consortium has identified important demographic characteristics that influence MS progression.109,110 PROs can also be used to determine risk of MS-related mortality111 and decline in quality of life.112,113 Limitations of these approaches include use of different PROMs, inconsistencies in data collection processes, and different follow-up intervals used across registries.102
Patient-Centered Care
The Institute of Medicine defines patient-centeredness as “care that is respectful and responsive to individual patient preferences, needs, and values and ensures that patient values guide all clinical decisions.”114 PROs are useful for identifying a patient’s individual health concerns and preferences, something that is needed when treating a highly variable chronic health condition like MS. The use of PROs can help clinicicans visualize the lived experience of persons with MS and identify personal preferences,115 as well as improve self-monitoring, self-management, self-efficacy, adherence, wellness, and coping ability.116 At the system level, PROs can inform improvement initiatives and patient-centered care design efforts.117-120
Selecting PROMs
Initiatives from groups like the COnsensus-based Standards for the Selection of health Measurement INstruments (COSMIN)121 and the International Society for Quality of Life Research (ISOQOL)108 offer guidance on selecting PROs. The NINDS has promoted common data collection between clinical studies of the brain and nervous system.122 General guidance from these sources recommends first considering the outcome and target population, selecting PROMs to measure the outcome through a synthesis of the available evidence, assessing validity and reliability of selected PROMs, and using standard measures that can be compared across studies or populations.108,121 Other factors include feasibility, acceptability, and burden of use for patients, clinicians, and systems, as well as literacy, cultural, and linguistic factors.123
The NQF recommends that consideration be given to individual patient needs, insurance factors, clinical setting constraints, and available resources when selecting PROMs.124 To maximize response rate, PROMs that are sensitive, reliable, valid, and developed in a comparative demographic of patients are advised.125 ISOQOL has released a User’s Guide and several companion guides on implementing and utilizing PROMs.108,126,127 Finally, PRO-Performance Measures (PRO-PMs) are sometimes used to assess whether PROMs are appropriately contributing to performance improvement and accountability.124
The Cons of PROs
PROs can disrupt busy clinical care environments and overextend clinical staff.125 Online collection of PROs outside of clinical encounters can relieve PRO-related burden, but this requires finding and funding appropriate secure online networks to effectively collect PROs.128 In 2015, only 60% of people seen for primary care visits could access or view their records online, and of those, only 57% used messaging for medical questions or concerns.129 Ideally, online patient portal or mobile health apps could synchronize directly to electronic health records or virtual scribes to transfer patient communications into clinical documentation.130 There has been limited success with this approach in European countries131 and with some chronic illness conditions in the United States.74
Electronic health technologies, including mobile health (mHealth) solutions, have improved the self-monitoring and self-management capability of patients with MS via information sharing in patient networks, assistive technologies, smartphone applications, and wearable devices.132,133 A recent study found that communication modes included secure online patient portal use (29%) and email use (21%), and among those who owned tablets or smartphones, 46% used mHealth apps.134 Social media use has been associated with increased peer/social/emotional support and increased access to health information, as well as clinical monitoring and behavior change.134,135 Individuals using mHealth apps are younger, have comorbidities, and have higher socioeconomic and education levels,135,136 suggesting that inequities in mHealth access exist.
Questionnaires can be time-consuming and cause mental distress if not appropriately facilitated.137 Decreasing questionnaire length and providing the option for PROMs to be delivered and completed online or outside of the clinic context can reduce burden.138 Additionally, while some people are consistent in sharing their PROs, others struggle with using computers, especially while experiencing severe symptoms, forget to complete PROMs, or simply do not have internet access due to financial or geographic constraints.139 A group of disabled and elderly persons with MS reported barriers to internet use due to visual deficits, small website font sizes, and distracting color schemes.140
Interpretability
Interpreting PROMs and displays of longitudinal PROM data can be a challenge for persons with MS and their clinicians. There is little standardization in how PROMs are scored and presented, and there is often confusion about thresholds for clinical significance and how PROM scores can be compared to other PROMs.141,142 While guidelines exist for implementing PRO scores in clinical settings,126,143 there are few that aid PROM interpretation. As a result, clinicians often seek research evidence for PROMs used in other similar patient populations as a benchmark,142-144 or compare them to other patients seen in their clinical practice.
Longitudinal PRO data are usually displayed in simple line graphs.145,146 Overall, line graphs have been found to have the highest ease of understanding by both patients and clinicians, but sometimes can be confusing.147 For example, upward trending lines are usually viewed as improvement and downward trending lines as decline; however, upward trending scores on a PROM can indicate decline, such as increasing fatigue severity. Annotation of visual displays can help. Patients and clinicians find that employing thresholds and color coding is useful, and better than “stoplight” red-yellow-green shading schemes or red-circle formats to indicate data that warrant attention.142
PROs are not free of risk for error, especially if they are used independently of other information sources, such as clinical interview, examination, and diagnostic testing, or if they are utilized too frequently, too infrequently, or are duplicated in practice. If a PRO instrument is employed too frequently, score changes may reflect learning effects rather than actual clinical status. Conversely, if used too infrequently, PRO information will not be timely enough to inform real-time clinical practice. Duplication of PRO assessments (eg, multiple measures of the same PRO for the same patient on the same day) or use of multiple PRO measures to assess the same aspect (eg, 2 measures used to assess fatigue) could introduce unnecessary complexity and confusion to interpretation of PRO results.
PRO measures also can be biased or modified by clinical status and/or perceptions of people with MS at the time of assessment. For example, cognitive impairment, whether at baseline state or due to a cognitive MS relapse event, could impact patients’ ability to understand and respond to PRO assessments, producing erroneous results. However, when used appropriately, PROs targeting cognitive dysfunction may be able to detect onset of cognitive events or help to measure recovery from them. Finally, PROs measure perceived (self-reported) status, which may not be an accurate depiction of actual status.
All of these potential pitfalls support the argument that PROs should be utilized to augment the clinical interview, examination, and diagnostic (objective) testing aspects of comprehensive MS care. In this way, PROs can be correlated with other information sources to deepen the shared understanding of health status between a person with MS and her clinician, increasing the potential to make better treatment decisions and care plans together in partnership.
Value and Cost
National groups such as the Patient-Centered Outcomes Research Institute (PCORI) are working with regulatory bodies, funding agencies, insurance providers, patient advocacy groups, researchers, providers, and specialty groups to investigate how PROMs can be implemented into value-based health care reforms, including value-based reimbursement.148 However, practical PRO implementation requires considerable time and resources, and many methodological and operational questions must be addressed before widespread adoption and reimbursement for PROMs will be feasible.148,149
Summary
PROs can generate valuable information about perceived health status, function, quality of life, and experience of care using self-reported sources. Validated PRO assessment tools include PROMs and PREMs. PROs are currently utilized in research settings (especially PROMs) but are also being used in clinical practice, quality improvement initiatives, and population health applications using LHS approaches. PROs have the advantages of empowering and informing persons with MS and clinicians to optimize patient-centered care, improve systems of care, and study population health outcomes. Barriers include PROM validity, reliability, comparability, specificity, interpretability, equity, time, and cost. Generic PROMs and PREMs, and some MS-specific PROMs, can be used for persons with MS. Unfortunately, no PREMs have been developed specifically for persons with MS, and this is an area for future research. With appropriate development and utilization in LHS applications, PROs can inform patient-centered clinical care, system-level improvement initiatives, and population health research, and have the potential to help facilitate coproduction of health care services.
Acknowledgments: The authors thank Ann Cabot, DO, of the MS Specialty Care Program at Concord Hospital and (especially) peer mentors from a peer outreach wellness program for people with MS (who have asked to remain anonymous) for interviews conducted with their permission to inform the case study described in this article. The case study used in this manuscript has been de-identified, with some aspects modified from actual, and the person in the case study is fictitiously named.
Corresponding author: Brant Oliver, PhD, MS, MPH, APRN-BC, Department of Community & Family Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756; [email protected].
Financial disclosures: None.
1. Goldenberg MM. Multiple sclerosis review. PT. 2012;37:175-184.
2. Doshi A, Chataway J. Multiple sclerosis, a treatable disease. Clin Med. 2016;16(Suppl 6):s53-s9.
3. Perrin Ross A. Management of multiple sclerosis. Am J Managed Care. 2013;19(16 Suppl):s301-s306.
4. Batalden M, Batalden P, Margolis P, et al. Coproduction of healthcare service. BMJ Qual Saf. 2016;25:509-517.
5. Chen J, Ou L, Hollis SJ. A systematic review of the impact of routine collection of patient reported outcome measures on patients, providers and health organisations in an oncologic setting. BMC Health Serv Res. 2013;13:211.
6. Knaup C, Koesters M, Schoefer D, et al. Effect of feedback of treatment outcome in specialist mental healthcare: meta-analysis. Br J Psychiatr. 2009;195:15-22.
7. Dudgeon D. The impact of measuring patient-reported outcome measures on quality of and access to palliative care. J Palliat Med. 2018;21(S1):S76-s80.
8. Snyder CF, Herman JM, White SM, et al. When using patient-reported outcomes in clinical practice, the measure matters: a randomized controlled trial. J Oncol Pract. 2014;10:e299-e306.
9. Guidance for industry: patient-reported outcome measures: use in medical product development to support labeling claims: draft guidance. Health Qual Life Outcomes. 2006;4:79.
10. de Jong MJ, Huibregtse R, Masclee AAM, et al. Patient-reported outcome measures for use in clinical trials and clinical practice in inflammatory bowel diseases: a systematic review. Clin Gastroenterol Hepatol. 2018;16:648-663.
11. Roman D, Osborne-Stafsnes J, Amy CH, et al. Early lessons from four ‘aligning forces for quality’ communities bolster the case for patient-centered care. Health Affairs. 2013;32:232-241.
12. Ehde DM, Alschuler KN, Sullivan MD, et al. Improving the quality of depression and pain care in multiple sclerosis using collaborative care: The MS-care trial protocol. Contemporary Clinical Trials. 2018;64:219-229.
13. Lavallee DC, Chenok KE, Love RM, et al. Incorporating patient-reported outcomes into health care to engage patients and enhance care. Health Affairs. 2016;35:575-582.
14. Schick-Makaroff K, Thummapol O, Thompson S, et al. Strategies for incorporating patient-reported outcomes in the care of people with chronic kidney disease (PRO kidney): a protocol for a realist synthesis. Clin Gastroenterol Hepatol. 2018;16:648-663.
15. Nelson EC, Dixon-Woods M, Batalden PB, et al. Patient focused registries can improve health, care, and science. BMJ. 2016;354:i3319.
16. Oliver BJ, Nelson EC, Kerrigan CL. Turning feed-forward and feedback processes on patient-reported data into intelligent action and informed decision-making: case studies and principles. Med Care. 2019;57 Suppl 1:S31-s37.
17. Deshpande PR, Rajan S, Sudeepthi BL, Abdul Nazir CP. Patient-reported outcomes: A new era in clinical research. Perspect Clin Res. 2011;2:137-144.
18. Epstein RM, Street RL, Jr. The values and value of patient-centered care. Ann Fam Med. 2011;9:100-103.
19. Payne SA. A study of quality of life in cancer patients receiving palliative chemotherapy. Soc Sci Med. 1992;35:1505-1509.
20. Borgaonkar MR, Irvine EJ. Quality of life measurement in gastrointestinal and liver disorders. Gut. 2000;47:444-454.
21. Macdonell R, Nagels G, Laplaud DA, et al. Improved patient-reported health impact of multiple sclerosis: The ENABLE study of PR-fampridine. Multiple Sclerosis. 2016;22:944-954.
22. Hobart J, Freeman J, Lamping D, et al. The SF-36 in multiple sclerosis: why basic assumptions must be tested. J Neurol Neurosurg Psychiatry. 2001;71:363-370.
23. Lins L, Carvalho FM. SF-36 total score as a single measure of health-related quality of life: Scoping review. SAGE Open Med. 2016;4:2050312116671725.
24. Parkinson’s Disease Society of the United Kingdom. The Parkinson’s Disease Questionnaire (PDQ-39). https://www.parkinsons.org.uk/professionals/resources/parkinsons-disease-questionnaire-pdq-39. Accessed October 20, 2019.
25. Basch E. The missing voice of patients in drug-safety reporting. N Engl J Med. 2010;362:865-869.
26. Calvert M, Brundage M, Jacobsen PB, et al. The CONSORT Patient-Reported Outcome (PRO) extension: implications for clinical trials and practice. Health Qual Life Outcomes. 2013;11:184.
27. Black N. Patient reported outcome measures could help transform healthcare. BMJ. 2013;346:f167.
28. Franks P, Fiscella K, Shields CG, et al. Are patients’ ratings of their physicians related to health outcomes? Ann Fam Med. 2005;3:229-234.
29. Hostetter M, Klein S. Using patient-reported outcomes to improve health care quality. The Commonwealth Fund 2019. www.commonwealthfund.org/publications/newsletter-article/using-patient-reported-outcomes-improve-health-care-quality. Accessed October 24, 2019.
30. Charlotte Kingsley SP. Patient-reported outcome measures and patient-reported experience measures. BJA Education. 2017;17:137-144.
31. Weldring T, Smith SM. Patient-Reported outcomes (PROs) and patient-reported outcome measures (PROMs). Health Services Insights. 2013;6:61-68.
32. Elwyn G, Barr PJ, Grande SW, et al. Developing CollaboRATE: A fast and frugal patient-reported measure of shared decision making in clinical encounters. Patient Educ Couns. 2013;93:102-107.
33. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:1444-1452.
34. Rudick RA, Miller D, Clough JD, et al. Quality of life in multiple sclerosis. Comparison with inflammatory bowel disease and rheumatoid arthritis. Arch Neurol. 1992;49:1237-1242.
35. Benito-Leon J, Morales JM, Rivera-Navarro J, Mitchell A. A review about the impact of multiple sclerosis on health-related quality of life. Disabil Rehabil. 2003;25:1291-1303.
36. RAND Corporation. 36-Item Short Form Survey (SF-36). [https://www.rand.org/health-care/surveys_tools/mos/36-item-short-form.html. Accessed October 20, 2019.
37. Bergner M, Bobbitt RA, Carter WB, Gilson BS. The sickness impact profile: development and final revision of a health status measure. Medical Care. 1981;19:787-805.
38. Horsman J, Furlong W, Feeny D, Torrance G. The Health Utilities Index (HUI): concepts, measurement properties and applications. Health Qual Life Outcomes. 2003;1:54.
39. Kinkel RP, Laforet G, You X. Disease-related determinants of quality of life 10 years after clinically isolated syndrome. Int J MS Care. 2015;17:26-34.
40. Baumstarck-Barrau K, Simeoni MC, Reuter F, et al. Cognitive function and quality of life in multiple sclerosis patients: a cross-sectional study. BMC Neurology. 2011;11:17.
41. Samartzis L, Gavala E, Zoukos Y, et al. Perceived cognitive decline in multiple sclerosis impacts quality of life independently of depression. Rehabil Res Pract. 2014;2014:128751.
42. Vitkova M, Rosenberger J, Krokavcova M, et al. Health-related quality of life in multiple sclerosis patients with bladder, bowel and sexual dysfunction. Disabil Rehabil. 2014;36:987-992.
43. Khurana V, Sharma H, Afroz N, et al. Patient-reported outcomes in multiple sclerosis: a systematic comparison of available measures. Eur J Neurol. 2017;24:1099-1107.
44. Hobart J, Lamping D, Fitzpatrick R, et al. The Multiple Sclerosis Impact Scale (MSIS-29): a new patient-based outcome measure. Brain. 2001;124(Pt 5):962-973.
45. Lily O, McFadden E, Hensor E, et al. Disease-specific quality of life in multiple sclerosis: the effect of disease modifying treatment. Multiple Sclerosis. 2006;12:808-813.
46. Ford HL, Gerry E, Tennant A, et al. Developing a disease-specific quality of life measure for people with multiple sclerosis. Clin Rehabil. 2001;15:247-258.
47. Cella DF, Dineen K, Arnason B, et al. Validation of the functional assessment of multiple sclerosis quality of life instrument. Neurology. 1996;47:129-139.
48. Gold SM, Heesen C, Schulz H, et al. Disease specific quality of life instruments in multiple sclerosis: validation of the Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS). Multiple Sclerosis. 2001;7:119-130.
49. Vickrey BG, Hays RD, Harooni R, et al. A health-related quality of life measure for multiple sclerosis. Qual Life Res. 1995;4:187-206.
50. Simeoni M, Auquier P, Fernandez O, et al. Validation of the Multiple Sclerosis International Quality of Life questionnaire. Multiple Sclerosis. 2008;14:219-230.
51. Doward LC, McKenna SP, Meads DM, et al. The development of patient-reported outcome indices for multiple sclerosis (PRIMUS). Multiple Sclerosis. 2009;15:1092-1102.
52. Ozakbas S, Akdede BB, Kosehasanogullari G, et al. Difference between generic and multiple sclerosis-specific quality of life instruments regarding the assessment of treatment efficacy. J Neurol Sci. 2007;256:30-34.
53. Cella DF, Wiklund I, Shumaker SA, Aaronson NK. Integrating health-related quality of life into cross-national clinical trials. Qual Life Res. 1993;2:433-440.
54. Nowinski CJ, Miller DM, Cella D. Evolution of patient-reported outcomes and their role in multiple sclerosis clinical trials. Neurotherapeutics. 2017;14:934-944.
55. Cella D, Nowinski C, Peterman A, et al. The neurology quality-of-life measurement initiative. Arch Phys Med Rehabil. 2011;92(10 Suppl):S28-S36.
56. HealthMeasures: PROMIS. http://www.healthmeasures.net/explore-measurement-systems/promis. Accessed October 20, 2019.
57. Valderas JM, Ferrer M, Mendivil J, et al. Development of EMPRO: a tool for the standardized assessment of patient-reported outcome measures. Value Health. 2008;11:700-708.
58. Bach K, Martling C, Mork PJ, et al. Design of a clinician dashboard to facilitate co-decision making in the management of non-specific low back pain. J Intelligent Helath Syst. 2019;52:269-284.
59. Karami M, Safdari R, Rahimi A. Effective radiology dashboards: key research findings. Radiology Management. 2013;35:42-45.
60. Dowding D, Randell R, Gardner P, et al. Dashboards for improving patient care: review of the literature. Int J Med Informatic. 2015;84:87-100.
61. Mlaver E, Schnipper JL, Boxer RB, et al. User-centered collaborative design and development of an inpatient safety dashboard. Jt Comm J Qual Patient Saf. 2017;43:676-685.
62. Dowding D, Merrill J, Russell D. Using feedback intervention theory to guide clinical dashboard design. AMIA Annu Symp Proc. 2018;2018:395-403.
63. Hartzler AL, Izard JP, Dalkin BL, et al. Design and feasibility of integrating personalized PRO dashboards into prostate cancer care. J Am Med Inform Assoc. 2016;23:38-47.
64. Lavallee DC, Chenok KE, Love RM, et al. Incorporating patient-reported outcomes into health care to engage patients and enhance care. Health Affairs. 2016;35:575-582.
65. U.S. Centers for Medicare & Medicaid Services. Comprehensive Care for Joint Replacement Model. https://innovation.cms.gov/initiatives/CJR. Accessed August 3, 2019.
66. National Quality Forum. Patient-reported outcomes: Accessed August 3, 2019. http://www.qualityforum.org/Patient-Reported_Outcomes.aspx. Accessed October 20, 2019.
67. Institute of Medicine Roundtable on Evidence-Based Medicine. The National Academies Collection: Reports funded by National Institutes of Health. In: Olsen LA, Aisner D, McGinnis JM, eds. The Learning Healthcare System: Workshop Summary. Washington (DC): National Academies Press (US).National Academy of Sciences; 2007.
68. About Learning Health Systems: Agency for Healthcare Research and Quality. https://www.ahrq.gov/learning-health-systems/about.html. Accessed August 3, 2019.
69. Best Care at Lower Cost: The Path to Continuously Learning Health Care in America. Washington (DC): National Academies Press; 2013.
70. Committee on Quality of Health Care in America. Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, DC: National Academies Press; 2001.
71. Oliver BJ, for the MS-CQI Investigators. The Multiple Sclerosis Continuous improvement collaborative: the first coproduction learning health system improvement science research collaborative for multiple sclerosis. The International Society for Quality in Health Care (ISQua) Annual International Conference; October 2019; Cape Town, South Africa.
72. Britto MT, Fuller SC, Kaplan HC, et al. Using a network organisational architecture to support the development of Learning Healthcare Systems. BMJ Qual Saf. 2018;27:937-946.
73. Care Centers: Cystic Fibrosis Foundation. https://www.cff.org/Care/Care-Centers/. Accessed August 3, 2019.
74. Schechter MS, Fink AK, Homa K, Goss CH. The Cystic Fibrosis Foundation patient registry as a tool for use in quality improvement. BMJ Qual Saf. 2014;23(Suppl 1):i9-i14.
75. Mogayzel PJ, Dunitz J, Marrow LC, Hazle LA. Improving chronic care delivery and outcomes: the impact of the cystic fibrosis Care Center Network. BMJ Qual Saf. 2014;23(Suppl 1):i3-i8.
76. Godfrey MM, Oliver BJ. Accelerating the rate of improvement in cystic fibrosis care: contributions and insights of the learning and leadership collaborative. BMJ Qual Saf. 2014;23(Suppl 1):i23-i32.
77. Nelson EC, Godfrey MM. Quality by Design: A Clinical Microsystems Approach. San Francisco, California: Jossey-Bass; 2007.
78. Crohn’s & Colitis Foundation.Quality of Care: IBD Qorus: https://www.crohnscolitisfoundation.org/research/ibd-qorus. Accessed October 23, 2019.
79. Johnson LC, Melmed GY, Nelson EC, et al. Fostering collaboration through creation of an ibd learning health system. Am J Gastroenterol. 2017;112:406-468.
80. Fernandez-Munoz JJ, Moron-Verdasco A, Cigaran-Mendez M, et al. Disability, quality of life, personality, cognitive and psychological variables associated with fatigue in patients with multiple sclerosis. Acta Neurologica Scandinavica. 2015;132:118-124.
81. Flachenecker P, Kumpfel T, Kallmann B, et al. Fatigue in multiple sclerosis: a comparison of different rating scales and correlation to clinical parameters. Multiple Sclerosis. 2002;8:523-526.
82. Tellez N, Rio J, Tintore M, et al. Does the Modified Fatigue Impact Scale offer a more comprehensive assessment of fatigue in MS? Multiple Sclerosis. 2005;11:198-202.
83. Salter A, Fox RJ, Tyry T, et al. The association of fatigue and social participation in multiple sclerosis as assessed using two different instruments. Mult Scler Relat Disord. 2019;31:165-72.
84. Solaro C, Trabucco E, Messmer Uccelli M. Pain and multiple sclerosis: pathophysiology and treatment. Curr Neurol Neurosci Rep. 2013;13:320.
85. Jawahar R, Oh U, Yang S, Lapane KL. A systematic review of pharmacological pain management in multiple sclerosis. Drugs. 2013;73:1711-1722.
86. Rintala A, Hakkinen A, Paltamaa J. Ten-year follow-up of health-related quality of life among ambulatory persons with multiple sclerosis at baseline. Qual Life Res. 2016;25:3119-3127.
87. Tepavcevic DK, Pekmezovic T, Stojsavljevic N, et al. Change in quality of life and predictors of change among patients with multiple sclerosis: a prospective cohort study. Qual Life Res. 2014;23:1027-1037.
88. DasGupta R, Fowler CJ. Bladder, bowel and sexual dysfunction in multiple sclerosis: management strategies. Drugs. 2003;63:153-166.
89. Marck CH, Jelinek PL, Weiland TJ, et al. Sexual function in multiple sclerosis and associations with demographic, disease and lifestyle characteristics: an international cross-sectional study. BMC Neurology. 2016;16:210.
90. Gajofatto A, Benedetti MD. Treatment strategies for multiple sclerosis: When to start, when to change, when to stop? World J Clinical Cases. 2015;3:545-555.
91. National Multiple Sclerosis Society. Disease-modifying therapies for MS. 2018.
92. Rudick RA, Panzara MA. Natalizumab for the treatment of relapsing multiple sclerosis. Biologics. 2008;2:189-199.
93. Cohen JA, Cutter GR, Fischer JS, et al. Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology. 2002;59:679-687.
94. Patti F, Pappalardo A, Montanari E, et al. Interferon-beta-1a treatment has a positive effect on quality of life of relapsing-remitting multiple sclerosis: results from a longitudinal study. J Neurol Sci. 2014;337:180-185.
95. Novartis. Exploring the efficacy and safety of Siponimod in patients with secondary progressive multiple sclerosis (EXPAND). Available from clinicaltrials.gov/ct2/show/NCT01665144. NLM identifier: NCT01665144.
96. Singal AG, Higgins PD, Waljee AK. A primer on effectiveness and efficacy trials. Clin Transl Gastroenterol. 2014;5:e45.
97. Jongen PJ. Health-related quality of life in patients with multiple sclerosis: impact of disease-modifying drugs. CNS Drugs. 2017;31:585-602.
98. Coretti S, Ruggeri M, McNamee P. The minimum clinically important difference for EQ-5D index: a critical review. Expert Rev Pharmacoecon Outcomes Res. 2014;14:221-233.
99. Clinical Review Report: Ocrelizumab (Ocrevus). CADTH Common Drug Review. 2018:Appendix 4, Validity of Outcome Measures.
100. iCounquer MS; Empowering patients: how individuals with ms are contributing to the fight to find a cure: 2018. https://www.iconquerms.org/empowering-patients-how-individuals-ms-are-contributing-fight-find-cure. Accessed October 23, 2019.
101. K M. Accelerated Cure Project Announces Collaboration with EMD Serono to Advance Patient-Focused Drug Development in Multiple Sclerosis2018. https://www.iconquerms.org/accelerated-cure-project-announces-collaboration-emd-serono-advance-patient-focused-drug-development. Accessed October 24, 2019.
102. Bebo BF Jr, Fox RJ, Lee K, et al. Landscape of MS patient cohorts and registries: Recommendations for maximizing impact. Multiple Sclerosis. 2018;24:579-586.
103. Hedstrom AK, Hillert J, Olsson T, Alfredsson L. Alcohol as a modifiable lifestyle factor affecting multiple sclerosis risk. JAMA Neurology. 2014;71:300-305.
104. Hedstrom AK, Baarnhielm M, Olsson T, Alfredsson L. Tobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis. Neurology. 2009;73:696-701.
105. Hedstrom AK, Akerstedt T, Hillert J, et al. Shift work at young age is associated with increased risk for multiple sclerosis. Ann Neurol. 2011;70:733-741.
106. Hadjimichael O, Vollmer T, Oleen-Burkey M. Fatigue characteristics in multiple sclerosis: the North American Research Committee on Multiple Sclerosis (NARCOMS) survey. Health Qual Life Outcomes. 2008;6:100.
107. Fox RJ, Salter AR, Tyry T, et al. Treatment discontinuation and disease progression with injectable disease-modifying therapies: findings from the North American research committee on multiple sclerosis database. Int J MS Care. 2013;15:194-201.
108. Reeve BB, Wyrwich KW, Wu AW, et al. ISOQOL recommends minimum standards for patient-reported outcome measures used in patient-centered outcomes and comparative effectiveness research. Qual Life Res. 2013;22:1889-1905.
109. Jacobs LD, Wende KE, Brownscheidle CM, et al. A profile of multiple sclerosis: the New York State Multiple Sclerosis Consortium. Multiple Sclerosis. 1999;5:369-376.
110. Weinstock-Guttman B, Jacobs LD, Brownscheidle CM, et al. Multiple sclerosis characteristics in African American patients in the New York State Multiple Sclerosis Consortium. Multiple Sclerosis. 2003;9:293-298.
111. Raffel J, Wallace A, Gveric D, et al. Patient-reported outcomes and survival in multiple sclerosis: A 10-year retrospective cohort study using the Multiple Sclerosis Impact Scale-29. PLoS Med. 2017;14:e1002346.
112. Vaughn CB, Kavak KS, Dwyer MG, et al. Fatigue at enrollment predicts EDSS worsening in the New York State Multiple Sclerosis Consortium. Multiple Sclerosis. 2018:1352458518816619.
113. Alroughani RA, Akhtar S, Ahmed SF, Al-Hashel JY. Clinical predictors of disease progression in multiple sclerosis patients with relapsing onset in a nation-wide cohort. Int J Neuroscience. 2015;125:831-837.
114. Dolan JG, Veazie PJ, Russ AJ. Development and initial evaluation of a treatment decision dashboard. BMC Med Inform Decision Mak. 2013;13:51.
115. Stuifbergen AK, Becker H, Blozis S, et al. A randomized clinical trial of a wellness intervention for women with multiple sclerosis. Arch Phys Med Rehabil. 2003;84:467-476.
116. Finkelstein J, Martin C, Bhushan A, et al. Feasibility of computer-assisted education in patients with multiple sclerosis. In: Proceedings of the IEEE Symposium on Computer-Based Medical Systems. Bethesda, MD; 2004.
117. Batalden P. Getting more health from healthcare: quality improvement must acknowledge patient coproduction—an essay by Paul Batalden. BMJ. 2018;362:k3617.
118. Batalden PB, Davidoff F. What is “quality improvement” and how can it transform healthcare? Qual Saf Health Care. 2007;16:2-3.
119. Ovretveit J, Zubkoff L, Nelson EC, et al. Using patient-reported outcome measurement to improve patient care. Int J Qual Health Care. 2017;29:874-879.
120. Prodinger B, Taylor P. Improving quality of care through patient-reported outcome measures (PROMs): expert interviews using the NHS PROMs Programme and the Swedish quality registers for knee and hip arthroplasty as examples. BMC Health Services Res. 2018;18:87.
121. Prinsen CA, Vohra S, Rose MR, et al. How to select outcome measurement instruments for outcomes included in a “Core Outcome Set” – a practical guideline. Trials. 2016;17:449.
122. NINDS. NINDS Common Data Elements: Streamline Your Neuroscience Clinical Research National Institute of Health. https://www.commondataelements.ninds.nih.gov/#page=Default. Accessed October 23, 2019.
123. Francis DO, McPheeters ML, Noud M, et al. Checklist to operationalize measurement characteristics of patient-reported outcome measures. Systematic Rev. 2016;5:129.
124. National Quality Forum. Patient-reported outcomes (PROs) in performance measurement. 2013. https://www.qualityforum.org/Publications/2012/12/Patient-Reported_Outcomes_in_Performance_Measurement.aspx. Accessed October 15, 2019.
125. Dawson J, Doll H, Fitzpatrick R, et al. The routine use of patient reported outcome measures in healthcare settings. BMJ. 2010;340:c186.
126. Aaronson N ET, Greenlhalgh J, Halyard M, et al. User’s guide to implementation of patient reported outcomes assessment in clinical practice. International Society for Quality of Life. 2015.
127. Chan EKH, Edwards TC, Haywood K, et al. Implementing patient-reported outcomes mesaures in clinical practice: a companion guide to the ISOQOL user’s guide. Qual Life Res. 2018;28:621-627.
128. Snyder CF, Wu AW, Miller RS, et al. The role of informatics in promoting patient-centered care. Cancer J. 2011;17:211-218
129. Osborn R, Moulds D, Schneider EC, et al. Primary care physicians in ten countries report challenges caring for patients with complex health needs. Health Affairs. 2015;34:2104-2112.
130. Wu AW, Kharrazi H, Boulware LE, Snyder CF. Measure once, cut 0wice--adding patient-reported outcome measures to the electronic health record for comparative effectiveness research. J Clin Epidemiol. 2013;66(8 Suppl):S12-S20.
131. Trojano M, Bergamaschi R, Amato MP, et al. The Italian multiple sclerosis register. Neurol Sci. 2019;40:155-165.
132. Moorhead SA, Hazlett DE, Harrison L, et al. A new dimension of health care: systematic review of the uses, benefits, and limitations of social media for health communication. J Med Internet Res. 2013;15:e85.
133. Luigi L, Francesco B, Marcello M, et al. e-Health and multiple sclerosis: An update. Multiple Sclerosis J. 2018;24:1657-1664.
134. Marrie RA, Leung S, Tyry T, et al. Use of eHealth and mHealth technology by persons with multiple sclerosis. Mult Scler Relat Dis. 2019;27:13-19.
135. Giunti G, Kool J, Rivera Romero O, Dorronzoro Zubiete E. Exploring the specific needs of persons with multiple sclerosis for mhealth solutions for physical activity: mixed-methods study. JMIR Mhealth Uhealth. 2018;6:e37.
136. Spooner KK, Salemi JL, Salihu HM, Zoorob RJ. eHealth patient-provider communication in the United States: interest, inequalities, and predictors. J Am Med Inform Assoc. 2017;24(e1):e18-e27.
137. Safdar N, Abbo LM, Knobloch MJ, Seo SK. Research methods in healthcare epidemiology: survey and qualitative research. Infect Control Hosp Epidemiol. 2016;37:1272-1277.
138. Rolstad S, Adler J, Rydén A. Response burden and questionnaire length: is shorter better? A review and meta-analysis. Value Health. 2011;14:1101-1108.
139. Chiu C, Bishop M, Pionke JJ, et al. Barriers to the accessibility and continuity of health-care services in people with multiple sclerosis: a literature review. Int J MS Care. 2017;19:313-321.
140. Atreja A, Mehta N, Miller D, et al. One size does not fit all: using qualitative methods to inform the development of an Internet portal for multiple sclerosis patients. AMIA Annu Symp Proc Symp. 2005:16-20.
141. Snyder CF, Blackford AL, Brahmer JR, et al. Needs assessments can identify scores on HRQOL questionnaires that represent problems for patients: an illustration with the Supportive Care Needs Survey and the QLQ-C30. Qual Life Res. 2010;19:837-845.
142. de Vet HC, Terwee CB. The minimal detectable change should not replace the minimal important difference. J Clin Epidemiol. 2010;63:804-805.
143. Snyder CF, Aaronson NK, Choucair AK, et al. Implementing patient-reported outcomes assessment in clinical practice: a review of the options and considerations. Qual Life. 2012;21:1305-1314.
144. Myla DG, Melanie DW, Robert WM, et al. Identification and validation of clinically meaningful benchmarks in the 12-item Multiple Sclerosis Walking Scale. Multiple Sclerosis J. 2017;23:1405-1414.
145. van Munster CEP, Uitdehaag BMJ. Outcome measures in clinical trials for multiple sclerosis. CNS Drugs. 2017;31:217-236.
146. Snyder CF, Jensen R, Courtin SO, Wu AW. PatientViewpoint: a website for patient-reported outcomes assessment. Quality Life Res. 2009;18:793-800.
147. Snyder CF, Smith KC, Bantug ET, et al. What do these scores mean? Presenting patient-reported outcomes data to patients and clinicians to improve interpretability. Cancer. 2017;123:1848-1859.
148. Squitieri L, Bozic KJ, Pusic AL. The role of patient-reported outcome measures in value-based payment reform. Value Health. 2017;20:834-836.
149. Boyce MB, Browne JP. The effectiveness of providing peer benchmarked feedback to hip replacement surgeons based on patient-reported outcome measures—results from the PROFILE trial: a cluster randomised controlled study. BMJ Open. 2015;5:e008325.
1. Goldenberg MM. Multiple sclerosis review. PT. 2012;37:175-184.
2. Doshi A, Chataway J. Multiple sclerosis, a treatable disease. Clin Med. 2016;16(Suppl 6):s53-s9.
3. Perrin Ross A. Management of multiple sclerosis. Am J Managed Care. 2013;19(16 Suppl):s301-s306.
4. Batalden M, Batalden P, Margolis P, et al. Coproduction of healthcare service. BMJ Qual Saf. 2016;25:509-517.
5. Chen J, Ou L, Hollis SJ. A systematic review of the impact of routine collection of patient reported outcome measures on patients, providers and health organisations in an oncologic setting. BMC Health Serv Res. 2013;13:211.
6. Knaup C, Koesters M, Schoefer D, et al. Effect of feedback of treatment outcome in specialist mental healthcare: meta-analysis. Br J Psychiatr. 2009;195:15-22.
7. Dudgeon D. The impact of measuring patient-reported outcome measures on quality of and access to palliative care. J Palliat Med. 2018;21(S1):S76-s80.
8. Snyder CF, Herman JM, White SM, et al. When using patient-reported outcomes in clinical practice, the measure matters: a randomized controlled trial. J Oncol Pract. 2014;10:e299-e306.
9. Guidance for industry: patient-reported outcome measures: use in medical product development to support labeling claims: draft guidance. Health Qual Life Outcomes. 2006;4:79.
10. de Jong MJ, Huibregtse R, Masclee AAM, et al. Patient-reported outcome measures for use in clinical trials and clinical practice in inflammatory bowel diseases: a systematic review. Clin Gastroenterol Hepatol. 2018;16:648-663.
11. Roman D, Osborne-Stafsnes J, Amy CH, et al. Early lessons from four ‘aligning forces for quality’ communities bolster the case for patient-centered care. Health Affairs. 2013;32:232-241.
12. Ehde DM, Alschuler KN, Sullivan MD, et al. Improving the quality of depression and pain care in multiple sclerosis using collaborative care: The MS-care trial protocol. Contemporary Clinical Trials. 2018;64:219-229.
13. Lavallee DC, Chenok KE, Love RM, et al. Incorporating patient-reported outcomes into health care to engage patients and enhance care. Health Affairs. 2016;35:575-582.
14. Schick-Makaroff K, Thummapol O, Thompson S, et al. Strategies for incorporating patient-reported outcomes in the care of people with chronic kidney disease (PRO kidney): a protocol for a realist synthesis. Clin Gastroenterol Hepatol. 2018;16:648-663.
15. Nelson EC, Dixon-Woods M, Batalden PB, et al. Patient focused registries can improve health, care, and science. BMJ. 2016;354:i3319.
16. Oliver BJ, Nelson EC, Kerrigan CL. Turning feed-forward and feedback processes on patient-reported data into intelligent action and informed decision-making: case studies and principles. Med Care. 2019;57 Suppl 1:S31-s37.
17. Deshpande PR, Rajan S, Sudeepthi BL, Abdul Nazir CP. Patient-reported outcomes: A new era in clinical research. Perspect Clin Res. 2011;2:137-144.
18. Epstein RM, Street RL, Jr. The values and value of patient-centered care. Ann Fam Med. 2011;9:100-103.
19. Payne SA. A study of quality of life in cancer patients receiving palliative chemotherapy. Soc Sci Med. 1992;35:1505-1509.
20. Borgaonkar MR, Irvine EJ. Quality of life measurement in gastrointestinal and liver disorders. Gut. 2000;47:444-454.
21. Macdonell R, Nagels G, Laplaud DA, et al. Improved patient-reported health impact of multiple sclerosis: The ENABLE study of PR-fampridine. Multiple Sclerosis. 2016;22:944-954.
22. Hobart J, Freeman J, Lamping D, et al. The SF-36 in multiple sclerosis: why basic assumptions must be tested. J Neurol Neurosurg Psychiatry. 2001;71:363-370.
23. Lins L, Carvalho FM. SF-36 total score as a single measure of health-related quality of life: Scoping review. SAGE Open Med. 2016;4:2050312116671725.
24. Parkinson’s Disease Society of the United Kingdom. The Parkinson’s Disease Questionnaire (PDQ-39). https://www.parkinsons.org.uk/professionals/resources/parkinsons-disease-questionnaire-pdq-39. Accessed October 20, 2019.
25. Basch E. The missing voice of patients in drug-safety reporting. N Engl J Med. 2010;362:865-869.
26. Calvert M, Brundage M, Jacobsen PB, et al. The CONSORT Patient-Reported Outcome (PRO) extension: implications for clinical trials and practice. Health Qual Life Outcomes. 2013;11:184.
27. Black N. Patient reported outcome measures could help transform healthcare. BMJ. 2013;346:f167.
28. Franks P, Fiscella K, Shields CG, et al. Are patients’ ratings of their physicians related to health outcomes? Ann Fam Med. 2005;3:229-234.
29. Hostetter M, Klein S. Using patient-reported outcomes to improve health care quality. The Commonwealth Fund 2019. www.commonwealthfund.org/publications/newsletter-article/using-patient-reported-outcomes-improve-health-care-quality. Accessed October 24, 2019.
30. Charlotte Kingsley SP. Patient-reported outcome measures and patient-reported experience measures. BJA Education. 2017;17:137-144.
31. Weldring T, Smith SM. Patient-Reported outcomes (PROs) and patient-reported outcome measures (PROMs). Health Services Insights. 2013;6:61-68.
32. Elwyn G, Barr PJ, Grande SW, et al. Developing CollaboRATE: A fast and frugal patient-reported measure of shared decision making in clinical encounters. Patient Educ Couns. 2013;93:102-107.
33. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:1444-1452.
34. Rudick RA, Miller D, Clough JD, et al. Quality of life in multiple sclerosis. Comparison with inflammatory bowel disease and rheumatoid arthritis. Arch Neurol. 1992;49:1237-1242.
35. Benito-Leon J, Morales JM, Rivera-Navarro J, Mitchell A. A review about the impact of multiple sclerosis on health-related quality of life. Disabil Rehabil. 2003;25:1291-1303.
36. RAND Corporation. 36-Item Short Form Survey (SF-36). [https://www.rand.org/health-care/surveys_tools/mos/36-item-short-form.html. Accessed October 20, 2019.
37. Bergner M, Bobbitt RA, Carter WB, Gilson BS. The sickness impact profile: development and final revision of a health status measure. Medical Care. 1981;19:787-805.
38. Horsman J, Furlong W, Feeny D, Torrance G. The Health Utilities Index (HUI): concepts, measurement properties and applications. Health Qual Life Outcomes. 2003;1:54.
39. Kinkel RP, Laforet G, You X. Disease-related determinants of quality of life 10 years after clinically isolated syndrome. Int J MS Care. 2015;17:26-34.
40. Baumstarck-Barrau K, Simeoni MC, Reuter F, et al. Cognitive function and quality of life in multiple sclerosis patients: a cross-sectional study. BMC Neurology. 2011;11:17.
41. Samartzis L, Gavala E, Zoukos Y, et al. Perceived cognitive decline in multiple sclerosis impacts quality of life independently of depression. Rehabil Res Pract. 2014;2014:128751.
42. Vitkova M, Rosenberger J, Krokavcova M, et al. Health-related quality of life in multiple sclerosis patients with bladder, bowel and sexual dysfunction. Disabil Rehabil. 2014;36:987-992.
43. Khurana V, Sharma H, Afroz N, et al. Patient-reported outcomes in multiple sclerosis: a systematic comparison of available measures. Eur J Neurol. 2017;24:1099-1107.
44. Hobart J, Lamping D, Fitzpatrick R, et al. The Multiple Sclerosis Impact Scale (MSIS-29): a new patient-based outcome measure. Brain. 2001;124(Pt 5):962-973.
45. Lily O, McFadden E, Hensor E, et al. Disease-specific quality of life in multiple sclerosis: the effect of disease modifying treatment. Multiple Sclerosis. 2006;12:808-813.
46. Ford HL, Gerry E, Tennant A, et al. Developing a disease-specific quality of life measure for people with multiple sclerosis. Clin Rehabil. 2001;15:247-258.
47. Cella DF, Dineen K, Arnason B, et al. Validation of the functional assessment of multiple sclerosis quality of life instrument. Neurology. 1996;47:129-139.
48. Gold SM, Heesen C, Schulz H, et al. Disease specific quality of life instruments in multiple sclerosis: validation of the Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS). Multiple Sclerosis. 2001;7:119-130.
49. Vickrey BG, Hays RD, Harooni R, et al. A health-related quality of life measure for multiple sclerosis. Qual Life Res. 1995;4:187-206.
50. Simeoni M, Auquier P, Fernandez O, et al. Validation of the Multiple Sclerosis International Quality of Life questionnaire. Multiple Sclerosis. 2008;14:219-230.
51. Doward LC, McKenna SP, Meads DM, et al. The development of patient-reported outcome indices for multiple sclerosis (PRIMUS). Multiple Sclerosis. 2009;15:1092-1102.
52. Ozakbas S, Akdede BB, Kosehasanogullari G, et al. Difference between generic and multiple sclerosis-specific quality of life instruments regarding the assessment of treatment efficacy. J Neurol Sci. 2007;256:30-34.
53. Cella DF, Wiklund I, Shumaker SA, Aaronson NK. Integrating health-related quality of life into cross-national clinical trials. Qual Life Res. 1993;2:433-440.
54. Nowinski CJ, Miller DM, Cella D. Evolution of patient-reported outcomes and their role in multiple sclerosis clinical trials. Neurotherapeutics. 2017;14:934-944.
55. Cella D, Nowinski C, Peterman A, et al. The neurology quality-of-life measurement initiative. Arch Phys Med Rehabil. 2011;92(10 Suppl):S28-S36.
56. HealthMeasures: PROMIS. http://www.healthmeasures.net/explore-measurement-systems/promis. Accessed October 20, 2019.
57. Valderas JM, Ferrer M, Mendivil J, et al. Development of EMPRO: a tool for the standardized assessment of patient-reported outcome measures. Value Health. 2008;11:700-708.
58. Bach K, Martling C, Mork PJ, et al. Design of a clinician dashboard to facilitate co-decision making in the management of non-specific low back pain. J Intelligent Helath Syst. 2019;52:269-284.
59. Karami M, Safdari R, Rahimi A. Effective radiology dashboards: key research findings. Radiology Management. 2013;35:42-45.
60. Dowding D, Randell R, Gardner P, et al. Dashboards for improving patient care: review of the literature. Int J Med Informatic. 2015;84:87-100.
61. Mlaver E, Schnipper JL, Boxer RB, et al. User-centered collaborative design and development of an inpatient safety dashboard. Jt Comm J Qual Patient Saf. 2017;43:676-685.
62. Dowding D, Merrill J, Russell D. Using feedback intervention theory to guide clinical dashboard design. AMIA Annu Symp Proc. 2018;2018:395-403.
63. Hartzler AL, Izard JP, Dalkin BL, et al. Design and feasibility of integrating personalized PRO dashboards into prostate cancer care. J Am Med Inform Assoc. 2016;23:38-47.
64. Lavallee DC, Chenok KE, Love RM, et al. Incorporating patient-reported outcomes into health care to engage patients and enhance care. Health Affairs. 2016;35:575-582.
65. U.S. Centers for Medicare & Medicaid Services. Comprehensive Care for Joint Replacement Model. https://innovation.cms.gov/initiatives/CJR. Accessed August 3, 2019.
66. National Quality Forum. Patient-reported outcomes: Accessed August 3, 2019. http://www.qualityforum.org/Patient-Reported_Outcomes.aspx. Accessed October 20, 2019.
67. Institute of Medicine Roundtable on Evidence-Based Medicine. The National Academies Collection: Reports funded by National Institutes of Health. In: Olsen LA, Aisner D, McGinnis JM, eds. The Learning Healthcare System: Workshop Summary. Washington (DC): National Academies Press (US).National Academy of Sciences; 2007.
68. About Learning Health Systems: Agency for Healthcare Research and Quality. https://www.ahrq.gov/learning-health-systems/about.html. Accessed August 3, 2019.
69. Best Care at Lower Cost: The Path to Continuously Learning Health Care in America. Washington (DC): National Academies Press; 2013.
70. Committee on Quality of Health Care in America. Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, DC: National Academies Press; 2001.
71. Oliver BJ, for the MS-CQI Investigators. The Multiple Sclerosis Continuous improvement collaborative: the first coproduction learning health system improvement science research collaborative for multiple sclerosis. The International Society for Quality in Health Care (ISQua) Annual International Conference; October 2019; Cape Town, South Africa.
72. Britto MT, Fuller SC, Kaplan HC, et al. Using a network organisational architecture to support the development of Learning Healthcare Systems. BMJ Qual Saf. 2018;27:937-946.
73. Care Centers: Cystic Fibrosis Foundation. https://www.cff.org/Care/Care-Centers/. Accessed August 3, 2019.
74. Schechter MS, Fink AK, Homa K, Goss CH. The Cystic Fibrosis Foundation patient registry as a tool for use in quality improvement. BMJ Qual Saf. 2014;23(Suppl 1):i9-i14.
75. Mogayzel PJ, Dunitz J, Marrow LC, Hazle LA. Improving chronic care delivery and outcomes: the impact of the cystic fibrosis Care Center Network. BMJ Qual Saf. 2014;23(Suppl 1):i3-i8.
76. Godfrey MM, Oliver BJ. Accelerating the rate of improvement in cystic fibrosis care: contributions and insights of the learning and leadership collaborative. BMJ Qual Saf. 2014;23(Suppl 1):i23-i32.
77. Nelson EC, Godfrey MM. Quality by Design: A Clinical Microsystems Approach. San Francisco, California: Jossey-Bass; 2007.
78. Crohn’s & Colitis Foundation.Quality of Care: IBD Qorus: https://www.crohnscolitisfoundation.org/research/ibd-qorus. Accessed October 23, 2019.
79. Johnson LC, Melmed GY, Nelson EC, et al. Fostering collaboration through creation of an ibd learning health system. Am J Gastroenterol. 2017;112:406-468.
80. Fernandez-Munoz JJ, Moron-Verdasco A, Cigaran-Mendez M, et al. Disability, quality of life, personality, cognitive and psychological variables associated with fatigue in patients with multiple sclerosis. Acta Neurologica Scandinavica. 2015;132:118-124.
81. Flachenecker P, Kumpfel T, Kallmann B, et al. Fatigue in multiple sclerosis: a comparison of different rating scales and correlation to clinical parameters. Multiple Sclerosis. 2002;8:523-526.
82. Tellez N, Rio J, Tintore M, et al. Does the Modified Fatigue Impact Scale offer a more comprehensive assessment of fatigue in MS? Multiple Sclerosis. 2005;11:198-202.
83. Salter A, Fox RJ, Tyry T, et al. The association of fatigue and social participation in multiple sclerosis as assessed using two different instruments. Mult Scler Relat Disord. 2019;31:165-72.
84. Solaro C, Trabucco E, Messmer Uccelli M. Pain and multiple sclerosis: pathophysiology and treatment. Curr Neurol Neurosci Rep. 2013;13:320.
85. Jawahar R, Oh U, Yang S, Lapane KL. A systematic review of pharmacological pain management in multiple sclerosis. Drugs. 2013;73:1711-1722.
86. Rintala A, Hakkinen A, Paltamaa J. Ten-year follow-up of health-related quality of life among ambulatory persons with multiple sclerosis at baseline. Qual Life Res. 2016;25:3119-3127.
87. Tepavcevic DK, Pekmezovic T, Stojsavljevic N, et al. Change in quality of life and predictors of change among patients with multiple sclerosis: a prospective cohort study. Qual Life Res. 2014;23:1027-1037.
88. DasGupta R, Fowler CJ. Bladder, bowel and sexual dysfunction in multiple sclerosis: management strategies. Drugs. 2003;63:153-166.
89. Marck CH, Jelinek PL, Weiland TJ, et al. Sexual function in multiple sclerosis and associations with demographic, disease and lifestyle characteristics: an international cross-sectional study. BMC Neurology. 2016;16:210.
90. Gajofatto A, Benedetti MD. Treatment strategies for multiple sclerosis: When to start, when to change, when to stop? World J Clinical Cases. 2015;3:545-555.
91. National Multiple Sclerosis Society. Disease-modifying therapies for MS. 2018.
92. Rudick RA, Panzara MA. Natalizumab for the treatment of relapsing multiple sclerosis. Biologics. 2008;2:189-199.
93. Cohen JA, Cutter GR, Fischer JS, et al. Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology. 2002;59:679-687.
94. Patti F, Pappalardo A, Montanari E, et al. Interferon-beta-1a treatment has a positive effect on quality of life of relapsing-remitting multiple sclerosis: results from a longitudinal study. J Neurol Sci. 2014;337:180-185.
95. Novartis. Exploring the efficacy and safety of Siponimod in patients with secondary progressive multiple sclerosis (EXPAND). Available from clinicaltrials.gov/ct2/show/NCT01665144. NLM identifier: NCT01665144.
96. Singal AG, Higgins PD, Waljee AK. A primer on effectiveness and efficacy trials. Clin Transl Gastroenterol. 2014;5:e45.
97. Jongen PJ. Health-related quality of life in patients with multiple sclerosis: impact of disease-modifying drugs. CNS Drugs. 2017;31:585-602.
98. Coretti S, Ruggeri M, McNamee P. The minimum clinically important difference for EQ-5D index: a critical review. Expert Rev Pharmacoecon Outcomes Res. 2014;14:221-233.
99. Clinical Review Report: Ocrelizumab (Ocrevus). CADTH Common Drug Review. 2018:Appendix 4, Validity of Outcome Measures.
100. iCounquer MS; Empowering patients: how individuals with ms are contributing to the fight to find a cure: 2018. https://www.iconquerms.org/empowering-patients-how-individuals-ms-are-contributing-fight-find-cure. Accessed October 23, 2019.
101. K M. Accelerated Cure Project Announces Collaboration with EMD Serono to Advance Patient-Focused Drug Development in Multiple Sclerosis2018. https://www.iconquerms.org/accelerated-cure-project-announces-collaboration-emd-serono-advance-patient-focused-drug-development. Accessed October 24, 2019.
102. Bebo BF Jr, Fox RJ, Lee K, et al. Landscape of MS patient cohorts and registries: Recommendations for maximizing impact. Multiple Sclerosis. 2018;24:579-586.
103. Hedstrom AK, Hillert J, Olsson T, Alfredsson L. Alcohol as a modifiable lifestyle factor affecting multiple sclerosis risk. JAMA Neurology. 2014;71:300-305.
104. Hedstrom AK, Baarnhielm M, Olsson T, Alfredsson L. Tobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis. Neurology. 2009;73:696-701.
105. Hedstrom AK, Akerstedt T, Hillert J, et al. Shift work at young age is associated with increased risk for multiple sclerosis. Ann Neurol. 2011;70:733-741.
106. Hadjimichael O, Vollmer T, Oleen-Burkey M. Fatigue characteristics in multiple sclerosis: the North American Research Committee on Multiple Sclerosis (NARCOMS) survey. Health Qual Life Outcomes. 2008;6:100.
107. Fox RJ, Salter AR, Tyry T, et al. Treatment discontinuation and disease progression with injectable disease-modifying therapies: findings from the North American research committee on multiple sclerosis database. Int J MS Care. 2013;15:194-201.
108. Reeve BB, Wyrwich KW, Wu AW, et al. ISOQOL recommends minimum standards for patient-reported outcome measures used in patient-centered outcomes and comparative effectiveness research. Qual Life Res. 2013;22:1889-1905.
109. Jacobs LD, Wende KE, Brownscheidle CM, et al. A profile of multiple sclerosis: the New York State Multiple Sclerosis Consortium. Multiple Sclerosis. 1999;5:369-376.
110. Weinstock-Guttman B, Jacobs LD, Brownscheidle CM, et al. Multiple sclerosis characteristics in African American patients in the New York State Multiple Sclerosis Consortium. Multiple Sclerosis. 2003;9:293-298.
111. Raffel J, Wallace A, Gveric D, et al. Patient-reported outcomes and survival in multiple sclerosis: A 10-year retrospective cohort study using the Multiple Sclerosis Impact Scale-29. PLoS Med. 2017;14:e1002346.
112. Vaughn CB, Kavak KS, Dwyer MG, et al. Fatigue at enrollment predicts EDSS worsening in the New York State Multiple Sclerosis Consortium. Multiple Sclerosis. 2018:1352458518816619.
113. Alroughani RA, Akhtar S, Ahmed SF, Al-Hashel JY. Clinical predictors of disease progression in multiple sclerosis patients with relapsing onset in a nation-wide cohort. Int J Neuroscience. 2015;125:831-837.
114. Dolan JG, Veazie PJ, Russ AJ. Development and initial evaluation of a treatment decision dashboard. BMC Med Inform Decision Mak. 2013;13:51.
115. Stuifbergen AK, Becker H, Blozis S, et al. A randomized clinical trial of a wellness intervention for women with multiple sclerosis. Arch Phys Med Rehabil. 2003;84:467-476.
116. Finkelstein J, Martin C, Bhushan A, et al. Feasibility of computer-assisted education in patients with multiple sclerosis. In: Proceedings of the IEEE Symposium on Computer-Based Medical Systems. Bethesda, MD; 2004.
117. Batalden P. Getting more health from healthcare: quality improvement must acknowledge patient coproduction—an essay by Paul Batalden. BMJ. 2018;362:k3617.
118. Batalden PB, Davidoff F. What is “quality improvement” and how can it transform healthcare? Qual Saf Health Care. 2007;16:2-3.
119. Ovretveit J, Zubkoff L, Nelson EC, et al. Using patient-reported outcome measurement to improve patient care. Int J Qual Health Care. 2017;29:874-879.
120. Prodinger B, Taylor P. Improving quality of care through patient-reported outcome measures (PROMs): expert interviews using the NHS PROMs Programme and the Swedish quality registers for knee and hip arthroplasty as examples. BMC Health Services Res. 2018;18:87.
121. Prinsen CA, Vohra S, Rose MR, et al. How to select outcome measurement instruments for outcomes included in a “Core Outcome Set” – a practical guideline. Trials. 2016;17:449.
122. NINDS. NINDS Common Data Elements: Streamline Your Neuroscience Clinical Research National Institute of Health. https://www.commondataelements.ninds.nih.gov/#page=Default. Accessed October 23, 2019.
123. Francis DO, McPheeters ML, Noud M, et al. Checklist to operationalize measurement characteristics of patient-reported outcome measures. Systematic Rev. 2016;5:129.
124. National Quality Forum. Patient-reported outcomes (PROs) in performance measurement. 2013. https://www.qualityforum.org/Publications/2012/12/Patient-Reported_Outcomes_in_Performance_Measurement.aspx. Accessed October 15, 2019.
125. Dawson J, Doll H, Fitzpatrick R, et al. The routine use of patient reported outcome measures in healthcare settings. BMJ. 2010;340:c186.
126. Aaronson N ET, Greenlhalgh J, Halyard M, et al. User’s guide to implementation of patient reported outcomes assessment in clinical practice. International Society for Quality of Life. 2015.
127. Chan EKH, Edwards TC, Haywood K, et al. Implementing patient-reported outcomes mesaures in clinical practice: a companion guide to the ISOQOL user’s guide. Qual Life Res. 2018;28:621-627.
128. Snyder CF, Wu AW, Miller RS, et al. The role of informatics in promoting patient-centered care. Cancer J. 2011;17:211-218
129. Osborn R, Moulds D, Schneider EC, et al. Primary care physicians in ten countries report challenges caring for patients with complex health needs. Health Affairs. 2015;34:2104-2112.
130. Wu AW, Kharrazi H, Boulware LE, Snyder CF. Measure once, cut 0wice--adding patient-reported outcome measures to the electronic health record for comparative effectiveness research. J Clin Epidemiol. 2013;66(8 Suppl):S12-S20.
131. Trojano M, Bergamaschi R, Amato MP, et al. The Italian multiple sclerosis register. Neurol Sci. 2019;40:155-165.
132. Moorhead SA, Hazlett DE, Harrison L, et al. A new dimension of health care: systematic review of the uses, benefits, and limitations of social media for health communication. J Med Internet Res. 2013;15:e85.
133. Luigi L, Francesco B, Marcello M, et al. e-Health and multiple sclerosis: An update. Multiple Sclerosis J. 2018;24:1657-1664.
134. Marrie RA, Leung S, Tyry T, et al. Use of eHealth and mHealth technology by persons with multiple sclerosis. Mult Scler Relat Dis. 2019;27:13-19.
135. Giunti G, Kool J, Rivera Romero O, Dorronzoro Zubiete E. Exploring the specific needs of persons with multiple sclerosis for mhealth solutions for physical activity: mixed-methods study. JMIR Mhealth Uhealth. 2018;6:e37.
136. Spooner KK, Salemi JL, Salihu HM, Zoorob RJ. eHealth patient-provider communication in the United States: interest, inequalities, and predictors. J Am Med Inform Assoc. 2017;24(e1):e18-e27.
137. Safdar N, Abbo LM, Knobloch MJ, Seo SK. Research methods in healthcare epidemiology: survey and qualitative research. Infect Control Hosp Epidemiol. 2016;37:1272-1277.
138. Rolstad S, Adler J, Rydén A. Response burden and questionnaire length: is shorter better? A review and meta-analysis. Value Health. 2011;14:1101-1108.
139. Chiu C, Bishop M, Pionke JJ, et al. Barriers to the accessibility and continuity of health-care services in people with multiple sclerosis: a literature review. Int J MS Care. 2017;19:313-321.
140. Atreja A, Mehta N, Miller D, et al. One size does not fit all: using qualitative methods to inform the development of an Internet portal for multiple sclerosis patients. AMIA Annu Symp Proc Symp. 2005:16-20.
141. Snyder CF, Blackford AL, Brahmer JR, et al. Needs assessments can identify scores on HRQOL questionnaires that represent problems for patients: an illustration with the Supportive Care Needs Survey and the QLQ-C30. Qual Life Res. 2010;19:837-845.
142. de Vet HC, Terwee CB. The minimal detectable change should not replace the minimal important difference. J Clin Epidemiol. 2010;63:804-805.
143. Snyder CF, Aaronson NK, Choucair AK, et al. Implementing patient-reported outcomes assessment in clinical practice: a review of the options and considerations. Qual Life. 2012;21:1305-1314.
144. Myla DG, Melanie DW, Robert WM, et al. Identification and validation of clinically meaningful benchmarks in the 12-item Multiple Sclerosis Walking Scale. Multiple Sclerosis J. 2017;23:1405-1414.
145. van Munster CEP, Uitdehaag BMJ. Outcome measures in clinical trials for multiple sclerosis. CNS Drugs. 2017;31:217-236.
146. Snyder CF, Jensen R, Courtin SO, Wu AW. PatientViewpoint: a website for patient-reported outcomes assessment. Quality Life Res. 2009;18:793-800.
147. Snyder CF, Smith KC, Bantug ET, et al. What do these scores mean? Presenting patient-reported outcomes data to patients and clinicians to improve interpretability. Cancer. 2017;123:1848-1859.
148. Squitieri L, Bozic KJ, Pusic AL. The role of patient-reported outcome measures in value-based payment reform. Value Health. 2017;20:834-836.
149. Boyce MB, Browne JP. The effectiveness of providing peer benchmarked feedback to hip replacement surgeons based on patient-reported outcome measures—results from the PROFILE trial: a cluster randomised controlled study. BMJ Open. 2015;5:e008325.
AVXS-101 may result in long-term motor improvements in SMA
CHARLOTTE, N.C. – AVXS-101, the Food and Drug Administration–approved therapy for spinal muscular atrophy (SMA), yields rapid, sustained improvements in CHOP INTEND scores, better survival, and motor function improvements at long-term follow-up, according to an analysis presented at the annual meeting of the Child Neurology Society. The results provide a clinical demonstration of continuous expression of the SMN protein, according to the investigators. In addition, AVXS-101 is associated with reduced health care utilization in treated infants, which could decrease costs, lessen the burden on patients and caregivers, and improve quality of life.
SMA1 is a progressive neurologic disease that causes loss of the lower motor neurons in the spinal cord and brainstem. Patients have increasing muscle weakness that leads to death or the need for permanent ventilation by age 2 years. The disease results from mutations in the SMN1 gene. AVXS-101 replaces the missing or nonfunctional SMN1 with a healthy copy of a human SMN gene.
AveXis, the company that developed the therapy, enrolled 12 patients with SMA1 in a phase 1/2a study between December 2014 and December 2015. All participants received one intravenous infusion of AVXS-101. Omar Dabbous, MD, vice president of global health economics, outcomes research, and real world evidence at AveXis in Bannockburn, Ill., and colleagues evaluated participants’ rates of event-free survival (i.e., absence of death or need for permanent ventilation), pulmonary or nutritional interventions, swallowing, hospitalization, and CHOP INTEND scores, as well as therapeutic safety at 2 years.
At study completion, all patients who had received a therapeutic dose had event-free survival. Seven participants did not need daily noninvasive ventilation. Eleven participants had stable or improved swallowing. All of the latter patients fed orally, and six fed exclusively by mouth. Eleven patients spoke.
Participants had a mean of 1.4 respiratory hospitalizations per year. Mean proportion of time participants spent hospitalized was 4.4%. Mean hospitalization rate per year was 2.1, and mean length of hospital stay was 6.7 days. In addition, participants’ CHOP INTEND scores increased from baseline by 9.8 points at 1 month and by 15.4 points at 3 months. Patients who received a therapeutic dose of AVXS-101 have maintained their motor milestones at long-term follow-up, which suggests that treatment effects persist over the long term. Adverse events included elevated serum aminotransferase levels, which were reduced by prednisolone.
Dr. Dabbous is an employee of AveXis, which developed AVXS-101.
SOURCE: Dabbous O et al. CNS 2019. Abstract 199.
CHARLOTTE, N.C. – AVXS-101, the Food and Drug Administration–approved therapy for spinal muscular atrophy (SMA), yields rapid, sustained improvements in CHOP INTEND scores, better survival, and motor function improvements at long-term follow-up, according to an analysis presented at the annual meeting of the Child Neurology Society. The results provide a clinical demonstration of continuous expression of the SMN protein, according to the investigators. In addition, AVXS-101 is associated with reduced health care utilization in treated infants, which could decrease costs, lessen the burden on patients and caregivers, and improve quality of life.
SMA1 is a progressive neurologic disease that causes loss of the lower motor neurons in the spinal cord and brainstem. Patients have increasing muscle weakness that leads to death or the need for permanent ventilation by age 2 years. The disease results from mutations in the SMN1 gene. AVXS-101 replaces the missing or nonfunctional SMN1 with a healthy copy of a human SMN gene.
AveXis, the company that developed the therapy, enrolled 12 patients with SMA1 in a phase 1/2a study between December 2014 and December 2015. All participants received one intravenous infusion of AVXS-101. Omar Dabbous, MD, vice president of global health economics, outcomes research, and real world evidence at AveXis in Bannockburn, Ill., and colleagues evaluated participants’ rates of event-free survival (i.e., absence of death or need for permanent ventilation), pulmonary or nutritional interventions, swallowing, hospitalization, and CHOP INTEND scores, as well as therapeutic safety at 2 years.
At study completion, all patients who had received a therapeutic dose had event-free survival. Seven participants did not need daily noninvasive ventilation. Eleven participants had stable or improved swallowing. All of the latter patients fed orally, and six fed exclusively by mouth. Eleven patients spoke.
Participants had a mean of 1.4 respiratory hospitalizations per year. Mean proportion of time participants spent hospitalized was 4.4%. Mean hospitalization rate per year was 2.1, and mean length of hospital stay was 6.7 days. In addition, participants’ CHOP INTEND scores increased from baseline by 9.8 points at 1 month and by 15.4 points at 3 months. Patients who received a therapeutic dose of AVXS-101 have maintained their motor milestones at long-term follow-up, which suggests that treatment effects persist over the long term. Adverse events included elevated serum aminotransferase levels, which were reduced by prednisolone.
Dr. Dabbous is an employee of AveXis, which developed AVXS-101.
SOURCE: Dabbous O et al. CNS 2019. Abstract 199.
CHARLOTTE, N.C. – AVXS-101, the Food and Drug Administration–approved therapy for spinal muscular atrophy (SMA), yields rapid, sustained improvements in CHOP INTEND scores, better survival, and motor function improvements at long-term follow-up, according to an analysis presented at the annual meeting of the Child Neurology Society. The results provide a clinical demonstration of continuous expression of the SMN protein, according to the investigators. In addition, AVXS-101 is associated with reduced health care utilization in treated infants, which could decrease costs, lessen the burden on patients and caregivers, and improve quality of life.
SMA1 is a progressive neurologic disease that causes loss of the lower motor neurons in the spinal cord and brainstem. Patients have increasing muscle weakness that leads to death or the need for permanent ventilation by age 2 years. The disease results from mutations in the SMN1 gene. AVXS-101 replaces the missing or nonfunctional SMN1 with a healthy copy of a human SMN gene.
AveXis, the company that developed the therapy, enrolled 12 patients with SMA1 in a phase 1/2a study between December 2014 and December 2015. All participants received one intravenous infusion of AVXS-101. Omar Dabbous, MD, vice president of global health economics, outcomes research, and real world evidence at AveXis in Bannockburn, Ill., and colleagues evaluated participants’ rates of event-free survival (i.e., absence of death or need for permanent ventilation), pulmonary or nutritional interventions, swallowing, hospitalization, and CHOP INTEND scores, as well as therapeutic safety at 2 years.
At study completion, all patients who had received a therapeutic dose had event-free survival. Seven participants did not need daily noninvasive ventilation. Eleven participants had stable or improved swallowing. All of the latter patients fed orally, and six fed exclusively by mouth. Eleven patients spoke.
Participants had a mean of 1.4 respiratory hospitalizations per year. Mean proportion of time participants spent hospitalized was 4.4%. Mean hospitalization rate per year was 2.1, and mean length of hospital stay was 6.7 days. In addition, participants’ CHOP INTEND scores increased from baseline by 9.8 points at 1 month and by 15.4 points at 3 months. Patients who received a therapeutic dose of AVXS-101 have maintained their motor milestones at long-term follow-up, which suggests that treatment effects persist over the long term. Adverse events included elevated serum aminotransferase levels, which were reduced by prednisolone.
Dr. Dabbous is an employee of AveXis, which developed AVXS-101.
SOURCE: Dabbous O et al. CNS 2019. Abstract 199.
REPORTING FROM CNS 2019
Psoriasis risk rises with TNF inhibitor use in children with inflammatory disorders
, a retrospective cohort study has determined.
“The incidence rate and risk factors of psoriasis in children with IBD [inflammatory bowel disease], JIA [juvenile idiopathic arthritis], or CNO [chronic nonbacterial osteomyelitis] who are exposed to TNFi [tumor necrosis factor inhibitors] are unknown. Additionally, there is a well-established association between these inflammatory conditions and psoriasis development. Yet, as TNFi can both treat and trigger psoriasis, it is not clear how TNFi exposure affects this relationship,” wrote Lisa H. Buckley, MD, of Children’s Hospital at Vanderbilt, Nashville, Tenn., and colleagues. Their report is in Arthritis Care & Research.
The team examined the relationship in children who were treated for an inflammatory disorder at Children’s Hospital of Philadelphia during 2008-2018. IBD was most common at 74%, followed by JIA at 24% and CNO at 2%.
Among 4,111 children with those inflammatory disorders, the psoriasis incidence was 12.3 per 1,000 person-years in exposed children and 3.8 per 1,000 person-years in unexposed. This significant difference equated to a hazard ratio of 3.84 for developing psoriasis after TNFi exposure.
“These data reflect the established association between inflammatory conditions and psoriasis development and suggest that TNFi exposure further increases the risk of psoriasis,” Dr. Buckley and coauthors wrote.
The median duration of follow-up in this study was about 2.5 years for patients exposed to TNFi and 2 years for those unexposed. Among the entire cohort, 39% had been exposed to a TNFi, with 4,705 person-years of follow-up. Among the unexposed children (61%), there were 6,604 person-years of follow-up.
In all, 83 cases of psoriasis developed: 58 in the exposed group and 25 in the unexposed group. Psoriasis incidence varied by disorder. Exposed children with IBD had a higher incidence than did unexposed children (10.9 vs. 2.6 per 1,000 person-years; HR = 4.52). Exposed children with JIA also had a higher incidence than did unexposed children (14.7 vs. 5.5 per 1,000 person-years; HR = 2.90). Among those with CNO, incidences were similar for exposed and unexposed children (33.5 and 38.9 per 1,000 person-years).
A family history of psoriasis significantly increased the risk of psoriasis with a hazard ratio of 3.11, the authors noted. But none of the other covariates (age, sex, race, obesity, methotrexate exposure, and underlying diagnosis) exerted a significant additional risk.
The study had no outside funding source. The authors had no financial disclosures. Dr. Buckley conducted the research when she was a pediatric rheumatology fellow at Children’s Hospital of Philadelphia.
SOURCE: Buckley LH et al. Arthritis Care Res. 2019 Oct 23. doi: 10.1002/ACR.24100
, a retrospective cohort study has determined.
“The incidence rate and risk factors of psoriasis in children with IBD [inflammatory bowel disease], JIA [juvenile idiopathic arthritis], or CNO [chronic nonbacterial osteomyelitis] who are exposed to TNFi [tumor necrosis factor inhibitors] are unknown. Additionally, there is a well-established association between these inflammatory conditions and psoriasis development. Yet, as TNFi can both treat and trigger psoriasis, it is not clear how TNFi exposure affects this relationship,” wrote Lisa H. Buckley, MD, of Children’s Hospital at Vanderbilt, Nashville, Tenn., and colleagues. Their report is in Arthritis Care & Research.
The team examined the relationship in children who were treated for an inflammatory disorder at Children’s Hospital of Philadelphia during 2008-2018. IBD was most common at 74%, followed by JIA at 24% and CNO at 2%.
Among 4,111 children with those inflammatory disorders, the psoriasis incidence was 12.3 per 1,000 person-years in exposed children and 3.8 per 1,000 person-years in unexposed. This significant difference equated to a hazard ratio of 3.84 for developing psoriasis after TNFi exposure.
“These data reflect the established association between inflammatory conditions and psoriasis development and suggest that TNFi exposure further increases the risk of psoriasis,” Dr. Buckley and coauthors wrote.
The median duration of follow-up in this study was about 2.5 years for patients exposed to TNFi and 2 years for those unexposed. Among the entire cohort, 39% had been exposed to a TNFi, with 4,705 person-years of follow-up. Among the unexposed children (61%), there were 6,604 person-years of follow-up.
In all, 83 cases of psoriasis developed: 58 in the exposed group and 25 in the unexposed group. Psoriasis incidence varied by disorder. Exposed children with IBD had a higher incidence than did unexposed children (10.9 vs. 2.6 per 1,000 person-years; HR = 4.52). Exposed children with JIA also had a higher incidence than did unexposed children (14.7 vs. 5.5 per 1,000 person-years; HR = 2.90). Among those with CNO, incidences were similar for exposed and unexposed children (33.5 and 38.9 per 1,000 person-years).
A family history of psoriasis significantly increased the risk of psoriasis with a hazard ratio of 3.11, the authors noted. But none of the other covariates (age, sex, race, obesity, methotrexate exposure, and underlying diagnosis) exerted a significant additional risk.
The study had no outside funding source. The authors had no financial disclosures. Dr. Buckley conducted the research when she was a pediatric rheumatology fellow at Children’s Hospital of Philadelphia.
SOURCE: Buckley LH et al. Arthritis Care Res. 2019 Oct 23. doi: 10.1002/ACR.24100
, a retrospective cohort study has determined.
“The incidence rate and risk factors of psoriasis in children with IBD [inflammatory bowel disease], JIA [juvenile idiopathic arthritis], or CNO [chronic nonbacterial osteomyelitis] who are exposed to TNFi [tumor necrosis factor inhibitors] are unknown. Additionally, there is a well-established association between these inflammatory conditions and psoriasis development. Yet, as TNFi can both treat and trigger psoriasis, it is not clear how TNFi exposure affects this relationship,” wrote Lisa H. Buckley, MD, of Children’s Hospital at Vanderbilt, Nashville, Tenn., and colleagues. Their report is in Arthritis Care & Research.
The team examined the relationship in children who were treated for an inflammatory disorder at Children’s Hospital of Philadelphia during 2008-2018. IBD was most common at 74%, followed by JIA at 24% and CNO at 2%.
Among 4,111 children with those inflammatory disorders, the psoriasis incidence was 12.3 per 1,000 person-years in exposed children and 3.8 per 1,000 person-years in unexposed. This significant difference equated to a hazard ratio of 3.84 for developing psoriasis after TNFi exposure.
“These data reflect the established association between inflammatory conditions and psoriasis development and suggest that TNFi exposure further increases the risk of psoriasis,” Dr. Buckley and coauthors wrote.
The median duration of follow-up in this study was about 2.5 years for patients exposed to TNFi and 2 years for those unexposed. Among the entire cohort, 39% had been exposed to a TNFi, with 4,705 person-years of follow-up. Among the unexposed children (61%), there were 6,604 person-years of follow-up.
In all, 83 cases of psoriasis developed: 58 in the exposed group and 25 in the unexposed group. Psoriasis incidence varied by disorder. Exposed children with IBD had a higher incidence than did unexposed children (10.9 vs. 2.6 per 1,000 person-years; HR = 4.52). Exposed children with JIA also had a higher incidence than did unexposed children (14.7 vs. 5.5 per 1,000 person-years; HR = 2.90). Among those with CNO, incidences were similar for exposed and unexposed children (33.5 and 38.9 per 1,000 person-years).
A family history of psoriasis significantly increased the risk of psoriasis with a hazard ratio of 3.11, the authors noted. But none of the other covariates (age, sex, race, obesity, methotrexate exposure, and underlying diagnosis) exerted a significant additional risk.
The study had no outside funding source. The authors had no financial disclosures. Dr. Buckley conducted the research when she was a pediatric rheumatology fellow at Children’s Hospital of Philadelphia.
SOURCE: Buckley LH et al. Arthritis Care Res. 2019 Oct 23. doi: 10.1002/ACR.24100
FROM ARTHRITIS RESEARCH & CARE
CBD: What physicians need to know about it
Cannabidiol is a derivative of marijuana that is sold everywhere from medical marijuana stores to health food markets to gas stations. While this chemical is derived from marijuana plants, it can be sold in many states as a supplement and is largely unregulated. The ubiquity of cannabidiol (CBD) and its potential benefits means that doctors need to be able to counsel patients about what we know, what we don’t, and how to use it safely. For conditions such as chronic pain and addiction, where we have few safe and effective alternatives, CBD may be reasonable to recommend.
To find out what physicians need to know about CBD, Elisabeth Poorman, MD, a general internist at a University of Washington neighborhood clinic in Kent and member of the editorial advisory board of Internal Medicine News, interviewed Peter Grinspoon, MD, who provides free consultation to primary care patients on the benefits and risks of using various forms of cannabis, including CBD. Dr. Grinspoon is an internist at Massachusetts General Hospital Chelsea Healthcare Center and is an instructor at Harvard Medical School, Boston. He has contributed to the Harvard Health Blog on the topic of medical marijuana, delivered grand rounds on cannabis at Massachusetts General Hospital, and lectured at the American College of Physicians. Dr. Grinspoon is also medical director for Galenas, a medical marijuana company.
Dr. Grinspoon is the son of Lester Grinspoon, MD, associate professor emeritus of psychiatry at Harvard Medical School, who researched the medicinal legitimacy of marijuana prohibition and has authored books on the medical benefits of marijuana.
and his knowledge of CBD’s efficacy for various medical conditions. Below are excerpts from that conversation.
Dr. Poorman: How do you explain the difference between THC and CBD to patients?
Dr. Grinspoon: Cannabis contains at least a hundred different chemicals called cannabinoids, of which tetrahydrocannabinol (THC) and CBD are the most prevalent. THC is the one that gets you high and can be used recreationally and medically. The CBD molecule is not intoxicating, and people use it for a variety of medical purposes, most commonly to treat anxiety, insomnia, and pain.
Dr. Poorman: There are a lot of gaps in what we now about CBD’s potential benefits. Why don’t we know more?
Dr. Grinspoon: CBD has no abuse liability according to the World Health Organization, but because it is a cannabinoid, it is still technically a schedule I substance under the Controlled Substances Act, and that makes it difficult to study.
Dr. Poorman: What kinds of conditions can CBD treat?
Dr. Grinspoon: In anxiety, the enthusiasm has outpaced the science; there’s no question about that. And most of the studies have done in animals. That said, some studies have shown that CBD helps treat components of anxiety, like public speaking. Unlike THC, it is nonintoxicating and non–habit forming. But we don’t have the wealth of randomized controlled trials that we have for official psychiatric medications.
CBD’s benefits have been most extensively studied in pediatric epilepsy. The one Food and Drug Administration–approved drug derived from cannabis is Epidiolex, used to treat rare forms of childhood epilepsy. There is some evidence that as an adjunct, it can be used for glioblastoma multiforme in patients receiving other appropriate therapy. There is also some preliminary evidence that it can be used for addiction, including to opioids, cannabis, tobacco, and stimulants.
Most of the evidence for using CBD in chronic pain comes from animal studies, including a study published in the European Journal of Pain in 2016. Among my patients to whom I have suggested CBD for chronic pain, a few have noticed great benefit, a few have noticed some benefit, and a lot have noticed no benefit. For those who have said they noticed benefit it is unclear whether that benefit was just the placebo effect.
In insomnia, I usually have them take CBD under the tongue half an hour time before bedtime, or if it’s an edible, an hour before bedtime. I start with a lower dose and slowly try higher doses. I also encourage them to do the other sleep hygiene things, like no screens, increasing exercise, and decreasing caffeine. It seems that CBD helps them fall asleep, though it’s hard to know if it’s the CBD or the fact that they have started taking something, and have simultaneously made various lifestyle changes.
Dr. Poorman: Can CBD interfere with your normal sleep architecture, the way benzodiazepines and Benadryl can?
Dr. Grinspoon: We know that THC affects your sleep architecture and affects what percentage of REM sleep you have. But I don’t know if the effects of CBD on sleep architecture have been studied.
Dr. Poorman: What harms do you counsel patients about when discussing CBD?
Dr. Grinspoon: There are four main harms. The first is the price. It’s overpriced, and the doses are very low. In most animal studies, the doses are about 20 milligrams per kilogram of weight. And you go to the market, and it’s like a dollar for a hundredth of that.
Number two is that it’s not regulated; it’s a supplement. A few years ago, the government tested a bunch of samples of CBD, and some didn’t actually contain CBD, some didn’t have the right amount; and worse, some contained THC that had not been disclosed in the packaging. So you can’t just go to a roadside gas station and assume that if you buy CBD, it’s actually that. You want a place that has a certificate of assurance. Make sure third-party testing was done, including testing for pesticides and other heavy metals.
The third thing is drug interactions. It affects the body like grapefruit and inhibits the cytochrome P450 system. The medications doctors should be most concerned about are blood thinners like Coumadin. And if you’re on blood thinners, you definitely want to tell your doctor that you are on CBD and he or she might want to check your blood levels more frequently than they usually do.
The fourth concern is liver inflammation. In the childhood epilepsy studies, a bump in some liver enzymes was seen, although I haven’t heard of any clinically significant cases of chemical hepatitis related to CBD. But if someone has liver disease you want to keep an eye on their liver enzymes.
Dr. Poorman: What methods of ingestion do you recommend or not recommend?
Dr. Grinspoon: It’s basically trial and error, but I usually recommend oral form. If people feel comfortable taking a gummy bear, or a pill, I’m not particular about that. If the product being taken contains less than 0.3% THC, it won’t get you high.
The topical form probably works better for treating chronic pain if it contains some THC, suggests a review article published in the Cleveland Clinic Journal of Medicine. Topical THC is nonintoxicating, unless you managed to sit in a bathtub for 8 hours after applying it.
I don’t recommend smoking CBD, and right now, I don’t recommend vaping anything.
If people have severe pain, like moderately severe arthritis, CBD may not be enough, whereas medical cannabis with THC could help, a report suggests.
Dr. Poorman: Do you ever encourage patients to stop using CBD products?
Dr. Grinspoon: I work in a low-income area, and my patients don’t have a ton of disposable income. If it’s not working, I worry about the expense.
Dr. Poorman: The CBD industry is growing quickly. What changes are you seeing in what products are out there, and what changes would you like to see?
Dr. Grinspoon: CBD is being put in everything, and it’s comical. On the one hand, you can say if people want to waste their money on a CBD emitting pillowcase, that’s fine. On the other hand, you can say that certainly seems like misleading advertising, because a CBD emitting pillowcase isn’t going to help you sleep any better.
I think the purported benefits are far beyond what we can say scientifically. We do know that CBD has anti-inflammatory characteristics. But that doesn’t mean that putting CBD in all skin products is good for your skin. It’s bad for your pocketbook, though. I would like there to be less of a gap between the claims and the science.
Dr. Elisabeth Poorman has no conflicts to disclose.
Cannabidiol is a derivative of marijuana that is sold everywhere from medical marijuana stores to health food markets to gas stations. While this chemical is derived from marijuana plants, it can be sold in many states as a supplement and is largely unregulated. The ubiquity of cannabidiol (CBD) and its potential benefits means that doctors need to be able to counsel patients about what we know, what we don’t, and how to use it safely. For conditions such as chronic pain and addiction, where we have few safe and effective alternatives, CBD may be reasonable to recommend.
To find out what physicians need to know about CBD, Elisabeth Poorman, MD, a general internist at a University of Washington neighborhood clinic in Kent and member of the editorial advisory board of Internal Medicine News, interviewed Peter Grinspoon, MD, who provides free consultation to primary care patients on the benefits and risks of using various forms of cannabis, including CBD. Dr. Grinspoon is an internist at Massachusetts General Hospital Chelsea Healthcare Center and is an instructor at Harvard Medical School, Boston. He has contributed to the Harvard Health Blog on the topic of medical marijuana, delivered grand rounds on cannabis at Massachusetts General Hospital, and lectured at the American College of Physicians. Dr. Grinspoon is also medical director for Galenas, a medical marijuana company.
Dr. Grinspoon is the son of Lester Grinspoon, MD, associate professor emeritus of psychiatry at Harvard Medical School, who researched the medicinal legitimacy of marijuana prohibition and has authored books on the medical benefits of marijuana.
and his knowledge of CBD’s efficacy for various medical conditions. Below are excerpts from that conversation.
Dr. Poorman: How do you explain the difference between THC and CBD to patients?
Dr. Grinspoon: Cannabis contains at least a hundred different chemicals called cannabinoids, of which tetrahydrocannabinol (THC) and CBD are the most prevalent. THC is the one that gets you high and can be used recreationally and medically. The CBD molecule is not intoxicating, and people use it for a variety of medical purposes, most commonly to treat anxiety, insomnia, and pain.
Dr. Poorman: There are a lot of gaps in what we now about CBD’s potential benefits. Why don’t we know more?
Dr. Grinspoon: CBD has no abuse liability according to the World Health Organization, but because it is a cannabinoid, it is still technically a schedule I substance under the Controlled Substances Act, and that makes it difficult to study.
Dr. Poorman: What kinds of conditions can CBD treat?
Dr. Grinspoon: In anxiety, the enthusiasm has outpaced the science; there’s no question about that. And most of the studies have done in animals. That said, some studies have shown that CBD helps treat components of anxiety, like public speaking. Unlike THC, it is nonintoxicating and non–habit forming. But we don’t have the wealth of randomized controlled trials that we have for official psychiatric medications.
CBD’s benefits have been most extensively studied in pediatric epilepsy. The one Food and Drug Administration–approved drug derived from cannabis is Epidiolex, used to treat rare forms of childhood epilepsy. There is some evidence that as an adjunct, it can be used for glioblastoma multiforme in patients receiving other appropriate therapy. There is also some preliminary evidence that it can be used for addiction, including to opioids, cannabis, tobacco, and stimulants.
Most of the evidence for using CBD in chronic pain comes from animal studies, including a study published in the European Journal of Pain in 2016. Among my patients to whom I have suggested CBD for chronic pain, a few have noticed great benefit, a few have noticed some benefit, and a lot have noticed no benefit. For those who have said they noticed benefit it is unclear whether that benefit was just the placebo effect.
In insomnia, I usually have them take CBD under the tongue half an hour time before bedtime, or if it’s an edible, an hour before bedtime. I start with a lower dose and slowly try higher doses. I also encourage them to do the other sleep hygiene things, like no screens, increasing exercise, and decreasing caffeine. It seems that CBD helps them fall asleep, though it’s hard to know if it’s the CBD or the fact that they have started taking something, and have simultaneously made various lifestyle changes.
Dr. Poorman: Can CBD interfere with your normal sleep architecture, the way benzodiazepines and Benadryl can?
Dr. Grinspoon: We know that THC affects your sleep architecture and affects what percentage of REM sleep you have. But I don’t know if the effects of CBD on sleep architecture have been studied.
Dr. Poorman: What harms do you counsel patients about when discussing CBD?
Dr. Grinspoon: There are four main harms. The first is the price. It’s overpriced, and the doses are very low. In most animal studies, the doses are about 20 milligrams per kilogram of weight. And you go to the market, and it’s like a dollar for a hundredth of that.
Number two is that it’s not regulated; it’s a supplement. A few years ago, the government tested a bunch of samples of CBD, and some didn’t actually contain CBD, some didn’t have the right amount; and worse, some contained THC that had not been disclosed in the packaging. So you can’t just go to a roadside gas station and assume that if you buy CBD, it’s actually that. You want a place that has a certificate of assurance. Make sure third-party testing was done, including testing for pesticides and other heavy metals.
The third thing is drug interactions. It affects the body like grapefruit and inhibits the cytochrome P450 system. The medications doctors should be most concerned about are blood thinners like Coumadin. And if you’re on blood thinners, you definitely want to tell your doctor that you are on CBD and he or she might want to check your blood levels more frequently than they usually do.
The fourth concern is liver inflammation. In the childhood epilepsy studies, a bump in some liver enzymes was seen, although I haven’t heard of any clinically significant cases of chemical hepatitis related to CBD. But if someone has liver disease you want to keep an eye on their liver enzymes.
Dr. Poorman: What methods of ingestion do you recommend or not recommend?
Dr. Grinspoon: It’s basically trial and error, but I usually recommend oral form. If people feel comfortable taking a gummy bear, or a pill, I’m not particular about that. If the product being taken contains less than 0.3% THC, it won’t get you high.
The topical form probably works better for treating chronic pain if it contains some THC, suggests a review article published in the Cleveland Clinic Journal of Medicine. Topical THC is nonintoxicating, unless you managed to sit in a bathtub for 8 hours after applying it.
I don’t recommend smoking CBD, and right now, I don’t recommend vaping anything.
If people have severe pain, like moderately severe arthritis, CBD may not be enough, whereas medical cannabis with THC could help, a report suggests.
Dr. Poorman: Do you ever encourage patients to stop using CBD products?
Dr. Grinspoon: I work in a low-income area, and my patients don’t have a ton of disposable income. If it’s not working, I worry about the expense.
Dr. Poorman: The CBD industry is growing quickly. What changes are you seeing in what products are out there, and what changes would you like to see?
Dr. Grinspoon: CBD is being put in everything, and it’s comical. On the one hand, you can say if people want to waste their money on a CBD emitting pillowcase, that’s fine. On the other hand, you can say that certainly seems like misleading advertising, because a CBD emitting pillowcase isn’t going to help you sleep any better.
I think the purported benefits are far beyond what we can say scientifically. We do know that CBD has anti-inflammatory characteristics. But that doesn’t mean that putting CBD in all skin products is good for your skin. It’s bad for your pocketbook, though. I would like there to be less of a gap between the claims and the science.
Dr. Elisabeth Poorman has no conflicts to disclose.
Cannabidiol is a derivative of marijuana that is sold everywhere from medical marijuana stores to health food markets to gas stations. While this chemical is derived from marijuana plants, it can be sold in many states as a supplement and is largely unregulated. The ubiquity of cannabidiol (CBD) and its potential benefits means that doctors need to be able to counsel patients about what we know, what we don’t, and how to use it safely. For conditions such as chronic pain and addiction, where we have few safe and effective alternatives, CBD may be reasonable to recommend.
To find out what physicians need to know about CBD, Elisabeth Poorman, MD, a general internist at a University of Washington neighborhood clinic in Kent and member of the editorial advisory board of Internal Medicine News, interviewed Peter Grinspoon, MD, who provides free consultation to primary care patients on the benefits and risks of using various forms of cannabis, including CBD. Dr. Grinspoon is an internist at Massachusetts General Hospital Chelsea Healthcare Center and is an instructor at Harvard Medical School, Boston. He has contributed to the Harvard Health Blog on the topic of medical marijuana, delivered grand rounds on cannabis at Massachusetts General Hospital, and lectured at the American College of Physicians. Dr. Grinspoon is also medical director for Galenas, a medical marijuana company.
Dr. Grinspoon is the son of Lester Grinspoon, MD, associate professor emeritus of psychiatry at Harvard Medical School, who researched the medicinal legitimacy of marijuana prohibition and has authored books on the medical benefits of marijuana.
and his knowledge of CBD’s efficacy for various medical conditions. Below are excerpts from that conversation.
Dr. Poorman: How do you explain the difference between THC and CBD to patients?
Dr. Grinspoon: Cannabis contains at least a hundred different chemicals called cannabinoids, of which tetrahydrocannabinol (THC) and CBD are the most prevalent. THC is the one that gets you high and can be used recreationally and medically. The CBD molecule is not intoxicating, and people use it for a variety of medical purposes, most commonly to treat anxiety, insomnia, and pain.
Dr. Poorman: There are a lot of gaps in what we now about CBD’s potential benefits. Why don’t we know more?
Dr. Grinspoon: CBD has no abuse liability according to the World Health Organization, but because it is a cannabinoid, it is still technically a schedule I substance under the Controlled Substances Act, and that makes it difficult to study.
Dr. Poorman: What kinds of conditions can CBD treat?
Dr. Grinspoon: In anxiety, the enthusiasm has outpaced the science; there’s no question about that. And most of the studies have done in animals. That said, some studies have shown that CBD helps treat components of anxiety, like public speaking. Unlike THC, it is nonintoxicating and non–habit forming. But we don’t have the wealth of randomized controlled trials that we have for official psychiatric medications.
CBD’s benefits have been most extensively studied in pediatric epilepsy. The one Food and Drug Administration–approved drug derived from cannabis is Epidiolex, used to treat rare forms of childhood epilepsy. There is some evidence that as an adjunct, it can be used for glioblastoma multiforme in patients receiving other appropriate therapy. There is also some preliminary evidence that it can be used for addiction, including to opioids, cannabis, tobacco, and stimulants.
Most of the evidence for using CBD in chronic pain comes from animal studies, including a study published in the European Journal of Pain in 2016. Among my patients to whom I have suggested CBD for chronic pain, a few have noticed great benefit, a few have noticed some benefit, and a lot have noticed no benefit. For those who have said they noticed benefit it is unclear whether that benefit was just the placebo effect.
In insomnia, I usually have them take CBD under the tongue half an hour time before bedtime, or if it’s an edible, an hour before bedtime. I start with a lower dose and slowly try higher doses. I also encourage them to do the other sleep hygiene things, like no screens, increasing exercise, and decreasing caffeine. It seems that CBD helps them fall asleep, though it’s hard to know if it’s the CBD or the fact that they have started taking something, and have simultaneously made various lifestyle changes.
Dr. Poorman: Can CBD interfere with your normal sleep architecture, the way benzodiazepines and Benadryl can?
Dr. Grinspoon: We know that THC affects your sleep architecture and affects what percentage of REM sleep you have. But I don’t know if the effects of CBD on sleep architecture have been studied.
Dr. Poorman: What harms do you counsel patients about when discussing CBD?
Dr. Grinspoon: There are four main harms. The first is the price. It’s overpriced, and the doses are very low. In most animal studies, the doses are about 20 milligrams per kilogram of weight. And you go to the market, and it’s like a dollar for a hundredth of that.
Number two is that it’s not regulated; it’s a supplement. A few years ago, the government tested a bunch of samples of CBD, and some didn’t actually contain CBD, some didn’t have the right amount; and worse, some contained THC that had not been disclosed in the packaging. So you can’t just go to a roadside gas station and assume that if you buy CBD, it’s actually that. You want a place that has a certificate of assurance. Make sure third-party testing was done, including testing for pesticides and other heavy metals.
The third thing is drug interactions. It affects the body like grapefruit and inhibits the cytochrome P450 system. The medications doctors should be most concerned about are blood thinners like Coumadin. And if you’re on blood thinners, you definitely want to tell your doctor that you are on CBD and he or she might want to check your blood levels more frequently than they usually do.
The fourth concern is liver inflammation. In the childhood epilepsy studies, a bump in some liver enzymes was seen, although I haven’t heard of any clinically significant cases of chemical hepatitis related to CBD. But if someone has liver disease you want to keep an eye on their liver enzymes.
Dr. Poorman: What methods of ingestion do you recommend or not recommend?
Dr. Grinspoon: It’s basically trial and error, but I usually recommend oral form. If people feel comfortable taking a gummy bear, or a pill, I’m not particular about that. If the product being taken contains less than 0.3% THC, it won’t get you high.
The topical form probably works better for treating chronic pain if it contains some THC, suggests a review article published in the Cleveland Clinic Journal of Medicine. Topical THC is nonintoxicating, unless you managed to sit in a bathtub for 8 hours after applying it.
I don’t recommend smoking CBD, and right now, I don’t recommend vaping anything.
If people have severe pain, like moderately severe arthritis, CBD may not be enough, whereas medical cannabis with THC could help, a report suggests.
Dr. Poorman: Do you ever encourage patients to stop using CBD products?
Dr. Grinspoon: I work in a low-income area, and my patients don’t have a ton of disposable income. If it’s not working, I worry about the expense.
Dr. Poorman: The CBD industry is growing quickly. What changes are you seeing in what products are out there, and what changes would you like to see?
Dr. Grinspoon: CBD is being put in everything, and it’s comical. On the one hand, you can say if people want to waste their money on a CBD emitting pillowcase, that’s fine. On the other hand, you can say that certainly seems like misleading advertising, because a CBD emitting pillowcase isn’t going to help you sleep any better.
I think the purported benefits are far beyond what we can say scientifically. We do know that CBD has anti-inflammatory characteristics. But that doesn’t mean that putting CBD in all skin products is good for your skin. It’s bad for your pocketbook, though. I would like there to be less of a gap between the claims and the science.
Dr. Elisabeth Poorman has no conflicts to disclose.
Hormone therapy in transgender patients is safe for bone
ORLANDO – according to a presentation at the annual meeting of the American Society for Bone and Mineral Research.
“Hormonal treatment of transgender people is safe with respect to bone,” said Martin den Heijer, MD, PhD, of the VU University Medical Center in Amsterdam.
At baseline, transwomen have lower bone mass than do male reference populations, said Dr. den Heijer, citing a study that found 25 transwomen had less muscle mass (P less than or equal to .001), strength (P less than or equal to .05), and lower BMD at the hip, femoral neck, and spine (P less than .001), compared with 25 cisgender men in a control group and 941 men in a male reference population (Bone. 2013;54[1]:92-7). In a 2019 study from his own group, Dr. den Heijer said the z score in the lumbar spine for 711 transwomen was -0.9 and the incidence of osteoporosis was 14.2%, compared with a z score of 0.0 and 2.4% incidence of osteoporosis in 543 transmen (J Bone Min Res. 2019;34[3]:447-54).
In the prospective European Network for the Investigation of Gender Incongruence (ENIGI) study, researchers examined short-term effects of hormone therapy on BMD in 144 transwomen and 162 transmen who had a normal body mass index and were mostly white. The percentage of patients who reported they were current smokers was between 25% and 30%, and fewer than 10% said they consumed more than seven units of alcohol per week. Transwomen received estradiol (an oral estradiol valerate at a dose of 4 mg/day or an estradiol patch) together with 100 mg/day of cyproterone acetate, and transmen received testosterone in the form of a gel (50 mg/day), intramuscular esters (250 mg every 2-3 weeks), or intramuscular undecanoate at a dose of 1,000 mg every 12 weeks (J Sex Med. 2016;13[6]:994-9).
After 1 year of treatment, there were significant increases in BMD in transwomen in the lumbar spine (3.67%; 95% confidence interval, 3.20%-4.13%), femoral neck (1.86%; 95% CI, 1.41%-2.31%), and total hip (0.97%; 95% CI, 0.62%-1.31%). Transmen also had increased BMD in the lumbar spine (0.86%; 95% CI, 0.38%-1.35%) and total hip (1.04%; 95% CI, 0.64%-1.44%), with a slight decrease in femoral neck BMD (–0.46%; 95% CI, –1.07% to 0.16%).
Dr. den Heijer also discussed the long-term effects of hormone therapy on BMD in the Amsterdam Cohort of Dysphoria (ACOG) study, which consisted of 711 transwomen and 543 transmen and followed some patients out to 2 years, 5 years, and 10 years after beginning hormone therapy (J Sex Med. 2018;15[4]:582-90). Among transwomen, the median age was 33 years, 68.9% had begun hormone therapy, and 75.3% received a gonadectomy; among transmen, the median age was 25 years, 72.9% had begun hormone therapy, and 83.8% received a gonadectomy. Of these patients, dual-energy x-ray absorptiometry data were available for the lumbar spine BMD for 234 transwomen and 236 transmen at 2 years, 174 transwomen and 95 transmen at 5 years, and 102 transwomen and 70 transmen at 10 years.
Although there was no significant mean change in absolute BMD over the 10-year period, the concentration of estradiol in transwomen and transmen affected change in BMD the longer the transperson was receiving hormone therapy: Transwomen who received an estradiol concentration of 118 pmol/L had a decrease of –0.026% at 2 years, –0.044% at 5 years, and –0.009% at 10 years, compared with a dose of 443 pmol/L (+0.044% at 2 years, +0.025% at 5 years, +0.063% at 10 years), whereas transmen also had decreased BMD at the lowest estradiol concentrations of 95 pmol/L (–0.007% at 2 years, –0.024% at 5 years, +0.010% at 10 years), compared with transmen receiving the highest doses of 323 pmol/L (+0.028% at 2 years, +0.002% at 5 years, +0.053% at 10 years). There was no significant change in BMD in either group at any time point with regard to testosterone concentration.
When the investigators linked these patients to a national statistics database in the Netherlands to evaluate fracture incidence (J Bone Miner Res. 2019 Sep 5. doi: 10.1002/jbmr.3862), pairing five cisgender female controls and five cisgender male controls to every transgender patient, the researchers found transwomen had a higher incidence of osteoporotic fracture of the hip, spine, forearm, and humerus (41.8%), compared with cisgender men (26.6%; P = .014) and cisgender women (36.0%; P = .381). There was not enough information in the study to examine fracture information for transmen, Dr. den Heijer said. Transwomen and transmen who experienced a fracture were more likely to be a current smoker and have lower estradiol concentrations than were transwomen and transmen, respectively, who did not have a fracture.
“Attention for lifestyle factors remains important, especially smoking cessation, vitamin D intake, and regular exercise,” Dr. den Heijer said. “It remains important for everybody, but especially for transgender women.”
Dr. den Heijer reported no relevant conflicts of interest.
ORLANDO – according to a presentation at the annual meeting of the American Society for Bone and Mineral Research.
“Hormonal treatment of transgender people is safe with respect to bone,” said Martin den Heijer, MD, PhD, of the VU University Medical Center in Amsterdam.
At baseline, transwomen have lower bone mass than do male reference populations, said Dr. den Heijer, citing a study that found 25 transwomen had less muscle mass (P less than or equal to .001), strength (P less than or equal to .05), and lower BMD at the hip, femoral neck, and spine (P less than .001), compared with 25 cisgender men in a control group and 941 men in a male reference population (Bone. 2013;54[1]:92-7). In a 2019 study from his own group, Dr. den Heijer said the z score in the lumbar spine for 711 transwomen was -0.9 and the incidence of osteoporosis was 14.2%, compared with a z score of 0.0 and 2.4% incidence of osteoporosis in 543 transmen (J Bone Min Res. 2019;34[3]:447-54).
In the prospective European Network for the Investigation of Gender Incongruence (ENIGI) study, researchers examined short-term effects of hormone therapy on BMD in 144 transwomen and 162 transmen who had a normal body mass index and were mostly white. The percentage of patients who reported they were current smokers was between 25% and 30%, and fewer than 10% said they consumed more than seven units of alcohol per week. Transwomen received estradiol (an oral estradiol valerate at a dose of 4 mg/day or an estradiol patch) together with 100 mg/day of cyproterone acetate, and transmen received testosterone in the form of a gel (50 mg/day), intramuscular esters (250 mg every 2-3 weeks), or intramuscular undecanoate at a dose of 1,000 mg every 12 weeks (J Sex Med. 2016;13[6]:994-9).
After 1 year of treatment, there were significant increases in BMD in transwomen in the lumbar spine (3.67%; 95% confidence interval, 3.20%-4.13%), femoral neck (1.86%; 95% CI, 1.41%-2.31%), and total hip (0.97%; 95% CI, 0.62%-1.31%). Transmen also had increased BMD in the lumbar spine (0.86%; 95% CI, 0.38%-1.35%) and total hip (1.04%; 95% CI, 0.64%-1.44%), with a slight decrease in femoral neck BMD (–0.46%; 95% CI, –1.07% to 0.16%).
Dr. den Heijer also discussed the long-term effects of hormone therapy on BMD in the Amsterdam Cohort of Dysphoria (ACOG) study, which consisted of 711 transwomen and 543 transmen and followed some patients out to 2 years, 5 years, and 10 years after beginning hormone therapy (J Sex Med. 2018;15[4]:582-90). Among transwomen, the median age was 33 years, 68.9% had begun hormone therapy, and 75.3% received a gonadectomy; among transmen, the median age was 25 years, 72.9% had begun hormone therapy, and 83.8% received a gonadectomy. Of these patients, dual-energy x-ray absorptiometry data were available for the lumbar spine BMD for 234 transwomen and 236 transmen at 2 years, 174 transwomen and 95 transmen at 5 years, and 102 transwomen and 70 transmen at 10 years.
Although there was no significant mean change in absolute BMD over the 10-year period, the concentration of estradiol in transwomen and transmen affected change in BMD the longer the transperson was receiving hormone therapy: Transwomen who received an estradiol concentration of 118 pmol/L had a decrease of –0.026% at 2 years, –0.044% at 5 years, and –0.009% at 10 years, compared with a dose of 443 pmol/L (+0.044% at 2 years, +0.025% at 5 years, +0.063% at 10 years), whereas transmen also had decreased BMD at the lowest estradiol concentrations of 95 pmol/L (–0.007% at 2 years, –0.024% at 5 years, +0.010% at 10 years), compared with transmen receiving the highest doses of 323 pmol/L (+0.028% at 2 years, +0.002% at 5 years, +0.053% at 10 years). There was no significant change in BMD in either group at any time point with regard to testosterone concentration.
When the investigators linked these patients to a national statistics database in the Netherlands to evaluate fracture incidence (J Bone Miner Res. 2019 Sep 5. doi: 10.1002/jbmr.3862), pairing five cisgender female controls and five cisgender male controls to every transgender patient, the researchers found transwomen had a higher incidence of osteoporotic fracture of the hip, spine, forearm, and humerus (41.8%), compared with cisgender men (26.6%; P = .014) and cisgender women (36.0%; P = .381). There was not enough information in the study to examine fracture information for transmen, Dr. den Heijer said. Transwomen and transmen who experienced a fracture were more likely to be a current smoker and have lower estradiol concentrations than were transwomen and transmen, respectively, who did not have a fracture.
“Attention for lifestyle factors remains important, especially smoking cessation, vitamin D intake, and regular exercise,” Dr. den Heijer said. “It remains important for everybody, but especially for transgender women.”
Dr. den Heijer reported no relevant conflicts of interest.
ORLANDO – according to a presentation at the annual meeting of the American Society for Bone and Mineral Research.
“Hormonal treatment of transgender people is safe with respect to bone,” said Martin den Heijer, MD, PhD, of the VU University Medical Center in Amsterdam.
At baseline, transwomen have lower bone mass than do male reference populations, said Dr. den Heijer, citing a study that found 25 transwomen had less muscle mass (P less than or equal to .001), strength (P less than or equal to .05), and lower BMD at the hip, femoral neck, and spine (P less than .001), compared with 25 cisgender men in a control group and 941 men in a male reference population (Bone. 2013;54[1]:92-7). In a 2019 study from his own group, Dr. den Heijer said the z score in the lumbar spine for 711 transwomen was -0.9 and the incidence of osteoporosis was 14.2%, compared with a z score of 0.0 and 2.4% incidence of osteoporosis in 543 transmen (J Bone Min Res. 2019;34[3]:447-54).
In the prospective European Network for the Investigation of Gender Incongruence (ENIGI) study, researchers examined short-term effects of hormone therapy on BMD in 144 transwomen and 162 transmen who had a normal body mass index and were mostly white. The percentage of patients who reported they were current smokers was between 25% and 30%, and fewer than 10% said they consumed more than seven units of alcohol per week. Transwomen received estradiol (an oral estradiol valerate at a dose of 4 mg/day or an estradiol patch) together with 100 mg/day of cyproterone acetate, and transmen received testosterone in the form of a gel (50 mg/day), intramuscular esters (250 mg every 2-3 weeks), or intramuscular undecanoate at a dose of 1,000 mg every 12 weeks (J Sex Med. 2016;13[6]:994-9).
After 1 year of treatment, there were significant increases in BMD in transwomen in the lumbar spine (3.67%; 95% confidence interval, 3.20%-4.13%), femoral neck (1.86%; 95% CI, 1.41%-2.31%), and total hip (0.97%; 95% CI, 0.62%-1.31%). Transmen also had increased BMD in the lumbar spine (0.86%; 95% CI, 0.38%-1.35%) and total hip (1.04%; 95% CI, 0.64%-1.44%), with a slight decrease in femoral neck BMD (–0.46%; 95% CI, –1.07% to 0.16%).
Dr. den Heijer also discussed the long-term effects of hormone therapy on BMD in the Amsterdam Cohort of Dysphoria (ACOG) study, which consisted of 711 transwomen and 543 transmen and followed some patients out to 2 years, 5 years, and 10 years after beginning hormone therapy (J Sex Med. 2018;15[4]:582-90). Among transwomen, the median age was 33 years, 68.9% had begun hormone therapy, and 75.3% received a gonadectomy; among transmen, the median age was 25 years, 72.9% had begun hormone therapy, and 83.8% received a gonadectomy. Of these patients, dual-energy x-ray absorptiometry data were available for the lumbar spine BMD for 234 transwomen and 236 transmen at 2 years, 174 transwomen and 95 transmen at 5 years, and 102 transwomen and 70 transmen at 10 years.
Although there was no significant mean change in absolute BMD over the 10-year period, the concentration of estradiol in transwomen and transmen affected change in BMD the longer the transperson was receiving hormone therapy: Transwomen who received an estradiol concentration of 118 pmol/L had a decrease of –0.026% at 2 years, –0.044% at 5 years, and –0.009% at 10 years, compared with a dose of 443 pmol/L (+0.044% at 2 years, +0.025% at 5 years, +0.063% at 10 years), whereas transmen also had decreased BMD at the lowest estradiol concentrations of 95 pmol/L (–0.007% at 2 years, –0.024% at 5 years, +0.010% at 10 years), compared with transmen receiving the highest doses of 323 pmol/L (+0.028% at 2 years, +0.002% at 5 years, +0.053% at 10 years). There was no significant change in BMD in either group at any time point with regard to testosterone concentration.
When the investigators linked these patients to a national statistics database in the Netherlands to evaluate fracture incidence (J Bone Miner Res. 2019 Sep 5. doi: 10.1002/jbmr.3862), pairing five cisgender female controls and five cisgender male controls to every transgender patient, the researchers found transwomen had a higher incidence of osteoporotic fracture of the hip, spine, forearm, and humerus (41.8%), compared with cisgender men (26.6%; P = .014) and cisgender women (36.0%; P = .381). There was not enough information in the study to examine fracture information for transmen, Dr. den Heijer said. Transwomen and transmen who experienced a fracture were more likely to be a current smoker and have lower estradiol concentrations than were transwomen and transmen, respectively, who did not have a fracture.
“Attention for lifestyle factors remains important, especially smoking cessation, vitamin D intake, and regular exercise,” Dr. den Heijer said. “It remains important for everybody, but especially for transgender women.”
Dr. den Heijer reported no relevant conflicts of interest.
EXPERT ANALYSIS FROM ASBMR 2019
Juvenile dermatomyositis derails growth and pubertal development
Children with juvenile dermatomyositis showed significant growth failure and pubertal delay, based on data from a longitudinal cohort study.
“Both the inflammatory activity of this severe chronic rheumatic disease and the well-known side effects of corticosteroid treatment may interfere with normal growth and pubertal development of children,” wrote Ellen Nordal, MD, of the University Hospital of Northern Norway, Tromsø, and colleagues.
The goal in treating juvenile dermatomyositis (JDM) is to achieve inactive disease and prevent permanent damage, but long-term data on growth and puberty in JDM patients are limited, they wrote.
In a study published in Arthritis Care & Research, the investigators reviewed data from 196 children and followed them for 2 years. The patients were part of the Paediatric Rheumatology International Trials Organisation (PRINTO) observational cohort study.
Overall, the researchers identified growth failure, height deflection, and/or delayed puberty in 94 children (48%) at the last study visit.
Growth failure was present at baseline in 17% of girls and 10% of boys. Over the 2-year study period, height deflection increased to 25% of girls and 31% of boys, but this change was not significant. Height deflection was defined as a change in the height z score of less than –0.25 per year from baseline. However, body mass index increased significantly from baseline during the study.
Catch-up growth had occurred by the final study visit in some patients, based on parent-adjusted z scores over time. Girls with a disease duration of 12 months or more showed no catch-up growth at 2 years and had significantly lower parent-adjusted height z scores.
In addition, the researchers observed a delay in the onset of puberty (including pubertal tempo and menarche) in approximately 36% of both boys and girls. However, neither growth failure nor height deflection was significantly associated with delayed puberty in either sex.
“In follow-up, clinicians should therefore be aware of both the pubertal development and the growth of the child, assess the milestones of development, and ensure that the children reach as much as possible of their genetic potential,” the researchers wrote.
The study participants were younger than 18 years at study enrollment, and all were in an active disease phase, defined as needing to start or receive a major dose increase of corticosteroids and/or immunosuppressants. Patients were assessed at baseline, at 6 months and/or at 12 months, and during a final visit at approximately 26 months. During the study, approximately half of the participants (50.5%) received methotrexate, 30 (15.3%) received cyclosporine A, 10 (5.1%) received cyclophosphamide, and 27 (13.8%) received intravenous immunoglobulin.
The study findings were limited by several factors, including the short follow-up period for assessing pubertal development and the inability to analyze any impact of corticosteroid use prior to the study, the researchers noted. However, “the overall frequency of growth failure was not significantly higher at the final study visit 2 years after baseline, indicating that the very high doses of corticosteroid treatment given during the study period is reasonably well tolerated with regards to growth,” they wrote. But monitoring remains essential, especially for children with previous growth failure or with disease onset early in pubertal development.
The study was supported by the European Union, Helse Nord Research grants, and by IRCCS Istituto Giannina Gaslini. Five authors of the study reported financial relationships with pharmaceutical companies.
SOURCE: Nordal E et al. Arthritis Care Res. 2019 Sep 10. doi: 10.1002/acr.24065.
Children with juvenile dermatomyositis showed significant growth failure and pubertal delay, based on data from a longitudinal cohort study.
“Both the inflammatory activity of this severe chronic rheumatic disease and the well-known side effects of corticosteroid treatment may interfere with normal growth and pubertal development of children,” wrote Ellen Nordal, MD, of the University Hospital of Northern Norway, Tromsø, and colleagues.
The goal in treating juvenile dermatomyositis (JDM) is to achieve inactive disease and prevent permanent damage, but long-term data on growth and puberty in JDM patients are limited, they wrote.
In a study published in Arthritis Care & Research, the investigators reviewed data from 196 children and followed them for 2 years. The patients were part of the Paediatric Rheumatology International Trials Organisation (PRINTO) observational cohort study.
Overall, the researchers identified growth failure, height deflection, and/or delayed puberty in 94 children (48%) at the last study visit.
Growth failure was present at baseline in 17% of girls and 10% of boys. Over the 2-year study period, height deflection increased to 25% of girls and 31% of boys, but this change was not significant. Height deflection was defined as a change in the height z score of less than –0.25 per year from baseline. However, body mass index increased significantly from baseline during the study.
Catch-up growth had occurred by the final study visit in some patients, based on parent-adjusted z scores over time. Girls with a disease duration of 12 months or more showed no catch-up growth at 2 years and had significantly lower parent-adjusted height z scores.
In addition, the researchers observed a delay in the onset of puberty (including pubertal tempo and menarche) in approximately 36% of both boys and girls. However, neither growth failure nor height deflection was significantly associated with delayed puberty in either sex.
“In follow-up, clinicians should therefore be aware of both the pubertal development and the growth of the child, assess the milestones of development, and ensure that the children reach as much as possible of their genetic potential,” the researchers wrote.
The study participants were younger than 18 years at study enrollment, and all were in an active disease phase, defined as needing to start or receive a major dose increase of corticosteroids and/or immunosuppressants. Patients were assessed at baseline, at 6 months and/or at 12 months, and during a final visit at approximately 26 months. During the study, approximately half of the participants (50.5%) received methotrexate, 30 (15.3%) received cyclosporine A, 10 (5.1%) received cyclophosphamide, and 27 (13.8%) received intravenous immunoglobulin.
The study findings were limited by several factors, including the short follow-up period for assessing pubertal development and the inability to analyze any impact of corticosteroid use prior to the study, the researchers noted. However, “the overall frequency of growth failure was not significantly higher at the final study visit 2 years after baseline, indicating that the very high doses of corticosteroid treatment given during the study period is reasonably well tolerated with regards to growth,” they wrote. But monitoring remains essential, especially for children with previous growth failure or with disease onset early in pubertal development.
The study was supported by the European Union, Helse Nord Research grants, and by IRCCS Istituto Giannina Gaslini. Five authors of the study reported financial relationships with pharmaceutical companies.
SOURCE: Nordal E et al. Arthritis Care Res. 2019 Sep 10. doi: 10.1002/acr.24065.
Children with juvenile dermatomyositis showed significant growth failure and pubertal delay, based on data from a longitudinal cohort study.
“Both the inflammatory activity of this severe chronic rheumatic disease and the well-known side effects of corticosteroid treatment may interfere with normal growth and pubertal development of children,” wrote Ellen Nordal, MD, of the University Hospital of Northern Norway, Tromsø, and colleagues.
The goal in treating juvenile dermatomyositis (JDM) is to achieve inactive disease and prevent permanent damage, but long-term data on growth and puberty in JDM patients are limited, they wrote.
In a study published in Arthritis Care & Research, the investigators reviewed data from 196 children and followed them for 2 years. The patients were part of the Paediatric Rheumatology International Trials Organisation (PRINTO) observational cohort study.
Overall, the researchers identified growth failure, height deflection, and/or delayed puberty in 94 children (48%) at the last study visit.
Growth failure was present at baseline in 17% of girls and 10% of boys. Over the 2-year study period, height deflection increased to 25% of girls and 31% of boys, but this change was not significant. Height deflection was defined as a change in the height z score of less than –0.25 per year from baseline. However, body mass index increased significantly from baseline during the study.
Catch-up growth had occurred by the final study visit in some patients, based on parent-adjusted z scores over time. Girls with a disease duration of 12 months or more showed no catch-up growth at 2 years and had significantly lower parent-adjusted height z scores.
In addition, the researchers observed a delay in the onset of puberty (including pubertal tempo and menarche) in approximately 36% of both boys and girls. However, neither growth failure nor height deflection was significantly associated with delayed puberty in either sex.
“In follow-up, clinicians should therefore be aware of both the pubertal development and the growth of the child, assess the milestones of development, and ensure that the children reach as much as possible of their genetic potential,” the researchers wrote.
The study participants were younger than 18 years at study enrollment, and all were in an active disease phase, defined as needing to start or receive a major dose increase of corticosteroids and/or immunosuppressants. Patients were assessed at baseline, at 6 months and/or at 12 months, and during a final visit at approximately 26 months. During the study, approximately half of the participants (50.5%) received methotrexate, 30 (15.3%) received cyclosporine A, 10 (5.1%) received cyclophosphamide, and 27 (13.8%) received intravenous immunoglobulin.
The study findings were limited by several factors, including the short follow-up period for assessing pubertal development and the inability to analyze any impact of corticosteroid use prior to the study, the researchers noted. However, “the overall frequency of growth failure was not significantly higher at the final study visit 2 years after baseline, indicating that the very high doses of corticosteroid treatment given during the study period is reasonably well tolerated with regards to growth,” they wrote. But monitoring remains essential, especially for children with previous growth failure or with disease onset early in pubertal development.
The study was supported by the European Union, Helse Nord Research grants, and by IRCCS Istituto Giannina Gaslini. Five authors of the study reported financial relationships with pharmaceutical companies.
SOURCE: Nordal E et al. Arthritis Care Res. 2019 Sep 10. doi: 10.1002/acr.24065.
FROM ARTHRITIS CARE & RESEARCH
MSK Clinic: Evaluating shoulder pain using IPASS
