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HLA gene variant predicts anti-TNF antibodies in Crohn’s
MAUI, HAWAII – A variant in the human leukocyte antigen gene – DQA1*05 – almost doubled the risk of antibodies forming against tumor necrosis factor (TNF) inhibitors in Crohn’s disease patients, irrespective of concomitant immunomodulator use, according to a report in Gastroenterology.
“Pretreatment genetic testing for HLA-DQA1*05 may help personalize the choice of anti-TNF and the need for combination therapy,” concluded investigators led by Aleksejs Sazonovs, of the Wellcome Sanger Institute in Hinxton, England.
The same variant increases the risk of celiac disease, and it is included in commercial celiac genotyping assays. The allele is carried by about 40% of Europeans.
“This is turning into a hot topic; people are talking about it, [and it’s] blowing up on Twitter,” said Edward Loftus, MD, a professor and consultant in the division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn. “It turns out this is really a significant predictor of immunogenicity. Whatever your risk of developing antibodies, it’s going to double if you have this HLA marker, and it’s common.
“I think we are going to start [stratifying] our decision on combination [or] monotherapy based on this,” added Dr. Loftus, speaking at the Gastroenterology Updates, IBD, Liver Disease Conference. “I would argue that, if your patient has this marker, it would be criminal to give that patient infliximab monotherapy.”
The finding also begs the question of whether to bypass anti-TNFs altogether if a patient has the marker, Dr. Loftus noted, and just use ustekinumab, vedolizumab, or another agent.
Checking for celiac disease in inflammatory bowel disease isn’t unusual and involves the same gene variant, he added, so payer coverage shouldn’t be much of a problem.
The investigators ran a genome-wide association study on 1,418 biologic-naive Crohn’s patients starting infliximab or adalimumab therapy. Patients were in their 30s, on average, with a disease duration of about 3 years; there were about equal numbers of men and women.
A total of 44% of patients developed antidrug antibodies within a year. Overall, the rate of immunogenicity – defined as an antidrug antibody titer of at least 10 AU/mL – was nearly doubled in HLA-DQA1*05 carriers (hazard ratio, 1.90; 95% confidence interval, 1.60-2.25).
The association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33) and for patients treated with anti-TNF therapy alone (HR, 1.75; 95% CI, 1.37-2.22) or in combination with an immunomodulator, usually azathioprine (HR, 2.01; 95% CI, 1.57-2.58).
The highest rates of immunogenicity, 92% at 1 year, were in HLA-DQA1*05 carriers on infliximab monotherapy. The lowest rates, 10% at 1 year, were in adalimumab patients on combination therapy who didn’t carry the variant. HLA-DQA1*05 was also associated with lower drug persistence rates.
The specific alleles HLA-DQA1*05:01 and HLA-DQA1*05:05 mediated most of the risk.
The study authors advised that “all patients treated with an anti-TNF should be prescribed an immunomodulator to lower the risk of immunogenicity.” Among HLA-DQA1*05 carriers “in whom immunomodulators are contraindicated or not tolerated, clinicians might advise against the use of anti-TNF drugs, particularly infliximab.”
In contrast, “patients who do not carry HLA-DQA1*05 might be given the choice between adalimumab or infliximab combination therapy,” the investigators said. “Patients without the risk allele and a history of adverse drug reactions to thiopurines and/or methotrexate, or who are at high risk of opportunistic infections, might be spared the additional risks of combination therapy and treated with adalimumab monotherapy.”
The mechanism for the association is unknown, the authors said.
The work was funded by the British Society of Gastroenterology, AbbVie, Merck, Pfizer, and others. The authors disclosed numerous ties to those or other pharmaceutical companies. Two authors were employees of AbbVie, marketer of the branded adalimumab Humira.
SOURCE: Sazonovs A et al. Gastroenterology. 2020 Jan;158(1):189-99.
MAUI, HAWAII – A variant in the human leukocyte antigen gene – DQA1*05 – almost doubled the risk of antibodies forming against tumor necrosis factor (TNF) inhibitors in Crohn’s disease patients, irrespective of concomitant immunomodulator use, according to a report in Gastroenterology.
“Pretreatment genetic testing for HLA-DQA1*05 may help personalize the choice of anti-TNF and the need for combination therapy,” concluded investigators led by Aleksejs Sazonovs, of the Wellcome Sanger Institute in Hinxton, England.
The same variant increases the risk of celiac disease, and it is included in commercial celiac genotyping assays. The allele is carried by about 40% of Europeans.
“This is turning into a hot topic; people are talking about it, [and it’s] blowing up on Twitter,” said Edward Loftus, MD, a professor and consultant in the division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn. “It turns out this is really a significant predictor of immunogenicity. Whatever your risk of developing antibodies, it’s going to double if you have this HLA marker, and it’s common.
“I think we are going to start [stratifying] our decision on combination [or] monotherapy based on this,” added Dr. Loftus, speaking at the Gastroenterology Updates, IBD, Liver Disease Conference. “I would argue that, if your patient has this marker, it would be criminal to give that patient infliximab monotherapy.”
The finding also begs the question of whether to bypass anti-TNFs altogether if a patient has the marker, Dr. Loftus noted, and just use ustekinumab, vedolizumab, or another agent.
Checking for celiac disease in inflammatory bowel disease isn’t unusual and involves the same gene variant, he added, so payer coverage shouldn’t be much of a problem.
The investigators ran a genome-wide association study on 1,418 biologic-naive Crohn’s patients starting infliximab or adalimumab therapy. Patients were in their 30s, on average, with a disease duration of about 3 years; there were about equal numbers of men and women.
A total of 44% of patients developed antidrug antibodies within a year. Overall, the rate of immunogenicity – defined as an antidrug antibody titer of at least 10 AU/mL – was nearly doubled in HLA-DQA1*05 carriers (hazard ratio, 1.90; 95% confidence interval, 1.60-2.25).
The association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33) and for patients treated with anti-TNF therapy alone (HR, 1.75; 95% CI, 1.37-2.22) or in combination with an immunomodulator, usually azathioprine (HR, 2.01; 95% CI, 1.57-2.58).
The highest rates of immunogenicity, 92% at 1 year, were in HLA-DQA1*05 carriers on infliximab monotherapy. The lowest rates, 10% at 1 year, were in adalimumab patients on combination therapy who didn’t carry the variant. HLA-DQA1*05 was also associated with lower drug persistence rates.
The specific alleles HLA-DQA1*05:01 and HLA-DQA1*05:05 mediated most of the risk.
The study authors advised that “all patients treated with an anti-TNF should be prescribed an immunomodulator to lower the risk of immunogenicity.” Among HLA-DQA1*05 carriers “in whom immunomodulators are contraindicated or not tolerated, clinicians might advise against the use of anti-TNF drugs, particularly infliximab.”
In contrast, “patients who do not carry HLA-DQA1*05 might be given the choice between adalimumab or infliximab combination therapy,” the investigators said. “Patients without the risk allele and a history of adverse drug reactions to thiopurines and/or methotrexate, or who are at high risk of opportunistic infections, might be spared the additional risks of combination therapy and treated with adalimumab monotherapy.”
The mechanism for the association is unknown, the authors said.
The work was funded by the British Society of Gastroenterology, AbbVie, Merck, Pfizer, and others. The authors disclosed numerous ties to those or other pharmaceutical companies. Two authors were employees of AbbVie, marketer of the branded adalimumab Humira.
SOURCE: Sazonovs A et al. Gastroenterology. 2020 Jan;158(1):189-99.
MAUI, HAWAII – A variant in the human leukocyte antigen gene – DQA1*05 – almost doubled the risk of antibodies forming against tumor necrosis factor (TNF) inhibitors in Crohn’s disease patients, irrespective of concomitant immunomodulator use, according to a report in Gastroenterology.
“Pretreatment genetic testing for HLA-DQA1*05 may help personalize the choice of anti-TNF and the need for combination therapy,” concluded investigators led by Aleksejs Sazonovs, of the Wellcome Sanger Institute in Hinxton, England.
The same variant increases the risk of celiac disease, and it is included in commercial celiac genotyping assays. The allele is carried by about 40% of Europeans.
“This is turning into a hot topic; people are talking about it, [and it’s] blowing up on Twitter,” said Edward Loftus, MD, a professor and consultant in the division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn. “It turns out this is really a significant predictor of immunogenicity. Whatever your risk of developing antibodies, it’s going to double if you have this HLA marker, and it’s common.
“I think we are going to start [stratifying] our decision on combination [or] monotherapy based on this,” added Dr. Loftus, speaking at the Gastroenterology Updates, IBD, Liver Disease Conference. “I would argue that, if your patient has this marker, it would be criminal to give that patient infliximab monotherapy.”
The finding also begs the question of whether to bypass anti-TNFs altogether if a patient has the marker, Dr. Loftus noted, and just use ustekinumab, vedolizumab, or another agent.
Checking for celiac disease in inflammatory bowel disease isn’t unusual and involves the same gene variant, he added, so payer coverage shouldn’t be much of a problem.
The investigators ran a genome-wide association study on 1,418 biologic-naive Crohn’s patients starting infliximab or adalimumab therapy. Patients were in their 30s, on average, with a disease duration of about 3 years; there were about equal numbers of men and women.
A total of 44% of patients developed antidrug antibodies within a year. Overall, the rate of immunogenicity – defined as an antidrug antibody titer of at least 10 AU/mL – was nearly doubled in HLA-DQA1*05 carriers (hazard ratio, 1.90; 95% confidence interval, 1.60-2.25).
The association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33) and for patients treated with anti-TNF therapy alone (HR, 1.75; 95% CI, 1.37-2.22) or in combination with an immunomodulator, usually azathioprine (HR, 2.01; 95% CI, 1.57-2.58).
The highest rates of immunogenicity, 92% at 1 year, were in HLA-DQA1*05 carriers on infliximab monotherapy. The lowest rates, 10% at 1 year, were in adalimumab patients on combination therapy who didn’t carry the variant. HLA-DQA1*05 was also associated with lower drug persistence rates.
The specific alleles HLA-DQA1*05:01 and HLA-DQA1*05:05 mediated most of the risk.
The study authors advised that “all patients treated with an anti-TNF should be prescribed an immunomodulator to lower the risk of immunogenicity.” Among HLA-DQA1*05 carriers “in whom immunomodulators are contraindicated or not tolerated, clinicians might advise against the use of anti-TNF drugs, particularly infliximab.”
In contrast, “patients who do not carry HLA-DQA1*05 might be given the choice between adalimumab or infliximab combination therapy,” the investigators said. “Patients without the risk allele and a history of adverse drug reactions to thiopurines and/or methotrexate, or who are at high risk of opportunistic infections, might be spared the additional risks of combination therapy and treated with adalimumab monotherapy.”
The mechanism for the association is unknown, the authors said.
The work was funded by the British Society of Gastroenterology, AbbVie, Merck, Pfizer, and others. The authors disclosed numerous ties to those or other pharmaceutical companies. Two authors were employees of AbbVie, marketer of the branded adalimumab Humira.
SOURCE: Sazonovs A et al. Gastroenterology. 2020 Jan;158(1):189-99.
REPORTING FROM GUILD 2020
Glucocorticoid use linked to mortality in RA with diabetes
Glucocorticoid use is associated with greater mortality and cardiovascular risk in RA patients, and the associated risk is greater still in patients with RA and comorbid diabetes. The findings come from a new retrospective analysis derived from U.K. primary care records.
Although patients with diabetes actually had a lower relative risk for mortality than the nondiabetes cohort, they had a greater mortality difference because of a greater baseline risk. Ultimately, glucocorticoid (GC) use was associated with an additional 44.9 deaths per 1,000 person-years in the diabetes group, compared with 34.4 per 1,000 person-years in the RA-only group.
The study, led by Ruth Costello and William Dixon, MBBS, PhD of the University of Manchester (England), was published in BMC Rheumatology.
The findings aren’t particularly surprising, given that steroid use and diabetes have associated cardiovascular risks, and physicians generally try to reduce or eliminate their use. “There’s a group [of physicians] saying that we don’t need to use steroids at all in rheumatoid arthritis, except maybe for [a] short time at diagnosis to bridge to other therapies, or during flares,” Gordon Starkebaum, MD, professor emeritus of rheumatology at the University of Washington, Seattle, said in an interview. He recounted a session at last year’s annual meeting of the American College of Rheumatology that advocated for only injectable steroid use during flare-ups. “That was provocative,” Dr. Starkebaum said.
“It’s a retrospective study, so it has some limitations, but it provides good insight, and some substantiation to what we already think,” added Brett Smith, DO, a rheumatologist practicing in Knoxville, Tenn.
Dr. Smith suggested that the study further underscores the need to follow treat-to-target protocols in RA. He emphasized that lifetime exposure to steroids is likely the greatest concern, and that steady accumulating doses are a sign of trouble. “If you need that much steroids, you need to go up on your medication – your methotrexate, or sulfasalazine, or your biologic,” said Dr. Smith. “At least 50% of people will need a biologic to [achieve] disease control, and if you get them on it, they’re going to have better disease control, compliance is typically better, and they’re going to have less steroid exposure.”
Dr. Smith also noted that comorbid diabetes shouldn’t affect treat-to-target strategies. In fact, in such patients “you should probably be following it more tightly to reduce the cardiovascular outcomes,” he said.
The retrospective analysis included 9,085 patients with RA and with or without type 2 diabetes, with a mean follow-up of 5.2 years. They were recruited to the study between 1998 and 2011. Among patients with comorbid diabetes, those exposed to GC had a mortality of 67.4 per 1,000 person-years, compared with 22.5 among those not exposed to GC. Among those with RA alone, mortality was 44.6 versus 10.2 with and without GC exposure, respectively. Those with diabetes had a lower risk ratio for mortality (2.99 vs. 4.37), but a higher mortality difference (44.9 vs. 34.4 per 1,000 person-years).
“The increased absolute hazard for all-cause mortality indicates the greater public health impact of people with RA using GCs if they have [diabetes],” the researchers wrote. “Rheumatologists should consider [diabetes] status when prescribing GCs to patients with RA given this potential impact of GC therapy on glucose control and mortality.”
The study was limited by a lack of information on GC dose and cumulative exposure. Given its retrospective nature, the study could have been affected by confounding by indication, as well as unknown confounders.
The study was funded by the Centre for Epidemiology Versus Arthritis and the National Institute for Health Research Biomedical Research Centre. Dr. Starkebaum has no relevant financial disclosures. Dr. Smith is on the speaker’s bureau for AbbVie and serves on the company’s advisory board. He is also on the advisory boards of Regeneron and Sanofi Genzyme.
SOURCE: Costello R et al. BMC Rheumatol. 2020 Feb 19. doi: 10.1186/s41927-019-0105-4.
Glucocorticoid use is associated with greater mortality and cardiovascular risk in RA patients, and the associated risk is greater still in patients with RA and comorbid diabetes. The findings come from a new retrospective analysis derived from U.K. primary care records.
Although patients with diabetes actually had a lower relative risk for mortality than the nondiabetes cohort, they had a greater mortality difference because of a greater baseline risk. Ultimately, glucocorticoid (GC) use was associated with an additional 44.9 deaths per 1,000 person-years in the diabetes group, compared with 34.4 per 1,000 person-years in the RA-only group.
The study, led by Ruth Costello and William Dixon, MBBS, PhD of the University of Manchester (England), was published in BMC Rheumatology.
The findings aren’t particularly surprising, given that steroid use and diabetes have associated cardiovascular risks, and physicians generally try to reduce or eliminate their use. “There’s a group [of physicians] saying that we don’t need to use steroids at all in rheumatoid arthritis, except maybe for [a] short time at diagnosis to bridge to other therapies, or during flares,” Gordon Starkebaum, MD, professor emeritus of rheumatology at the University of Washington, Seattle, said in an interview. He recounted a session at last year’s annual meeting of the American College of Rheumatology that advocated for only injectable steroid use during flare-ups. “That was provocative,” Dr. Starkebaum said.
“It’s a retrospective study, so it has some limitations, but it provides good insight, and some substantiation to what we already think,” added Brett Smith, DO, a rheumatologist practicing in Knoxville, Tenn.
Dr. Smith suggested that the study further underscores the need to follow treat-to-target protocols in RA. He emphasized that lifetime exposure to steroids is likely the greatest concern, and that steady accumulating doses are a sign of trouble. “If you need that much steroids, you need to go up on your medication – your methotrexate, or sulfasalazine, or your biologic,” said Dr. Smith. “At least 50% of people will need a biologic to [achieve] disease control, and if you get them on it, they’re going to have better disease control, compliance is typically better, and they’re going to have less steroid exposure.”
Dr. Smith also noted that comorbid diabetes shouldn’t affect treat-to-target strategies. In fact, in such patients “you should probably be following it more tightly to reduce the cardiovascular outcomes,” he said.
The retrospective analysis included 9,085 patients with RA and with or without type 2 diabetes, with a mean follow-up of 5.2 years. They were recruited to the study between 1998 and 2011. Among patients with comorbid diabetes, those exposed to GC had a mortality of 67.4 per 1,000 person-years, compared with 22.5 among those not exposed to GC. Among those with RA alone, mortality was 44.6 versus 10.2 with and without GC exposure, respectively. Those with diabetes had a lower risk ratio for mortality (2.99 vs. 4.37), but a higher mortality difference (44.9 vs. 34.4 per 1,000 person-years).
“The increased absolute hazard for all-cause mortality indicates the greater public health impact of people with RA using GCs if they have [diabetes],” the researchers wrote. “Rheumatologists should consider [diabetes] status when prescribing GCs to patients with RA given this potential impact of GC therapy on glucose control and mortality.”
The study was limited by a lack of information on GC dose and cumulative exposure. Given its retrospective nature, the study could have been affected by confounding by indication, as well as unknown confounders.
The study was funded by the Centre for Epidemiology Versus Arthritis and the National Institute for Health Research Biomedical Research Centre. Dr. Starkebaum has no relevant financial disclosures. Dr. Smith is on the speaker’s bureau for AbbVie and serves on the company’s advisory board. He is also on the advisory boards of Regeneron and Sanofi Genzyme.
SOURCE: Costello R et al. BMC Rheumatol. 2020 Feb 19. doi: 10.1186/s41927-019-0105-4.
Glucocorticoid use is associated with greater mortality and cardiovascular risk in RA patients, and the associated risk is greater still in patients with RA and comorbid diabetes. The findings come from a new retrospective analysis derived from U.K. primary care records.
Although patients with diabetes actually had a lower relative risk for mortality than the nondiabetes cohort, they had a greater mortality difference because of a greater baseline risk. Ultimately, glucocorticoid (GC) use was associated with an additional 44.9 deaths per 1,000 person-years in the diabetes group, compared with 34.4 per 1,000 person-years in the RA-only group.
The study, led by Ruth Costello and William Dixon, MBBS, PhD of the University of Manchester (England), was published in BMC Rheumatology.
The findings aren’t particularly surprising, given that steroid use and diabetes have associated cardiovascular risks, and physicians generally try to reduce or eliminate their use. “There’s a group [of physicians] saying that we don’t need to use steroids at all in rheumatoid arthritis, except maybe for [a] short time at diagnosis to bridge to other therapies, or during flares,” Gordon Starkebaum, MD, professor emeritus of rheumatology at the University of Washington, Seattle, said in an interview. He recounted a session at last year’s annual meeting of the American College of Rheumatology that advocated for only injectable steroid use during flare-ups. “That was provocative,” Dr. Starkebaum said.
“It’s a retrospective study, so it has some limitations, but it provides good insight, and some substantiation to what we already think,” added Brett Smith, DO, a rheumatologist practicing in Knoxville, Tenn.
Dr. Smith suggested that the study further underscores the need to follow treat-to-target protocols in RA. He emphasized that lifetime exposure to steroids is likely the greatest concern, and that steady accumulating doses are a sign of trouble. “If you need that much steroids, you need to go up on your medication – your methotrexate, or sulfasalazine, or your biologic,” said Dr. Smith. “At least 50% of people will need a biologic to [achieve] disease control, and if you get them on it, they’re going to have better disease control, compliance is typically better, and they’re going to have less steroid exposure.”
Dr. Smith also noted that comorbid diabetes shouldn’t affect treat-to-target strategies. In fact, in such patients “you should probably be following it more tightly to reduce the cardiovascular outcomes,” he said.
The retrospective analysis included 9,085 patients with RA and with or without type 2 diabetes, with a mean follow-up of 5.2 years. They were recruited to the study between 1998 and 2011. Among patients with comorbid diabetes, those exposed to GC had a mortality of 67.4 per 1,000 person-years, compared with 22.5 among those not exposed to GC. Among those with RA alone, mortality was 44.6 versus 10.2 with and without GC exposure, respectively. Those with diabetes had a lower risk ratio for mortality (2.99 vs. 4.37), but a higher mortality difference (44.9 vs. 34.4 per 1,000 person-years).
“The increased absolute hazard for all-cause mortality indicates the greater public health impact of people with RA using GCs if they have [diabetes],” the researchers wrote. “Rheumatologists should consider [diabetes] status when prescribing GCs to patients with RA given this potential impact of GC therapy on glucose control and mortality.”
The study was limited by a lack of information on GC dose and cumulative exposure. Given its retrospective nature, the study could have been affected by confounding by indication, as well as unknown confounders.
The study was funded by the Centre for Epidemiology Versus Arthritis and the National Institute for Health Research Biomedical Research Centre. Dr. Starkebaum has no relevant financial disclosures. Dr. Smith is on the speaker’s bureau for AbbVie and serves on the company’s advisory board. He is also on the advisory boards of Regeneron and Sanofi Genzyme.
SOURCE: Costello R et al. BMC Rheumatol. 2020 Feb 19. doi: 10.1186/s41927-019-0105-4.
REPORTING FROM BMC RHEUMATOLOGY
New guideline offers recommendations for reproductive health in patients with rheumatic diseases
A new guideline from the American College of Rheumatology offers the organization’s first clinical recommendations on how to manage reproductive health issues in patients with rheumatic and musculoskeletal diseases (RMDs).
“With the development of this guideline, the ACR recognizes the key role of clinical rheumatologists not only in managing disease activity but also in understanding the interactions of RMDs and their therapies in the context of reproductive health,” wrote Lisa R. Sammaritano, MD, of Weill Cornell Medicine and the Hospital for Special Surgery in New York, and coauthors. The guideline was published in Arthritis & Rheumatology.
To develop an evidence-based guideline on reproductive health in RMD patients, the researchers embarked on a systematic review of studies in areas like contraception, pregnancy and lactation, assisted reproductive technology (ART), fertility preservation, and hormone therapy. The guideline contains 12 ungraded good practice statements and 131 graded recommendations, all developed through the Grading of Recommendations Assessment, Development, and Evaluation methodology.
In counseling patients about these areas of care, the guideline says that rheumatologists and other clinicians “must collaborate with specialists in the fields of obstetrics-gynecology, maternal-fetal medicine, and reproductive endocrinology and infertility.”
“One thing this guideline does well is highlight the importance of involving maternal-fetal medicine colleagues,” Alison Cahill, MD, a professor in the department of women’s health at the University of Texas at Austin and a maternal-fetal medicine specialist within UT Health Austin’s Women’s Health Institute, said when asked for comment on the guideline. “We’re always very happy to see patients ahead of time who are planning pregnancy to be able to discuss what the care plan would look like. And specifically, to address medications, if required, for their rheumatologic care.
“As we learn more and more,” she added, “we’ve come to understand that most treatments and medications are actually safe or relatively safe to take in pregnancy. Certainly, the benefit of taking them outweighs any small or theoretic risks. On the flip side, the guideline does a nice job of highlighting the importance of good disease control, both at the time of conception and during pregnancy.”
Contraception
In regard to contraception, the guideline strongly recommends the use of effective contraceptives – with a conditional recommendation of IUDs or a subdermal progestin implant – in fertile women with a RMD who have neither systemic lupus erythematosus (SLE) nor positive antiphospholipid antibody (aPL). They also strongly recommend discussing the use of emergency contraception with all RMD patients.
For SLE patients, the guideline strongly recommends the use of effective contraceptives in those with stable or low disease activity who are not positive for aPL. They also strongly recommend progestin‐only or IUD contraceptives over combined estrogen‐progestin contraception. For aPL-positive patients, the guideline strongly recommends against combined estrogen‐progestin contraceptives and for levonorgestrel or copper IUDs or the progestin‐only pill.
Assisted reproductive technology
In regard to ART, the guideline strongly recommends proceeding as needed in aPL-negative women with uncomplicated, stable RMD who are on pregnancy‐compatible medications. They also strongly recommend deferring ART in any RMD patients with moderately or severely active disease.
For aPL-positive patients undergoing ART procedures, they strongly recommend prophylactic anticoagulation with heparin or low-molecular-weight heparin (LMWH) in women with obstetric antiphospholipid syndrome (APS) and therapeutic anticoagulation in women with thrombotic APS. In patients undergoing embryo and oocyte cryopreservation, they strongly recommend continuing immunosuppressive and biologic therapies – the exception being cyclophosphamide (CYC) – for anyone in stable condition.
Fertility preservation
In regard to fertility preservation in patients taking CYC, the guideline strongly suggests sperm cryopreservation as good practice prior to treatment. They also conditionally recommend monthly gonadotropin‐releasing hormone agonist cotherapy in premenopausal women with RMD.
Hormone therapy
In regard to menopause and hormone therapy, the guideline strongly suggests hormone therapy as good practice in postmenopausal women with RMD, without SLE or positive aPL, and who have severe vasomotor symptoms. Hormone therapy is conditionally recommended in patients with SLE, without positive aPL, and with no contraindications. For aPL-positive patients, they strongly recommend against hormone therapy in women with obstetric and/or thrombotic APS.
Pregnancy assessment and management
Among the many recommendations regarding pregnancy assessment and management, the guideline strongly suggests counseling women with RMD who are considering pregnancy to take into account the improved outcomes for pregnant women with low disease activity. They strongly recommend that women considering pregnancy should switch to pregnancy‐compatible medication and pause to assess its efficacy and tolerability before moving forward, along with strongly recommending that pregnant women with active disease initiate or continue a pregnancy‐compatible steroid‐sparing medication. They also recommend testing for anti‐Ro/SS-A and anti‐La/SS-B in women with SLE, Sjögren’s syndrome, systemic sclerosis, or rheumatoid arthritis, but only once and only before or early in the pregnancy.
For women with systemic sclerosis who develop scleroderma renal crisis during pregnancy, the authors strongly advise using ACE inhibitors or angiotensin receptor blockers “because the risk of maternal or fetal death with untreated disease is higher than the risk associated with use of these medications during pregnancy.”
Among women with SLE, the recommendations strongly call for testing either before or early in pregnancy for anticardiolipin antibody, anti–beta2-glycoprotein I, or positive lupus anticoagulant, as well as initiating or continuing hydroxychloroquine (HCQ) if possible. Starting in the first trimester, the authors also conditionally recommend that SLE patients take low-dose aspirin daily
For pregnant women who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the guideline conditionally recommends prophylactic treatment with low-dose aspirin daily to protect against preeclampsia. When obstetric APS criteria are met, the guideline strongly advises combined treatment with daily low-dose aspirin and prophylactic-dose heparin (or LMWH), as well as prophylactic-dose anticoagulation for 6-12 weeks post partum. When patients have thrombotic APS, this combination treatment should contain heparin dose at a therapeutic level throughout pregnancy and postpartum. However, the authors conditionally recommend against giving low-dose aspirin plus prophylactic-dose heparin to women without obstetric APS. For refractory obstetric APS, the guideline also contains recommendations that are conditionally against treatment with intravenous immunoglobulin or an increased LMWH dose and strongly against adding prednisone to prophylactic-dose heparin or LMWH and low-dose aspirin. In pregnant patients with primary APS, the authors conditionally advise adding HCQ to prophylactic-dose heparin or LMWH and low-dose aspirin therapy. However, women with aPL who do not meet APS criteria or have another indication for HCQ are conditionally advised against prophylactic treatment with the antimalarial.
For women with Anti-Ro/SS-A and/or anti-La/SS-B antibodies in pregnancy, there is conditional advice to use HCQ. When there is no history of an infant with complete heart block or neonatal lupus erythematosus among women with these antibodies, the guideline conditionally advises serial fetal echocardiography (less often than weekly) starting between 16 and 18 weeks and continuing through 26 weeks, but this should be weekly when there is a prior history. Treatment with oral dexamethasone 4 mg daily is conditionally advised when there is echocardiographic evidence of fetal first- or second-degree heart block, but dexamethasone is not recommended when complete heart block is present.
Finally, in regard to medication use, the authors strongly recommend that men who are planning to be fathers continue on HCQ, azathioprine, 6‐mercaptopurine, colchicine, or tumor necrosis factor inhibitors. Conditional treatment recommendations for men planning for pregnancy include methotrexate, mycophenolate mofetil/mycophenolic acid (MMF), leflunomide, sulfasalazine, calcineurin inhibitors, and NSAIDs. They also strongly recommend that this group of men discontinue CYC and thalidomide.
Pregnant women are strongly recommended to discontinue methotrexate, leflunomide (with cholestyramine washout if there are detectable serum levels of its metabolite prior to pregnancy or as soon as it is confirmed), MMF, CYC, and thalidomide within 3 months prior to conception, and they strongly recommend HCQ (in women with SLE), azathioprine/6‐mercaptopurine, colchicine, or sulfasalazine for use throughout pregnancy. They strongly recommend a combination of low‐dose aspirin and prophylactic‐dose heparin for pregnant women with obstetric APS, along with low‐dose aspirin and therapeutic‐dose heparin for women with thrombotic APS throughout pregnancy and postpartum. However, for women with SLE and those who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the authors conditionally recommend low-dose aspirin starting in the first trimester.
The guideline suggests that women with RMD should be encouraged to breastfeed if they are willing and able; they also suggest that disease control be maintained through lactation‐compatible medications and that the risks and benefits be reviewed on a patient-by-patient basis. Treatment with HCQ, colchicine, sulfasalazine, rituximab, and all tumor necrosis factor inhibitors are strongly recommended as being compatible with breastfeeding, and they strongly recommend against using CYC, leflunomide, MMF, and thalidomide while breastfeeding.
The authors acknowledged the limitations of their guideline, including the literature review being conducted on studies involving adults and an “inability to include recommendations for uncommon but important clinical situations,” including those involving transgender patients and hormonal therapies.
The authors reported numerous potential conflicts of interest, including receiving research support, consulting fees, speaking fees, and honoraria from various pharmaceutical companies.
SOURCE: Sammaritano LR et al. Arthritis Rheumatol. 2020 Feb 23. doi: 10.1002/art.41191.
A new guideline from the American College of Rheumatology offers the organization’s first clinical recommendations on how to manage reproductive health issues in patients with rheumatic and musculoskeletal diseases (RMDs).
“With the development of this guideline, the ACR recognizes the key role of clinical rheumatologists not only in managing disease activity but also in understanding the interactions of RMDs and their therapies in the context of reproductive health,” wrote Lisa R. Sammaritano, MD, of Weill Cornell Medicine and the Hospital for Special Surgery in New York, and coauthors. The guideline was published in Arthritis & Rheumatology.
To develop an evidence-based guideline on reproductive health in RMD patients, the researchers embarked on a systematic review of studies in areas like contraception, pregnancy and lactation, assisted reproductive technology (ART), fertility preservation, and hormone therapy. The guideline contains 12 ungraded good practice statements and 131 graded recommendations, all developed through the Grading of Recommendations Assessment, Development, and Evaluation methodology.
In counseling patients about these areas of care, the guideline says that rheumatologists and other clinicians “must collaborate with specialists in the fields of obstetrics-gynecology, maternal-fetal medicine, and reproductive endocrinology and infertility.”
“One thing this guideline does well is highlight the importance of involving maternal-fetal medicine colleagues,” Alison Cahill, MD, a professor in the department of women’s health at the University of Texas at Austin and a maternal-fetal medicine specialist within UT Health Austin’s Women’s Health Institute, said when asked for comment on the guideline. “We’re always very happy to see patients ahead of time who are planning pregnancy to be able to discuss what the care plan would look like. And specifically, to address medications, if required, for their rheumatologic care.
“As we learn more and more,” she added, “we’ve come to understand that most treatments and medications are actually safe or relatively safe to take in pregnancy. Certainly, the benefit of taking them outweighs any small or theoretic risks. On the flip side, the guideline does a nice job of highlighting the importance of good disease control, both at the time of conception and during pregnancy.”
Contraception
In regard to contraception, the guideline strongly recommends the use of effective contraceptives – with a conditional recommendation of IUDs or a subdermal progestin implant – in fertile women with a RMD who have neither systemic lupus erythematosus (SLE) nor positive antiphospholipid antibody (aPL). They also strongly recommend discussing the use of emergency contraception with all RMD patients.
For SLE patients, the guideline strongly recommends the use of effective contraceptives in those with stable or low disease activity who are not positive for aPL. They also strongly recommend progestin‐only or IUD contraceptives over combined estrogen‐progestin contraception. For aPL-positive patients, the guideline strongly recommends against combined estrogen‐progestin contraceptives and for levonorgestrel or copper IUDs or the progestin‐only pill.
Assisted reproductive technology
In regard to ART, the guideline strongly recommends proceeding as needed in aPL-negative women with uncomplicated, stable RMD who are on pregnancy‐compatible medications. They also strongly recommend deferring ART in any RMD patients with moderately or severely active disease.
For aPL-positive patients undergoing ART procedures, they strongly recommend prophylactic anticoagulation with heparin or low-molecular-weight heparin (LMWH) in women with obstetric antiphospholipid syndrome (APS) and therapeutic anticoagulation in women with thrombotic APS. In patients undergoing embryo and oocyte cryopreservation, they strongly recommend continuing immunosuppressive and biologic therapies – the exception being cyclophosphamide (CYC) – for anyone in stable condition.
Fertility preservation
In regard to fertility preservation in patients taking CYC, the guideline strongly suggests sperm cryopreservation as good practice prior to treatment. They also conditionally recommend monthly gonadotropin‐releasing hormone agonist cotherapy in premenopausal women with RMD.
Hormone therapy
In regard to menopause and hormone therapy, the guideline strongly suggests hormone therapy as good practice in postmenopausal women with RMD, without SLE or positive aPL, and who have severe vasomotor symptoms. Hormone therapy is conditionally recommended in patients with SLE, without positive aPL, and with no contraindications. For aPL-positive patients, they strongly recommend against hormone therapy in women with obstetric and/or thrombotic APS.
Pregnancy assessment and management
Among the many recommendations regarding pregnancy assessment and management, the guideline strongly suggests counseling women with RMD who are considering pregnancy to take into account the improved outcomes for pregnant women with low disease activity. They strongly recommend that women considering pregnancy should switch to pregnancy‐compatible medication and pause to assess its efficacy and tolerability before moving forward, along with strongly recommending that pregnant women with active disease initiate or continue a pregnancy‐compatible steroid‐sparing medication. They also recommend testing for anti‐Ro/SS-A and anti‐La/SS-B in women with SLE, Sjögren’s syndrome, systemic sclerosis, or rheumatoid arthritis, but only once and only before or early in the pregnancy.
For women with systemic sclerosis who develop scleroderma renal crisis during pregnancy, the authors strongly advise using ACE inhibitors or angiotensin receptor blockers “because the risk of maternal or fetal death with untreated disease is higher than the risk associated with use of these medications during pregnancy.”
Among women with SLE, the recommendations strongly call for testing either before or early in pregnancy for anticardiolipin antibody, anti–beta2-glycoprotein I, or positive lupus anticoagulant, as well as initiating or continuing hydroxychloroquine (HCQ) if possible. Starting in the first trimester, the authors also conditionally recommend that SLE patients take low-dose aspirin daily
For pregnant women who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the guideline conditionally recommends prophylactic treatment with low-dose aspirin daily to protect against preeclampsia. When obstetric APS criteria are met, the guideline strongly advises combined treatment with daily low-dose aspirin and prophylactic-dose heparin (or LMWH), as well as prophylactic-dose anticoagulation for 6-12 weeks post partum. When patients have thrombotic APS, this combination treatment should contain heparin dose at a therapeutic level throughout pregnancy and postpartum. However, the authors conditionally recommend against giving low-dose aspirin plus prophylactic-dose heparin to women without obstetric APS. For refractory obstetric APS, the guideline also contains recommendations that are conditionally against treatment with intravenous immunoglobulin or an increased LMWH dose and strongly against adding prednisone to prophylactic-dose heparin or LMWH and low-dose aspirin. In pregnant patients with primary APS, the authors conditionally advise adding HCQ to prophylactic-dose heparin or LMWH and low-dose aspirin therapy. However, women with aPL who do not meet APS criteria or have another indication for HCQ are conditionally advised against prophylactic treatment with the antimalarial.
For women with Anti-Ro/SS-A and/or anti-La/SS-B antibodies in pregnancy, there is conditional advice to use HCQ. When there is no history of an infant with complete heart block or neonatal lupus erythematosus among women with these antibodies, the guideline conditionally advises serial fetal echocardiography (less often than weekly) starting between 16 and 18 weeks and continuing through 26 weeks, but this should be weekly when there is a prior history. Treatment with oral dexamethasone 4 mg daily is conditionally advised when there is echocardiographic evidence of fetal first- or second-degree heart block, but dexamethasone is not recommended when complete heart block is present.
Finally, in regard to medication use, the authors strongly recommend that men who are planning to be fathers continue on HCQ, azathioprine, 6‐mercaptopurine, colchicine, or tumor necrosis factor inhibitors. Conditional treatment recommendations for men planning for pregnancy include methotrexate, mycophenolate mofetil/mycophenolic acid (MMF), leflunomide, sulfasalazine, calcineurin inhibitors, and NSAIDs. They also strongly recommend that this group of men discontinue CYC and thalidomide.
Pregnant women are strongly recommended to discontinue methotrexate, leflunomide (with cholestyramine washout if there are detectable serum levels of its metabolite prior to pregnancy or as soon as it is confirmed), MMF, CYC, and thalidomide within 3 months prior to conception, and they strongly recommend HCQ (in women with SLE), azathioprine/6‐mercaptopurine, colchicine, or sulfasalazine for use throughout pregnancy. They strongly recommend a combination of low‐dose aspirin and prophylactic‐dose heparin for pregnant women with obstetric APS, along with low‐dose aspirin and therapeutic‐dose heparin for women with thrombotic APS throughout pregnancy and postpartum. However, for women with SLE and those who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the authors conditionally recommend low-dose aspirin starting in the first trimester.
The guideline suggests that women with RMD should be encouraged to breastfeed if they are willing and able; they also suggest that disease control be maintained through lactation‐compatible medications and that the risks and benefits be reviewed on a patient-by-patient basis. Treatment with HCQ, colchicine, sulfasalazine, rituximab, and all tumor necrosis factor inhibitors are strongly recommended as being compatible with breastfeeding, and they strongly recommend against using CYC, leflunomide, MMF, and thalidomide while breastfeeding.
The authors acknowledged the limitations of their guideline, including the literature review being conducted on studies involving adults and an “inability to include recommendations for uncommon but important clinical situations,” including those involving transgender patients and hormonal therapies.
The authors reported numerous potential conflicts of interest, including receiving research support, consulting fees, speaking fees, and honoraria from various pharmaceutical companies.
SOURCE: Sammaritano LR et al. Arthritis Rheumatol. 2020 Feb 23. doi: 10.1002/art.41191.
A new guideline from the American College of Rheumatology offers the organization’s first clinical recommendations on how to manage reproductive health issues in patients with rheumatic and musculoskeletal diseases (RMDs).
“With the development of this guideline, the ACR recognizes the key role of clinical rheumatologists not only in managing disease activity but also in understanding the interactions of RMDs and their therapies in the context of reproductive health,” wrote Lisa R. Sammaritano, MD, of Weill Cornell Medicine and the Hospital for Special Surgery in New York, and coauthors. The guideline was published in Arthritis & Rheumatology.
To develop an evidence-based guideline on reproductive health in RMD patients, the researchers embarked on a systematic review of studies in areas like contraception, pregnancy and lactation, assisted reproductive technology (ART), fertility preservation, and hormone therapy. The guideline contains 12 ungraded good practice statements and 131 graded recommendations, all developed through the Grading of Recommendations Assessment, Development, and Evaluation methodology.
In counseling patients about these areas of care, the guideline says that rheumatologists and other clinicians “must collaborate with specialists in the fields of obstetrics-gynecology, maternal-fetal medicine, and reproductive endocrinology and infertility.”
“One thing this guideline does well is highlight the importance of involving maternal-fetal medicine colleagues,” Alison Cahill, MD, a professor in the department of women’s health at the University of Texas at Austin and a maternal-fetal medicine specialist within UT Health Austin’s Women’s Health Institute, said when asked for comment on the guideline. “We’re always very happy to see patients ahead of time who are planning pregnancy to be able to discuss what the care plan would look like. And specifically, to address medications, if required, for their rheumatologic care.
“As we learn more and more,” she added, “we’ve come to understand that most treatments and medications are actually safe or relatively safe to take in pregnancy. Certainly, the benefit of taking them outweighs any small or theoretic risks. On the flip side, the guideline does a nice job of highlighting the importance of good disease control, both at the time of conception and during pregnancy.”
Contraception
In regard to contraception, the guideline strongly recommends the use of effective contraceptives – with a conditional recommendation of IUDs or a subdermal progestin implant – in fertile women with a RMD who have neither systemic lupus erythematosus (SLE) nor positive antiphospholipid antibody (aPL). They also strongly recommend discussing the use of emergency contraception with all RMD patients.
For SLE patients, the guideline strongly recommends the use of effective contraceptives in those with stable or low disease activity who are not positive for aPL. They also strongly recommend progestin‐only or IUD contraceptives over combined estrogen‐progestin contraception. For aPL-positive patients, the guideline strongly recommends against combined estrogen‐progestin contraceptives and for levonorgestrel or copper IUDs or the progestin‐only pill.
Assisted reproductive technology
In regard to ART, the guideline strongly recommends proceeding as needed in aPL-negative women with uncomplicated, stable RMD who are on pregnancy‐compatible medications. They also strongly recommend deferring ART in any RMD patients with moderately or severely active disease.
For aPL-positive patients undergoing ART procedures, they strongly recommend prophylactic anticoagulation with heparin or low-molecular-weight heparin (LMWH) in women with obstetric antiphospholipid syndrome (APS) and therapeutic anticoagulation in women with thrombotic APS. In patients undergoing embryo and oocyte cryopreservation, they strongly recommend continuing immunosuppressive and biologic therapies – the exception being cyclophosphamide (CYC) – for anyone in stable condition.
Fertility preservation
In regard to fertility preservation in patients taking CYC, the guideline strongly suggests sperm cryopreservation as good practice prior to treatment. They also conditionally recommend monthly gonadotropin‐releasing hormone agonist cotherapy in premenopausal women with RMD.
Hormone therapy
In regard to menopause and hormone therapy, the guideline strongly suggests hormone therapy as good practice in postmenopausal women with RMD, without SLE or positive aPL, and who have severe vasomotor symptoms. Hormone therapy is conditionally recommended in patients with SLE, without positive aPL, and with no contraindications. For aPL-positive patients, they strongly recommend against hormone therapy in women with obstetric and/or thrombotic APS.
Pregnancy assessment and management
Among the many recommendations regarding pregnancy assessment and management, the guideline strongly suggests counseling women with RMD who are considering pregnancy to take into account the improved outcomes for pregnant women with low disease activity. They strongly recommend that women considering pregnancy should switch to pregnancy‐compatible medication and pause to assess its efficacy and tolerability before moving forward, along with strongly recommending that pregnant women with active disease initiate or continue a pregnancy‐compatible steroid‐sparing medication. They also recommend testing for anti‐Ro/SS-A and anti‐La/SS-B in women with SLE, Sjögren’s syndrome, systemic sclerosis, or rheumatoid arthritis, but only once and only before or early in the pregnancy.
For women with systemic sclerosis who develop scleroderma renal crisis during pregnancy, the authors strongly advise using ACE inhibitors or angiotensin receptor blockers “because the risk of maternal or fetal death with untreated disease is higher than the risk associated with use of these medications during pregnancy.”
Among women with SLE, the recommendations strongly call for testing either before or early in pregnancy for anticardiolipin antibody, anti–beta2-glycoprotein I, or positive lupus anticoagulant, as well as initiating or continuing hydroxychloroquine (HCQ) if possible. Starting in the first trimester, the authors also conditionally recommend that SLE patients take low-dose aspirin daily
For pregnant women who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the guideline conditionally recommends prophylactic treatment with low-dose aspirin daily to protect against preeclampsia. When obstetric APS criteria are met, the guideline strongly advises combined treatment with daily low-dose aspirin and prophylactic-dose heparin (or LMWH), as well as prophylactic-dose anticoagulation for 6-12 weeks post partum. When patients have thrombotic APS, this combination treatment should contain heparin dose at a therapeutic level throughout pregnancy and postpartum. However, the authors conditionally recommend against giving low-dose aspirin plus prophylactic-dose heparin to women without obstetric APS. For refractory obstetric APS, the guideline also contains recommendations that are conditionally against treatment with intravenous immunoglobulin or an increased LMWH dose and strongly against adding prednisone to prophylactic-dose heparin or LMWH and low-dose aspirin. In pregnant patients with primary APS, the authors conditionally advise adding HCQ to prophylactic-dose heparin or LMWH and low-dose aspirin therapy. However, women with aPL who do not meet APS criteria or have another indication for HCQ are conditionally advised against prophylactic treatment with the antimalarial.
For women with Anti-Ro/SS-A and/or anti-La/SS-B antibodies in pregnancy, there is conditional advice to use HCQ. When there is no history of an infant with complete heart block or neonatal lupus erythematosus among women with these antibodies, the guideline conditionally advises serial fetal echocardiography (less often than weekly) starting between 16 and 18 weeks and continuing through 26 weeks, but this should be weekly when there is a prior history. Treatment with oral dexamethasone 4 mg daily is conditionally advised when there is echocardiographic evidence of fetal first- or second-degree heart block, but dexamethasone is not recommended when complete heart block is present.
Finally, in regard to medication use, the authors strongly recommend that men who are planning to be fathers continue on HCQ, azathioprine, 6‐mercaptopurine, colchicine, or tumor necrosis factor inhibitors. Conditional treatment recommendations for men planning for pregnancy include methotrexate, mycophenolate mofetil/mycophenolic acid (MMF), leflunomide, sulfasalazine, calcineurin inhibitors, and NSAIDs. They also strongly recommend that this group of men discontinue CYC and thalidomide.
Pregnant women are strongly recommended to discontinue methotrexate, leflunomide (with cholestyramine washout if there are detectable serum levels of its metabolite prior to pregnancy or as soon as it is confirmed), MMF, CYC, and thalidomide within 3 months prior to conception, and they strongly recommend HCQ (in women with SLE), azathioprine/6‐mercaptopurine, colchicine, or sulfasalazine for use throughout pregnancy. They strongly recommend a combination of low‐dose aspirin and prophylactic‐dose heparin for pregnant women with obstetric APS, along with low‐dose aspirin and therapeutic‐dose heparin for women with thrombotic APS throughout pregnancy and postpartum. However, for women with SLE and those who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the authors conditionally recommend low-dose aspirin starting in the first trimester.
The guideline suggests that women with RMD should be encouraged to breastfeed if they are willing and able; they also suggest that disease control be maintained through lactation‐compatible medications and that the risks and benefits be reviewed on a patient-by-patient basis. Treatment with HCQ, colchicine, sulfasalazine, rituximab, and all tumor necrosis factor inhibitors are strongly recommended as being compatible with breastfeeding, and they strongly recommend against using CYC, leflunomide, MMF, and thalidomide while breastfeeding.
The authors acknowledged the limitations of their guideline, including the literature review being conducted on studies involving adults and an “inability to include recommendations for uncommon but important clinical situations,” including those involving transgender patients and hormonal therapies.
The authors reported numerous potential conflicts of interest, including receiving research support, consulting fees, speaking fees, and honoraria from various pharmaceutical companies.
SOURCE: Sammaritano LR et al. Arthritis Rheumatol. 2020 Feb 23. doi: 10.1002/art.41191.
FROM ARTHRITIS & RHEUMATOLOGY
Joint replacement: What’s new in 2020
MAUI, HAWAII – Outpatient total hip and knee replacement is “the latest craze” in orthopedic surgery, and it’s being driven by the might of Medicare, William Bugbee, MD, said at the 2020 Rheumatology Winter Clinical Symposium.
“In 2019, Medicare took total knee replacement off the inpatient-only list, meaning you could do it as an outpatient. And just in January 2020, they took total hips off that list. So I have to designate most of my hip and knee replacements as outpatients, even if I do it in the hospital and keep them for 1 night. And some of the private insurers have already gone to that, so they’ll deny coverage if I say I want a 1-day hospital stay, believe it or not,” according to Dr. Bugbee, chief of joint reconstruction in the department of orthopedics at the Scripps Clinic in La Jolla, Calif.
He provided a behind-the-scenes look at contemporary trends in joint replacement as well as tips on how rheumatologists can best help their patients get through the experience with excellent outcomes.
Joint replacement remains the best treatment for advanced arthritis of the hips and knees, he said. There is a high degree of confidence about the predictability and durability of the results. But joint replacement has become highly commoditized.
“We’re getting pummeled by Medicare to make this as cheap as possible,” the orthopedic surgeon explained. “An implant costs the hospital $3,000-$6,000. A care episode for a primary total joint replacement should cost a hospital $8,000-$15,000, which is about what Medicare pays for the [Diagnosis Related Group], so the margins are small. That’s why we’re being drilled on about how much we spend on every little thing. We hardly do any labs, x-rays, anything.”
As a result of recent advances in pre-, peri-, and postoperative management, outpatient joint replacement has become a safe and comparatively economical option for generally healthy patients.
“We’ve engineered a much better patient experience, so the assault and battery of 5, 10, 15 years ago isn’t so bad anymore,” Dr. Bugbee said.
Rheumatologists can expect to see a growing number of their patients undergoing total knee or hip replacement at outpatient surgery centers. That’s not a bad thing so long as the procedure is being done there because the outpatient center employs best practices in order to provide a highly efficient episode of care supported by excellent outcome data, he continued.
State-of-the-art perioperative management in 2020 includes accelerated-care pathways that allow ambulation within an hour or 2 after surgery along with same-day discharge, regional anesthesia with motor-sparing nerve blocks, and multimodal pain management with avoidance of intravenous narcotics except in opioid-tolerant patients. Tranexamic acid is now widely used in order to reduce operative blood loss.
“When I started practice 25 years ago, 50% of patients got a blood transfusion. I haven’t given a blood transfusion to a patient in probably 2 years. Tranexamic acid reduces blood loss by 500-700 cc with no discernible adverse effects. It’s truly remarkable,” he said.
Another important technical advance has been the routine use of oral dexamethasone. “Decadron is an antiemetic, it has anti-inflammatory effects, and it makes people happy. It’s a simple, cheap drug that has revolutionized care,” the surgeon continued.
Postoperative management has been streamlined. Dr. Bugbee is among many orthopedic surgeons who no longer routinely prescribe therapist-directed formal physical therapy for total hip arthroplasty patients, relying instead upon online tools and apps for self-administered physical therapy. Pedal exercise devices available online for $30 or so have been shown to be as effective as supervised physical therapy for knee rehabilitation.
What patients want to know about joint replacement
The question patients most often ask both their referring physician and the orthopedic surgeon is, “How long will my joint replacement last?” The best available data come from a couple of recent paired meta-analyses. The investigators reported 82% implant survivorship 25 years after primary total knee arthroplasty and 70% after unicondylar knee arthroplasty as well as a 25-year implant survivorship rate of 77% for total hip arthroplasty.
“I expected that hip arthroplasty survivorship rate to be much higher than 77%. The reason it’s not is probably because of the metal-on-metal bearing surface debacle of about 10 years ago. There’ve been lots of revisions because of that. We thought metal-on-metal implants were going to be all that, with microscopically low wear, but they turned out to be a nightmare because of metal ion release,” Dr. Bugbee observed.
The long-term joint survivorship data are based upon older implants. Encouraging albeit still preliminary data suggest contemporary implants may last significantly longer. The “clear winner,” he said, is a 36-mm ceramic head and a highly crosslinked polyethylene liner.
“That’s been a game changer, with a 10- to 20-fold decrease in wear compared to plastics for weight-bearing surfaces,” Dr. Bugbee said.
In terms of functional improvement, by various measures 85%-97% of patients are satisfied with the results of their total hip replacement, and 60% report returning to high-level recreational activities. Patient satisfaction scores are lower – 75%-90% – after total knee arthroplasty.
“The total knee replacement just doesn’t work like a regular joint,” the surgeon observed. “When I think of hip and knee replacements, I think of a hip as a Ferrari – it’s a high-performance joint replacement – and I think of the knee as a Ford – it’s serviceable, it does the job, and it’s okay but not fantastic.”
How referring physicians can optimize preoperative management and long-term follow-up
Orthopedic surgeons would appreciate help from rheumatologists and primary care physicians in preoperatively addressing the known modifiable risk factors for poor outcomes of joint replacement. These include obesity, smoking, depression, a hemoglobin A1c of 7% or more, and being on opioids. These risk factors are incompatible with outpatient hip or knee replacement.
“Let the surgeon know if you think outpatient joint replacement is a bad idea in your patient for medical reasons,” Dr. Bugbee urged.
Also, orthopedic surgeons can generally benefit from rheumatologist input regarding perioperative management of patients on standard disease-modifying antirheumatic drugs, biologics, or Janus kinase inhibitors as recommended in the guidelines published jointly by the American College of Rheumatology and the American Association of Hip and Knee Surgeons.
“I can guarantee you that most orthopedic surgeons don’t know about these guidelines. The evidence base for these recommendations is not great, but these are the best guidelines we have,” Dr. Bugbee said.
After joint replacement surgery a patient should get an x-ray of the replacement every 5 years. And if a patient develops a painful hip after arthroplasty, it’s worthwhile to order blood chromium and cobalt levels.
“The implant weight-bearing surface matters. You can’t necessarily tell on x-ray what’s a metal-on-metal hip and what’s metal-on-plastic or ceramic. You already send people for a lot of labs. If you see a patient with a painful total hip replacement, just add a cobalt and chromium. If they’re elevated, talk to the orthopedist,” he advised.
The road ahead
Hip and knee replacement is an $18 billion market today. And it’s a major growth industry: According to a recent projection, there will be 1 million total hip replacements and 4 million total knee replacements annually 10 years from now, figures four times greater than projected for 2030 in an earlier 2005 estimate. The rapid growth is coming from the expanding elderly population combined with a virtual epidemic of posttraumatic arthritis in young people – but decidedly not from patients with joint failure attributable to rheumatoid arthritis.
“Congratulations! You’ve eradicated rheumatoid arthritis from my practice,” Dr. Bugbee declared. “Most of the rheumatoid arthritis patients who come to me come because they have osteoarthritis in their joint, not because of their rheumatoid arthritis.”
He reported serving as a consultant to Orthalign, Insight Medical, and Arthrex, and receiving royalties from Smith and Nephew and Depuy.
MAUI, HAWAII – Outpatient total hip and knee replacement is “the latest craze” in orthopedic surgery, and it’s being driven by the might of Medicare, William Bugbee, MD, said at the 2020 Rheumatology Winter Clinical Symposium.
“In 2019, Medicare took total knee replacement off the inpatient-only list, meaning you could do it as an outpatient. And just in January 2020, they took total hips off that list. So I have to designate most of my hip and knee replacements as outpatients, even if I do it in the hospital and keep them for 1 night. And some of the private insurers have already gone to that, so they’ll deny coverage if I say I want a 1-day hospital stay, believe it or not,” according to Dr. Bugbee, chief of joint reconstruction in the department of orthopedics at the Scripps Clinic in La Jolla, Calif.
He provided a behind-the-scenes look at contemporary trends in joint replacement as well as tips on how rheumatologists can best help their patients get through the experience with excellent outcomes.
Joint replacement remains the best treatment for advanced arthritis of the hips and knees, he said. There is a high degree of confidence about the predictability and durability of the results. But joint replacement has become highly commoditized.
“We’re getting pummeled by Medicare to make this as cheap as possible,” the orthopedic surgeon explained. “An implant costs the hospital $3,000-$6,000. A care episode for a primary total joint replacement should cost a hospital $8,000-$15,000, which is about what Medicare pays for the [Diagnosis Related Group], so the margins are small. That’s why we’re being drilled on about how much we spend on every little thing. We hardly do any labs, x-rays, anything.”
As a result of recent advances in pre-, peri-, and postoperative management, outpatient joint replacement has become a safe and comparatively economical option for generally healthy patients.
“We’ve engineered a much better patient experience, so the assault and battery of 5, 10, 15 years ago isn’t so bad anymore,” Dr. Bugbee said.
Rheumatologists can expect to see a growing number of their patients undergoing total knee or hip replacement at outpatient surgery centers. That’s not a bad thing so long as the procedure is being done there because the outpatient center employs best practices in order to provide a highly efficient episode of care supported by excellent outcome data, he continued.
State-of-the-art perioperative management in 2020 includes accelerated-care pathways that allow ambulation within an hour or 2 after surgery along with same-day discharge, regional anesthesia with motor-sparing nerve blocks, and multimodal pain management with avoidance of intravenous narcotics except in opioid-tolerant patients. Tranexamic acid is now widely used in order to reduce operative blood loss.
“When I started practice 25 years ago, 50% of patients got a blood transfusion. I haven’t given a blood transfusion to a patient in probably 2 years. Tranexamic acid reduces blood loss by 500-700 cc with no discernible adverse effects. It’s truly remarkable,” he said.
Another important technical advance has been the routine use of oral dexamethasone. “Decadron is an antiemetic, it has anti-inflammatory effects, and it makes people happy. It’s a simple, cheap drug that has revolutionized care,” the surgeon continued.
Postoperative management has been streamlined. Dr. Bugbee is among many orthopedic surgeons who no longer routinely prescribe therapist-directed formal physical therapy for total hip arthroplasty patients, relying instead upon online tools and apps for self-administered physical therapy. Pedal exercise devices available online for $30 or so have been shown to be as effective as supervised physical therapy for knee rehabilitation.
What patients want to know about joint replacement
The question patients most often ask both their referring physician and the orthopedic surgeon is, “How long will my joint replacement last?” The best available data come from a couple of recent paired meta-analyses. The investigators reported 82% implant survivorship 25 years after primary total knee arthroplasty and 70% after unicondylar knee arthroplasty as well as a 25-year implant survivorship rate of 77% for total hip arthroplasty.
“I expected that hip arthroplasty survivorship rate to be much higher than 77%. The reason it’s not is probably because of the metal-on-metal bearing surface debacle of about 10 years ago. There’ve been lots of revisions because of that. We thought metal-on-metal implants were going to be all that, with microscopically low wear, but they turned out to be a nightmare because of metal ion release,” Dr. Bugbee observed.
The long-term joint survivorship data are based upon older implants. Encouraging albeit still preliminary data suggest contemporary implants may last significantly longer. The “clear winner,” he said, is a 36-mm ceramic head and a highly crosslinked polyethylene liner.
“That’s been a game changer, with a 10- to 20-fold decrease in wear compared to plastics for weight-bearing surfaces,” Dr. Bugbee said.
In terms of functional improvement, by various measures 85%-97% of patients are satisfied with the results of their total hip replacement, and 60% report returning to high-level recreational activities. Patient satisfaction scores are lower – 75%-90% – after total knee arthroplasty.
“The total knee replacement just doesn’t work like a regular joint,” the surgeon observed. “When I think of hip and knee replacements, I think of a hip as a Ferrari – it’s a high-performance joint replacement – and I think of the knee as a Ford – it’s serviceable, it does the job, and it’s okay but not fantastic.”
How referring physicians can optimize preoperative management and long-term follow-up
Orthopedic surgeons would appreciate help from rheumatologists and primary care physicians in preoperatively addressing the known modifiable risk factors for poor outcomes of joint replacement. These include obesity, smoking, depression, a hemoglobin A1c of 7% or more, and being on opioids. These risk factors are incompatible with outpatient hip or knee replacement.
“Let the surgeon know if you think outpatient joint replacement is a bad idea in your patient for medical reasons,” Dr. Bugbee urged.
Also, orthopedic surgeons can generally benefit from rheumatologist input regarding perioperative management of patients on standard disease-modifying antirheumatic drugs, biologics, or Janus kinase inhibitors as recommended in the guidelines published jointly by the American College of Rheumatology and the American Association of Hip and Knee Surgeons.
“I can guarantee you that most orthopedic surgeons don’t know about these guidelines. The evidence base for these recommendations is not great, but these are the best guidelines we have,” Dr. Bugbee said.
After joint replacement surgery a patient should get an x-ray of the replacement every 5 years. And if a patient develops a painful hip after arthroplasty, it’s worthwhile to order blood chromium and cobalt levels.
“The implant weight-bearing surface matters. You can’t necessarily tell on x-ray what’s a metal-on-metal hip and what’s metal-on-plastic or ceramic. You already send people for a lot of labs. If you see a patient with a painful total hip replacement, just add a cobalt and chromium. If they’re elevated, talk to the orthopedist,” he advised.
The road ahead
Hip and knee replacement is an $18 billion market today. And it’s a major growth industry: According to a recent projection, there will be 1 million total hip replacements and 4 million total knee replacements annually 10 years from now, figures four times greater than projected for 2030 in an earlier 2005 estimate. The rapid growth is coming from the expanding elderly population combined with a virtual epidemic of posttraumatic arthritis in young people – but decidedly not from patients with joint failure attributable to rheumatoid arthritis.
“Congratulations! You’ve eradicated rheumatoid arthritis from my practice,” Dr. Bugbee declared. “Most of the rheumatoid arthritis patients who come to me come because they have osteoarthritis in their joint, not because of their rheumatoid arthritis.”
He reported serving as a consultant to Orthalign, Insight Medical, and Arthrex, and receiving royalties from Smith and Nephew and Depuy.
MAUI, HAWAII – Outpatient total hip and knee replacement is “the latest craze” in orthopedic surgery, and it’s being driven by the might of Medicare, William Bugbee, MD, said at the 2020 Rheumatology Winter Clinical Symposium.
“In 2019, Medicare took total knee replacement off the inpatient-only list, meaning you could do it as an outpatient. And just in January 2020, they took total hips off that list. So I have to designate most of my hip and knee replacements as outpatients, even if I do it in the hospital and keep them for 1 night. And some of the private insurers have already gone to that, so they’ll deny coverage if I say I want a 1-day hospital stay, believe it or not,” according to Dr. Bugbee, chief of joint reconstruction in the department of orthopedics at the Scripps Clinic in La Jolla, Calif.
He provided a behind-the-scenes look at contemporary trends in joint replacement as well as tips on how rheumatologists can best help their patients get through the experience with excellent outcomes.
Joint replacement remains the best treatment for advanced arthritis of the hips and knees, he said. There is a high degree of confidence about the predictability and durability of the results. But joint replacement has become highly commoditized.
“We’re getting pummeled by Medicare to make this as cheap as possible,” the orthopedic surgeon explained. “An implant costs the hospital $3,000-$6,000. A care episode for a primary total joint replacement should cost a hospital $8,000-$15,000, which is about what Medicare pays for the [Diagnosis Related Group], so the margins are small. That’s why we’re being drilled on about how much we spend on every little thing. We hardly do any labs, x-rays, anything.”
As a result of recent advances in pre-, peri-, and postoperative management, outpatient joint replacement has become a safe and comparatively economical option for generally healthy patients.
“We’ve engineered a much better patient experience, so the assault and battery of 5, 10, 15 years ago isn’t so bad anymore,” Dr. Bugbee said.
Rheumatologists can expect to see a growing number of their patients undergoing total knee or hip replacement at outpatient surgery centers. That’s not a bad thing so long as the procedure is being done there because the outpatient center employs best practices in order to provide a highly efficient episode of care supported by excellent outcome data, he continued.
State-of-the-art perioperative management in 2020 includes accelerated-care pathways that allow ambulation within an hour or 2 after surgery along with same-day discharge, regional anesthesia with motor-sparing nerve blocks, and multimodal pain management with avoidance of intravenous narcotics except in opioid-tolerant patients. Tranexamic acid is now widely used in order to reduce operative blood loss.
“When I started practice 25 years ago, 50% of patients got a blood transfusion. I haven’t given a blood transfusion to a patient in probably 2 years. Tranexamic acid reduces blood loss by 500-700 cc with no discernible adverse effects. It’s truly remarkable,” he said.
Another important technical advance has been the routine use of oral dexamethasone. “Decadron is an antiemetic, it has anti-inflammatory effects, and it makes people happy. It’s a simple, cheap drug that has revolutionized care,” the surgeon continued.
Postoperative management has been streamlined. Dr. Bugbee is among many orthopedic surgeons who no longer routinely prescribe therapist-directed formal physical therapy for total hip arthroplasty patients, relying instead upon online tools and apps for self-administered physical therapy. Pedal exercise devices available online for $30 or so have been shown to be as effective as supervised physical therapy for knee rehabilitation.
What patients want to know about joint replacement
The question patients most often ask both their referring physician and the orthopedic surgeon is, “How long will my joint replacement last?” The best available data come from a couple of recent paired meta-analyses. The investigators reported 82% implant survivorship 25 years after primary total knee arthroplasty and 70% after unicondylar knee arthroplasty as well as a 25-year implant survivorship rate of 77% for total hip arthroplasty.
“I expected that hip arthroplasty survivorship rate to be much higher than 77%. The reason it’s not is probably because of the metal-on-metal bearing surface debacle of about 10 years ago. There’ve been lots of revisions because of that. We thought metal-on-metal implants were going to be all that, with microscopically low wear, but they turned out to be a nightmare because of metal ion release,” Dr. Bugbee observed.
The long-term joint survivorship data are based upon older implants. Encouraging albeit still preliminary data suggest contemporary implants may last significantly longer. The “clear winner,” he said, is a 36-mm ceramic head and a highly crosslinked polyethylene liner.
“That’s been a game changer, with a 10- to 20-fold decrease in wear compared to plastics for weight-bearing surfaces,” Dr. Bugbee said.
In terms of functional improvement, by various measures 85%-97% of patients are satisfied with the results of their total hip replacement, and 60% report returning to high-level recreational activities. Patient satisfaction scores are lower – 75%-90% – after total knee arthroplasty.
“The total knee replacement just doesn’t work like a regular joint,” the surgeon observed. “When I think of hip and knee replacements, I think of a hip as a Ferrari – it’s a high-performance joint replacement – and I think of the knee as a Ford – it’s serviceable, it does the job, and it’s okay but not fantastic.”
How referring physicians can optimize preoperative management and long-term follow-up
Orthopedic surgeons would appreciate help from rheumatologists and primary care physicians in preoperatively addressing the known modifiable risk factors for poor outcomes of joint replacement. These include obesity, smoking, depression, a hemoglobin A1c of 7% or more, and being on opioids. These risk factors are incompatible with outpatient hip or knee replacement.
“Let the surgeon know if you think outpatient joint replacement is a bad idea in your patient for medical reasons,” Dr. Bugbee urged.
Also, orthopedic surgeons can generally benefit from rheumatologist input regarding perioperative management of patients on standard disease-modifying antirheumatic drugs, biologics, or Janus kinase inhibitors as recommended in the guidelines published jointly by the American College of Rheumatology and the American Association of Hip and Knee Surgeons.
“I can guarantee you that most orthopedic surgeons don’t know about these guidelines. The evidence base for these recommendations is not great, but these are the best guidelines we have,” Dr. Bugbee said.
After joint replacement surgery a patient should get an x-ray of the replacement every 5 years. And if a patient develops a painful hip after arthroplasty, it’s worthwhile to order blood chromium and cobalt levels.
“The implant weight-bearing surface matters. You can’t necessarily tell on x-ray what’s a metal-on-metal hip and what’s metal-on-plastic or ceramic. You already send people for a lot of labs. If you see a patient with a painful total hip replacement, just add a cobalt and chromium. If they’re elevated, talk to the orthopedist,” he advised.
The road ahead
Hip and knee replacement is an $18 billion market today. And it’s a major growth industry: According to a recent projection, there will be 1 million total hip replacements and 4 million total knee replacements annually 10 years from now, figures four times greater than projected for 2030 in an earlier 2005 estimate. The rapid growth is coming from the expanding elderly population combined with a virtual epidemic of posttraumatic arthritis in young people – but decidedly not from patients with joint failure attributable to rheumatoid arthritis.
“Congratulations! You’ve eradicated rheumatoid arthritis from my practice,” Dr. Bugbee declared. “Most of the rheumatoid arthritis patients who come to me come because they have osteoarthritis in their joint, not because of their rheumatoid arthritis.”
He reported serving as a consultant to Orthalign, Insight Medical, and Arthrex, and receiving royalties from Smith and Nephew and Depuy.
REPORTING FROM RWCS 2020
Comparison shows tighter treat-to-target approach provides better outcomes in RA
Implementing a more stringent treat‐to‐target strategy could provide better outcomes for patients with early RA, according to a recent comparative study.
The findings confirm the feasibility of adopting a treat‐to‐target approach to ensure optimal outcomes are achieved for patients with early-stage disease.
“The objective of the present study was to compare achievement of remission during 2 years of follow-up in two early RA cohorts implementing different treat‐to‐target strategies,” wrote Vibeke Norvang, MD, of the department of rheumatology at Diakonhjemmet Hospital in Oslo, and colleagues. The findings were published in Arthritis & Rheumatology.
The researchers performed a pooled analysis of data from the randomized ARCTIC trial and the Norwegian Very Early Arthritis Clinic (NOR-VEAC) observational study. The combined cohort included a total of 429 disease-modifying antirheumatic drug (DMARD)–naive early RA patients, 189 and 330 from each study, respectively.
The American College of Rheumatology/European League Against Rheumatism Boolean remission criteria differed between the two cohorts, with more stringent criteria in ARCTIC than in NOR-VEAC. Remission was defined as scores of less than 1.6 and 2.6 on the Disease Activity Scores in 44 joints and 28 joints, respectively.
At 12- and 24-month follow-up, the researchers found that the odds of achieving remission were greater in ARCTIC than in NOR-VEAC (odds ratios, 1.97; 95% confidence interval, 1.21-3.20 vs. OR, 1.82; 95% CI, 1.05-3.16).
“We found that more than half of patients in each cohort had reached the study-specific remission targets at 6 months, and this increased to more than 60% in each cohort at 12 and 24 months,” they reported.
With respect to drug therapy, all study patients started with methotrexate monotherapy at a mean dose of 16.0 mg and 15.5 mg in ARCTIC and NOR-VEAC, respectively. In addition, similar rates of escalation to a biologic DMARD were observed in both studies (25.6% vs. 25.4%) at 24 months.
The researchers acknowledged that a key limitation of the study was comparing outcomes in two cohorts with different study designs; hence, the risk of bias in estimates of effect cannot be excluded.
“Targeting a more stringent remission and implementing more frequent visits provide further potential for favorable outcomes of a treat‐to‐target strategy,” they concluded.
The study was supported by legacy funds provided to the department of rheumatology at Diakonhjemmet Hospital. Three authors reported financial relationships with AbbVie, Amgen, Corrona, Genentech, Janssen, Mylan, Pfizer, and other companies.
SOURCE: Norvang V et al. Arthritis Rheumatol. 2020 Feb 23. doi: 10.1002/art.41232.
Implementing a more stringent treat‐to‐target strategy could provide better outcomes for patients with early RA, according to a recent comparative study.
The findings confirm the feasibility of adopting a treat‐to‐target approach to ensure optimal outcomes are achieved for patients with early-stage disease.
“The objective of the present study was to compare achievement of remission during 2 years of follow-up in two early RA cohorts implementing different treat‐to‐target strategies,” wrote Vibeke Norvang, MD, of the department of rheumatology at Diakonhjemmet Hospital in Oslo, and colleagues. The findings were published in Arthritis & Rheumatology.
The researchers performed a pooled analysis of data from the randomized ARCTIC trial and the Norwegian Very Early Arthritis Clinic (NOR-VEAC) observational study. The combined cohort included a total of 429 disease-modifying antirheumatic drug (DMARD)–naive early RA patients, 189 and 330 from each study, respectively.
The American College of Rheumatology/European League Against Rheumatism Boolean remission criteria differed between the two cohorts, with more stringent criteria in ARCTIC than in NOR-VEAC. Remission was defined as scores of less than 1.6 and 2.6 on the Disease Activity Scores in 44 joints and 28 joints, respectively.
At 12- and 24-month follow-up, the researchers found that the odds of achieving remission were greater in ARCTIC than in NOR-VEAC (odds ratios, 1.97; 95% confidence interval, 1.21-3.20 vs. OR, 1.82; 95% CI, 1.05-3.16).
“We found that more than half of patients in each cohort had reached the study-specific remission targets at 6 months, and this increased to more than 60% in each cohort at 12 and 24 months,” they reported.
With respect to drug therapy, all study patients started with methotrexate monotherapy at a mean dose of 16.0 mg and 15.5 mg in ARCTIC and NOR-VEAC, respectively. In addition, similar rates of escalation to a biologic DMARD were observed in both studies (25.6% vs. 25.4%) at 24 months.
The researchers acknowledged that a key limitation of the study was comparing outcomes in two cohorts with different study designs; hence, the risk of bias in estimates of effect cannot be excluded.
“Targeting a more stringent remission and implementing more frequent visits provide further potential for favorable outcomes of a treat‐to‐target strategy,” they concluded.
The study was supported by legacy funds provided to the department of rheumatology at Diakonhjemmet Hospital. Three authors reported financial relationships with AbbVie, Amgen, Corrona, Genentech, Janssen, Mylan, Pfizer, and other companies.
SOURCE: Norvang V et al. Arthritis Rheumatol. 2020 Feb 23. doi: 10.1002/art.41232.
Implementing a more stringent treat‐to‐target strategy could provide better outcomes for patients with early RA, according to a recent comparative study.
The findings confirm the feasibility of adopting a treat‐to‐target approach to ensure optimal outcomes are achieved for patients with early-stage disease.
“The objective of the present study was to compare achievement of remission during 2 years of follow-up in two early RA cohorts implementing different treat‐to‐target strategies,” wrote Vibeke Norvang, MD, of the department of rheumatology at Diakonhjemmet Hospital in Oslo, and colleagues. The findings were published in Arthritis & Rheumatology.
The researchers performed a pooled analysis of data from the randomized ARCTIC trial and the Norwegian Very Early Arthritis Clinic (NOR-VEAC) observational study. The combined cohort included a total of 429 disease-modifying antirheumatic drug (DMARD)–naive early RA patients, 189 and 330 from each study, respectively.
The American College of Rheumatology/European League Against Rheumatism Boolean remission criteria differed between the two cohorts, with more stringent criteria in ARCTIC than in NOR-VEAC. Remission was defined as scores of less than 1.6 and 2.6 on the Disease Activity Scores in 44 joints and 28 joints, respectively.
At 12- and 24-month follow-up, the researchers found that the odds of achieving remission were greater in ARCTIC than in NOR-VEAC (odds ratios, 1.97; 95% confidence interval, 1.21-3.20 vs. OR, 1.82; 95% CI, 1.05-3.16).
“We found that more than half of patients in each cohort had reached the study-specific remission targets at 6 months, and this increased to more than 60% in each cohort at 12 and 24 months,” they reported.
With respect to drug therapy, all study patients started with methotrexate monotherapy at a mean dose of 16.0 mg and 15.5 mg in ARCTIC and NOR-VEAC, respectively. In addition, similar rates of escalation to a biologic DMARD were observed in both studies (25.6% vs. 25.4%) at 24 months.
The researchers acknowledged that a key limitation of the study was comparing outcomes in two cohorts with different study designs; hence, the risk of bias in estimates of effect cannot be excluded.
“Targeting a more stringent remission and implementing more frequent visits provide further potential for favorable outcomes of a treat‐to‐target strategy,” they concluded.
The study was supported by legacy funds provided to the department of rheumatology at Diakonhjemmet Hospital. Three authors reported financial relationships with AbbVie, Amgen, Corrona, Genentech, Janssen, Mylan, Pfizer, and other companies.
SOURCE: Norvang V et al. Arthritis Rheumatol. 2020 Feb 23. doi: 10.1002/art.41232.
FROM ARTHRITIS & RHEUMATOLOGY
Synovial biopsy findings drive precision medicine for RA closer to the clinic
Researchers are mining the synovium for potential treasure: robust markers to bring precision medicine to the rheumatoid arthritis (RA) arena. The signs, according to a number of recent reports, point toward a gold strike via synovial tissue biopsy.
“I have no doubt about that – I am very confident that this concept of going straight to the tissue and using functional genomics will help us stratify our patients and will be a predictive model for patients with respect to therapy,” Harris R. Perlman, PhD, the Mabel Greene Myers Professor of Medicine and chief of the division of rheumatology at Northwestern University, Chicago, said in an interview.
Dr. Perlman is the principle investigator for the REASON (Rheumatoid Arthritis Synovial Tissue Network) study, and in a 2018 report on the network’s efforts to train participants across the United States in ultrasound-guided joint biopsy techniques and to collect and analyze synovial tissue samples submitted by the six participating centers, he and the coinvestigators explained why a precision approach can’t come soon enough.
“Currently, the standard of care for RA is to prescribe biologic therapy through a costly and time‐consuming trial‐and‐error process. Therefore, the utility of a biomarker to identify how a patient will respond to a particular therapy cannot be overstated,” they wrote (Arthritis Rheumatol. 2018 Jun;70[6]:841-54).
Since that REASON report was published, efforts by the investigators and others, such as those involved with the Accelerating Medicines Partnership (AMP) in RA and Lupus Network, to identify such biomarkers have continued to yield encouraging results.
In fact, data from the phase 4 R4-RA (Response, Relapse and Resistance to Rituximab Therapy in patients with RA) trial – the first randomized, controlled, biopsy-driven trial in RA – were reported in November 2019 at the annual meeting of the American College of Rheumatology. R4-RA demonstrated that patients with B cell–poor RA identified on synovial tissue biopsy (STB) responded better to tocilizumab (Actemra) than to rituximab (Rituxan), whereas those with B cell–rich RA on STB did not, Constantino Pitzalis, MD, head of the Centre for Experimental Medicine & Rheumatology at Queen Mary University of London said, noting that the findings could have “massive implications” for RA management and outcomes.
Numerous treatments exist for RA, but methods for determining which to use for a given patient are sorely lacking and the field of rheumatology lags behind others, like oncology, in bringing individualized medicine to the clinic, he explained.
Why STB?
Despite extensive efforts, blood testing has failed to yield markers sufficient for guiding RA treatment, and although the synovium has long been considered a potentially better source of information to guide treatment given the damage it sustains from RA, biopsies have generally been accessible only during arthroscopic or joint replacement surgery in patients with severe disease, which doesn’t reflect the population of patients who could benefit from early intervention, Dr. Perlman and colleagues explained in their 2018 report.
Musculoskeletal ultrasound (US) technology, however, has advanced dramatically over the past decade, is available and used by rheumatologists in clinical practice, and has brought US-guided joint biopsies to the forefront of research. Such techniques have been used in Europe for years, and as a result, an extensive catalog of literature supports the safety, feasibility, and tolerability of the approach.
A recent study in Portugal by Romao et al., for example, showed “remarkably high” patient tolerability (70%) with 64 US-guided procedures, including 52 in clinical practice and 12 for research purposes. No major adverse events occurred, and biopsy usefulness was high, with 37% having a direct diagnostic impact and with 100% and 95% positive- and negative-predictive values for infection. Further, synovial tissues were retrieved in 88% of biopsies and a median of 75% of samples were gradable (Arthritis Care Res. 2019 Aug 17. doi: 10.1002/acr.24050).
A 2018 study of 524 synovial biopsies, including 402 performed using US-guided needle biopsy, performed at five centers across Europe similarly demonstrated safety and patient tolerability (RMD Open. 2018;4[2]:e000799. doi: 10.1136/mdopen-2018-000799).
Building on the work in Europe, investigators at Northwestern launched the REASON study, assembling a consortium of academic rheumatology groups across the United States, training participants in minimally invasive US-guided joint biopsy techniques, and collecting and analyzing synovial tissue samples submitted by the participating centers.
Laura B. Hughes, MD, a professor at the University of Alabama at Birmingham and an investigator in both the REASON study and AMP, said in an interview that her experience with patients is similar.
“It has been very, very well tolerated,” she said of the biopsy procedure used in the course of the studies – and that’s despite the time and commitment required, she added, explaining that 12 samples, each requiring a separate injection, are obtained over a 30- to 45-minute visit.
“We’ve had no problems, no complications,” she said, also noting the importance of careful patient selection.
Patients are altruistic; they want to be a part of moving things forward and helping other patients, and they have been more than willing to participate, both she and Dr. Perlman noted.
In fact, the REASON study investigators reported that performance of STB by rheumatologists in the United States is feasible and generates high-quality samples.
Further, the transcriptional profiles of isolated RA synovial macrophages identified from samples submitted by Dr. Hughes and others in the network characterized subpopulations of patients and identified six novel transcriptional modules associated with disease activity and therapy, underscoring the potential for precision medicine in RA.
“We posit that transcriptional signatures in macrophages ... will predict responsiveness to specific nonbiologic and/or biologic therapies,” they wrote, adding that future studies will “entail collection of synovial biopsy specimens from a larger cohort longitudinally, prior to, and following therapy.”
The ongoing National Institutes of Health–funded AMP Network research is also using synovial biopsies, but more for identification of molecular pathways with a focus on potential drug development.
A 2019 report from the AMP investigators described their integrated use of single-cell transcriptomics and mass cytometry to reveal cell states expanded in RA synovia and the mapping of inflammatory mediators to their source cell populations, which may be key mediators of RA pathogenesis.
“We observed upregulation of chemokines (CXCL8, CXCL9, and CXCL13), cytokines (IFNG and IL15), and surface receptors (PDGFRB and SMAMF7) in distinct immune and stromal cell populations, suggesting potential novel targets,” they wrote (Nat Immunol. 2019 Jul;20[7]:928-42).
Next steps
These reports, along with the thousands of papers published over the past few decades describing phenotypic and functional abnormalities in synovial tissue obtained from RA patients undergoing joint replacement surgery or, more recently, via STB early in the course of disease, have provided a wealth of information, Helen Michelle McGettrick, MD, noted in an editorial addressing the potential of STB analysis for “unlocking the hidden secrets to personalized medicine.”
The question, however, is whether they have moved the field closer to “translating this discovery science into new biomarkers or drugs to improve diagnosis or prognosis,” she wrote (Arthritis Res Ther. 2019;21[90]. doi: 10.1186/s13075-019-1871-5).
“Three sides of our square are in place: clinical expertise, technology, and patient willingness,” she said, arguing that the fourth side is “standardization in the handling, evaluation, and interpretation of STB.”
In fact, her editorial focused on a joint consensus of the European League Against Rheumatism Synovitis Study Group and the OMERACT Synovial Tissue Biopsy Group (Arthritis Res Ther. 2018;20[265]. doi: 10.1186/s13075-018-1762-1).
The groups, based on member survey responses, proposed a “consensual set of analysis items” to be used for synovial biopsies in clinical practice and translational research, including matters such as biopsy sampling, histologic criteria, and biopsy interpretation. Their work, according to Dr. McGettrick and the authors themselves, marked a step forward, but provided only a foundation for a standardization framework.
One particular area of synovial research that has received recent attention and which illustrates the need for standardization involves the role of synovial B cells in RA. The R4-RA researchers, in conjunction with the Pathobiology of Early Arthritis Cohort, are working to better define the relationship of synovial B cells to clinical RA phenotypes at various disease stages and drug exposures as a potential source of predictive and prognostic biomarkers, and in an article accepted for publication in Arthritis & Rheumatology, they describe a “robust semiquantitative histological B cell score that closely replicates the quantification of B cells by digital or molecular analyses.”
In their study of 329 patients, they demonstrated an ongoing B cell–rich synovitis more prevalent in patients with established RA who had inadequate response to tumor necrosis factor inhibitor therapy than in those with early RA (47.4% vs. 35%), but which does not appear to be captured by standard clinimetric assessment (Arthritis Rheumatol. 2019 Nov 29. doi: 10.1002/art.41184).
“Overall, our study confirms the relevance of synovial B cells in RA and suggests that the classification of patients into B cell–rich/–poor can contribute to patient stratification,” they concluded.
In a related editorial, Dana E. Orange, MD, and Laura T. Donlin, PhD, of the Hospital for Special Surgery, New York, note that previously discrepant findings with respect to the value of B cell infiltrate scores for predicting RA treatment response may relate to the lack of a standardized scoring system (Arthritis Rheumatol. 2019 Nov 29. doi: 10.1002/art.41185).
Together, these emerging findings are “advancing our understanding of the transcriptional and cellular characteristics of the synovium in RA,” they wrote, concluding that incorporation of synovial assessments into clinical management of patients is “the next step in empowering clinicians to apply advances in molecular immunology to better tailor treatment decisions.”
Indeed, an important goal is empowering rheumatologists to become adept in obtaining synovial biopsies in clinical practice, much like gastroenterologists collect tissue for biopsy via colonoscopy, Dr. Pitzalis said in an interview following his R4-RA presentation at the ACR meeting.
Dr. Hughes predicts that a subset will embrace the concept, but not all rheumatologists are interested and not all use musculoskeletal US in their practice.
“It requires a lot of training, there is a credentialing exam, and it’s not necessary for practicing rheumatology, but there is a lot of growth,” she said, noting that training is being promoted through the ACR and other organizations, and Europeans who are well-versed in US-guided STB have served as mentors. “It’s been a nice collaboration, and I think it’s just going to push the field forward ... it really is exciting – I think synovial biopsies will yield a lot of information and really, hopefully, help us target therapy and find new therapeutic targets that we haven’t even thought of.”
However, Dr. Pitzalis stressed that there remains much work to do.
“It’s important to understand this is early data and will require validation in larger and target-driven and biopsy-driven treatment clinical trials,” he said of the R4-RA findings.
Those efforts are underway; the REASON study, for example, is moving forward, having recently been awarded a National Institutes of Health Research Project Grant, Dr. Perlman said, explaining that the latest goal is to determine whether the transcription modules the investigators have identified to date can be predictive of treatment response.
He expects to report outcomes at ACR 2020, and noted that preliminary findings suggest that “we can tell, by 4 weeks, which patients will respond or not.”
Dr. Pitzalis and his colleagues are also working on their “next set of trials,” which are using biopsies for treatment allocation (B cell–poor patients get one drug, B cell–rich patients, another, for example), and he, too said he expects to have additional data to present at ACR 2020.
“If we are to demonstrate clinical utility, I think rheumatology will be ready to implement this methodology in clinical practice,” he said.
The authors interviewed for this article reported having no relevant financial disclosures.
Researchers are mining the synovium for potential treasure: robust markers to bring precision medicine to the rheumatoid arthritis (RA) arena. The signs, according to a number of recent reports, point toward a gold strike via synovial tissue biopsy.
“I have no doubt about that – I am very confident that this concept of going straight to the tissue and using functional genomics will help us stratify our patients and will be a predictive model for patients with respect to therapy,” Harris R. Perlman, PhD, the Mabel Greene Myers Professor of Medicine and chief of the division of rheumatology at Northwestern University, Chicago, said in an interview.
Dr. Perlman is the principle investigator for the REASON (Rheumatoid Arthritis Synovial Tissue Network) study, and in a 2018 report on the network’s efforts to train participants across the United States in ultrasound-guided joint biopsy techniques and to collect and analyze synovial tissue samples submitted by the six participating centers, he and the coinvestigators explained why a precision approach can’t come soon enough.
“Currently, the standard of care for RA is to prescribe biologic therapy through a costly and time‐consuming trial‐and‐error process. Therefore, the utility of a biomarker to identify how a patient will respond to a particular therapy cannot be overstated,” they wrote (Arthritis Rheumatol. 2018 Jun;70[6]:841-54).
Since that REASON report was published, efforts by the investigators and others, such as those involved with the Accelerating Medicines Partnership (AMP) in RA and Lupus Network, to identify such biomarkers have continued to yield encouraging results.
In fact, data from the phase 4 R4-RA (Response, Relapse and Resistance to Rituximab Therapy in patients with RA) trial – the first randomized, controlled, biopsy-driven trial in RA – were reported in November 2019 at the annual meeting of the American College of Rheumatology. R4-RA demonstrated that patients with B cell–poor RA identified on synovial tissue biopsy (STB) responded better to tocilizumab (Actemra) than to rituximab (Rituxan), whereas those with B cell–rich RA on STB did not, Constantino Pitzalis, MD, head of the Centre for Experimental Medicine & Rheumatology at Queen Mary University of London said, noting that the findings could have “massive implications” for RA management and outcomes.
Numerous treatments exist for RA, but methods for determining which to use for a given patient are sorely lacking and the field of rheumatology lags behind others, like oncology, in bringing individualized medicine to the clinic, he explained.
Why STB?
Despite extensive efforts, blood testing has failed to yield markers sufficient for guiding RA treatment, and although the synovium has long been considered a potentially better source of information to guide treatment given the damage it sustains from RA, biopsies have generally been accessible only during arthroscopic or joint replacement surgery in patients with severe disease, which doesn’t reflect the population of patients who could benefit from early intervention, Dr. Perlman and colleagues explained in their 2018 report.
Musculoskeletal ultrasound (US) technology, however, has advanced dramatically over the past decade, is available and used by rheumatologists in clinical practice, and has brought US-guided joint biopsies to the forefront of research. Such techniques have been used in Europe for years, and as a result, an extensive catalog of literature supports the safety, feasibility, and tolerability of the approach.
A recent study in Portugal by Romao et al., for example, showed “remarkably high” patient tolerability (70%) with 64 US-guided procedures, including 52 in clinical practice and 12 for research purposes. No major adverse events occurred, and biopsy usefulness was high, with 37% having a direct diagnostic impact and with 100% and 95% positive- and negative-predictive values for infection. Further, synovial tissues were retrieved in 88% of biopsies and a median of 75% of samples were gradable (Arthritis Care Res. 2019 Aug 17. doi: 10.1002/acr.24050).
A 2018 study of 524 synovial biopsies, including 402 performed using US-guided needle biopsy, performed at five centers across Europe similarly demonstrated safety and patient tolerability (RMD Open. 2018;4[2]:e000799. doi: 10.1136/mdopen-2018-000799).
Building on the work in Europe, investigators at Northwestern launched the REASON study, assembling a consortium of academic rheumatology groups across the United States, training participants in minimally invasive US-guided joint biopsy techniques, and collecting and analyzing synovial tissue samples submitted by the participating centers.
Laura B. Hughes, MD, a professor at the University of Alabama at Birmingham and an investigator in both the REASON study and AMP, said in an interview that her experience with patients is similar.
“It has been very, very well tolerated,” she said of the biopsy procedure used in the course of the studies – and that’s despite the time and commitment required, she added, explaining that 12 samples, each requiring a separate injection, are obtained over a 30- to 45-minute visit.
“We’ve had no problems, no complications,” she said, also noting the importance of careful patient selection.
Patients are altruistic; they want to be a part of moving things forward and helping other patients, and they have been more than willing to participate, both she and Dr. Perlman noted.
In fact, the REASON study investigators reported that performance of STB by rheumatologists in the United States is feasible and generates high-quality samples.
Further, the transcriptional profiles of isolated RA synovial macrophages identified from samples submitted by Dr. Hughes and others in the network characterized subpopulations of patients and identified six novel transcriptional modules associated with disease activity and therapy, underscoring the potential for precision medicine in RA.
“We posit that transcriptional signatures in macrophages ... will predict responsiveness to specific nonbiologic and/or biologic therapies,” they wrote, adding that future studies will “entail collection of synovial biopsy specimens from a larger cohort longitudinally, prior to, and following therapy.”
The ongoing National Institutes of Health–funded AMP Network research is also using synovial biopsies, but more for identification of molecular pathways with a focus on potential drug development.
A 2019 report from the AMP investigators described their integrated use of single-cell transcriptomics and mass cytometry to reveal cell states expanded in RA synovia and the mapping of inflammatory mediators to their source cell populations, which may be key mediators of RA pathogenesis.
“We observed upregulation of chemokines (CXCL8, CXCL9, and CXCL13), cytokines (IFNG and IL15), and surface receptors (PDGFRB and SMAMF7) in distinct immune and stromal cell populations, suggesting potential novel targets,” they wrote (Nat Immunol. 2019 Jul;20[7]:928-42).
Next steps
These reports, along with the thousands of papers published over the past few decades describing phenotypic and functional abnormalities in synovial tissue obtained from RA patients undergoing joint replacement surgery or, more recently, via STB early in the course of disease, have provided a wealth of information, Helen Michelle McGettrick, MD, noted in an editorial addressing the potential of STB analysis for “unlocking the hidden secrets to personalized medicine.”
The question, however, is whether they have moved the field closer to “translating this discovery science into new biomarkers or drugs to improve diagnosis or prognosis,” she wrote (Arthritis Res Ther. 2019;21[90]. doi: 10.1186/s13075-019-1871-5).
“Three sides of our square are in place: clinical expertise, technology, and patient willingness,” she said, arguing that the fourth side is “standardization in the handling, evaluation, and interpretation of STB.”
In fact, her editorial focused on a joint consensus of the European League Against Rheumatism Synovitis Study Group and the OMERACT Synovial Tissue Biopsy Group (Arthritis Res Ther. 2018;20[265]. doi: 10.1186/s13075-018-1762-1).
The groups, based on member survey responses, proposed a “consensual set of analysis items” to be used for synovial biopsies in clinical practice and translational research, including matters such as biopsy sampling, histologic criteria, and biopsy interpretation. Their work, according to Dr. McGettrick and the authors themselves, marked a step forward, but provided only a foundation for a standardization framework.
One particular area of synovial research that has received recent attention and which illustrates the need for standardization involves the role of synovial B cells in RA. The R4-RA researchers, in conjunction with the Pathobiology of Early Arthritis Cohort, are working to better define the relationship of synovial B cells to clinical RA phenotypes at various disease stages and drug exposures as a potential source of predictive and prognostic biomarkers, and in an article accepted for publication in Arthritis & Rheumatology, they describe a “robust semiquantitative histological B cell score that closely replicates the quantification of B cells by digital or molecular analyses.”
In their study of 329 patients, they demonstrated an ongoing B cell–rich synovitis more prevalent in patients with established RA who had inadequate response to tumor necrosis factor inhibitor therapy than in those with early RA (47.4% vs. 35%), but which does not appear to be captured by standard clinimetric assessment (Arthritis Rheumatol. 2019 Nov 29. doi: 10.1002/art.41184).
“Overall, our study confirms the relevance of synovial B cells in RA and suggests that the classification of patients into B cell–rich/–poor can contribute to patient stratification,” they concluded.
In a related editorial, Dana E. Orange, MD, and Laura T. Donlin, PhD, of the Hospital for Special Surgery, New York, note that previously discrepant findings with respect to the value of B cell infiltrate scores for predicting RA treatment response may relate to the lack of a standardized scoring system (Arthritis Rheumatol. 2019 Nov 29. doi: 10.1002/art.41185).
Together, these emerging findings are “advancing our understanding of the transcriptional and cellular characteristics of the synovium in RA,” they wrote, concluding that incorporation of synovial assessments into clinical management of patients is “the next step in empowering clinicians to apply advances in molecular immunology to better tailor treatment decisions.”
Indeed, an important goal is empowering rheumatologists to become adept in obtaining synovial biopsies in clinical practice, much like gastroenterologists collect tissue for biopsy via colonoscopy, Dr. Pitzalis said in an interview following his R4-RA presentation at the ACR meeting.
Dr. Hughes predicts that a subset will embrace the concept, but not all rheumatologists are interested and not all use musculoskeletal US in their practice.
“It requires a lot of training, there is a credentialing exam, and it’s not necessary for practicing rheumatology, but there is a lot of growth,” she said, noting that training is being promoted through the ACR and other organizations, and Europeans who are well-versed in US-guided STB have served as mentors. “It’s been a nice collaboration, and I think it’s just going to push the field forward ... it really is exciting – I think synovial biopsies will yield a lot of information and really, hopefully, help us target therapy and find new therapeutic targets that we haven’t even thought of.”
However, Dr. Pitzalis stressed that there remains much work to do.
“It’s important to understand this is early data and will require validation in larger and target-driven and biopsy-driven treatment clinical trials,” he said of the R4-RA findings.
Those efforts are underway; the REASON study, for example, is moving forward, having recently been awarded a National Institutes of Health Research Project Grant, Dr. Perlman said, explaining that the latest goal is to determine whether the transcription modules the investigators have identified to date can be predictive of treatment response.
He expects to report outcomes at ACR 2020, and noted that preliminary findings suggest that “we can tell, by 4 weeks, which patients will respond or not.”
Dr. Pitzalis and his colleagues are also working on their “next set of trials,” which are using biopsies for treatment allocation (B cell–poor patients get one drug, B cell–rich patients, another, for example), and he, too said he expects to have additional data to present at ACR 2020.
“If we are to demonstrate clinical utility, I think rheumatology will be ready to implement this methodology in clinical practice,” he said.
The authors interviewed for this article reported having no relevant financial disclosures.
Researchers are mining the synovium for potential treasure: robust markers to bring precision medicine to the rheumatoid arthritis (RA) arena. The signs, according to a number of recent reports, point toward a gold strike via synovial tissue biopsy.
“I have no doubt about that – I am very confident that this concept of going straight to the tissue and using functional genomics will help us stratify our patients and will be a predictive model for patients with respect to therapy,” Harris R. Perlman, PhD, the Mabel Greene Myers Professor of Medicine and chief of the division of rheumatology at Northwestern University, Chicago, said in an interview.
Dr. Perlman is the principle investigator for the REASON (Rheumatoid Arthritis Synovial Tissue Network) study, and in a 2018 report on the network’s efforts to train participants across the United States in ultrasound-guided joint biopsy techniques and to collect and analyze synovial tissue samples submitted by the six participating centers, he and the coinvestigators explained why a precision approach can’t come soon enough.
“Currently, the standard of care for RA is to prescribe biologic therapy through a costly and time‐consuming trial‐and‐error process. Therefore, the utility of a biomarker to identify how a patient will respond to a particular therapy cannot be overstated,” they wrote (Arthritis Rheumatol. 2018 Jun;70[6]:841-54).
Since that REASON report was published, efforts by the investigators and others, such as those involved with the Accelerating Medicines Partnership (AMP) in RA and Lupus Network, to identify such biomarkers have continued to yield encouraging results.
In fact, data from the phase 4 R4-RA (Response, Relapse and Resistance to Rituximab Therapy in patients with RA) trial – the first randomized, controlled, biopsy-driven trial in RA – were reported in November 2019 at the annual meeting of the American College of Rheumatology. R4-RA demonstrated that patients with B cell–poor RA identified on synovial tissue biopsy (STB) responded better to tocilizumab (Actemra) than to rituximab (Rituxan), whereas those with B cell–rich RA on STB did not, Constantino Pitzalis, MD, head of the Centre for Experimental Medicine & Rheumatology at Queen Mary University of London said, noting that the findings could have “massive implications” for RA management and outcomes.
Numerous treatments exist for RA, but methods for determining which to use for a given patient are sorely lacking and the field of rheumatology lags behind others, like oncology, in bringing individualized medicine to the clinic, he explained.
Why STB?
Despite extensive efforts, blood testing has failed to yield markers sufficient for guiding RA treatment, and although the synovium has long been considered a potentially better source of information to guide treatment given the damage it sustains from RA, biopsies have generally been accessible only during arthroscopic or joint replacement surgery in patients with severe disease, which doesn’t reflect the population of patients who could benefit from early intervention, Dr. Perlman and colleagues explained in their 2018 report.
Musculoskeletal ultrasound (US) technology, however, has advanced dramatically over the past decade, is available and used by rheumatologists in clinical practice, and has brought US-guided joint biopsies to the forefront of research. Such techniques have been used in Europe for years, and as a result, an extensive catalog of literature supports the safety, feasibility, and tolerability of the approach.
A recent study in Portugal by Romao et al., for example, showed “remarkably high” patient tolerability (70%) with 64 US-guided procedures, including 52 in clinical practice and 12 for research purposes. No major adverse events occurred, and biopsy usefulness was high, with 37% having a direct diagnostic impact and with 100% and 95% positive- and negative-predictive values for infection. Further, synovial tissues were retrieved in 88% of biopsies and a median of 75% of samples were gradable (Arthritis Care Res. 2019 Aug 17. doi: 10.1002/acr.24050).
A 2018 study of 524 synovial biopsies, including 402 performed using US-guided needle biopsy, performed at five centers across Europe similarly demonstrated safety and patient tolerability (RMD Open. 2018;4[2]:e000799. doi: 10.1136/mdopen-2018-000799).
Building on the work in Europe, investigators at Northwestern launched the REASON study, assembling a consortium of academic rheumatology groups across the United States, training participants in minimally invasive US-guided joint biopsy techniques, and collecting and analyzing synovial tissue samples submitted by the participating centers.
Laura B. Hughes, MD, a professor at the University of Alabama at Birmingham and an investigator in both the REASON study and AMP, said in an interview that her experience with patients is similar.
“It has been very, very well tolerated,” she said of the biopsy procedure used in the course of the studies – and that’s despite the time and commitment required, she added, explaining that 12 samples, each requiring a separate injection, are obtained over a 30- to 45-minute visit.
“We’ve had no problems, no complications,” she said, also noting the importance of careful patient selection.
Patients are altruistic; they want to be a part of moving things forward and helping other patients, and they have been more than willing to participate, both she and Dr. Perlman noted.
In fact, the REASON study investigators reported that performance of STB by rheumatologists in the United States is feasible and generates high-quality samples.
Further, the transcriptional profiles of isolated RA synovial macrophages identified from samples submitted by Dr. Hughes and others in the network characterized subpopulations of patients and identified six novel transcriptional modules associated with disease activity and therapy, underscoring the potential for precision medicine in RA.
“We posit that transcriptional signatures in macrophages ... will predict responsiveness to specific nonbiologic and/or biologic therapies,” they wrote, adding that future studies will “entail collection of synovial biopsy specimens from a larger cohort longitudinally, prior to, and following therapy.”
The ongoing National Institutes of Health–funded AMP Network research is also using synovial biopsies, but more for identification of molecular pathways with a focus on potential drug development.
A 2019 report from the AMP investigators described their integrated use of single-cell transcriptomics and mass cytometry to reveal cell states expanded in RA synovia and the mapping of inflammatory mediators to their source cell populations, which may be key mediators of RA pathogenesis.
“We observed upregulation of chemokines (CXCL8, CXCL9, and CXCL13), cytokines (IFNG and IL15), and surface receptors (PDGFRB and SMAMF7) in distinct immune and stromal cell populations, suggesting potential novel targets,” they wrote (Nat Immunol. 2019 Jul;20[7]:928-42).
Next steps
These reports, along with the thousands of papers published over the past few decades describing phenotypic and functional abnormalities in synovial tissue obtained from RA patients undergoing joint replacement surgery or, more recently, via STB early in the course of disease, have provided a wealth of information, Helen Michelle McGettrick, MD, noted in an editorial addressing the potential of STB analysis for “unlocking the hidden secrets to personalized medicine.”
The question, however, is whether they have moved the field closer to “translating this discovery science into new biomarkers or drugs to improve diagnosis or prognosis,” she wrote (Arthritis Res Ther. 2019;21[90]. doi: 10.1186/s13075-019-1871-5).
“Three sides of our square are in place: clinical expertise, technology, and patient willingness,” she said, arguing that the fourth side is “standardization in the handling, evaluation, and interpretation of STB.”
In fact, her editorial focused on a joint consensus of the European League Against Rheumatism Synovitis Study Group and the OMERACT Synovial Tissue Biopsy Group (Arthritis Res Ther. 2018;20[265]. doi: 10.1186/s13075-018-1762-1).
The groups, based on member survey responses, proposed a “consensual set of analysis items” to be used for synovial biopsies in clinical practice and translational research, including matters such as biopsy sampling, histologic criteria, and biopsy interpretation. Their work, according to Dr. McGettrick and the authors themselves, marked a step forward, but provided only a foundation for a standardization framework.
One particular area of synovial research that has received recent attention and which illustrates the need for standardization involves the role of synovial B cells in RA. The R4-RA researchers, in conjunction with the Pathobiology of Early Arthritis Cohort, are working to better define the relationship of synovial B cells to clinical RA phenotypes at various disease stages and drug exposures as a potential source of predictive and prognostic biomarkers, and in an article accepted for publication in Arthritis & Rheumatology, they describe a “robust semiquantitative histological B cell score that closely replicates the quantification of B cells by digital or molecular analyses.”
In their study of 329 patients, they demonstrated an ongoing B cell–rich synovitis more prevalent in patients with established RA who had inadequate response to tumor necrosis factor inhibitor therapy than in those with early RA (47.4% vs. 35%), but which does not appear to be captured by standard clinimetric assessment (Arthritis Rheumatol. 2019 Nov 29. doi: 10.1002/art.41184).
“Overall, our study confirms the relevance of synovial B cells in RA and suggests that the classification of patients into B cell–rich/–poor can contribute to patient stratification,” they concluded.
In a related editorial, Dana E. Orange, MD, and Laura T. Donlin, PhD, of the Hospital for Special Surgery, New York, note that previously discrepant findings with respect to the value of B cell infiltrate scores for predicting RA treatment response may relate to the lack of a standardized scoring system (Arthritis Rheumatol. 2019 Nov 29. doi: 10.1002/art.41185).
Together, these emerging findings are “advancing our understanding of the transcriptional and cellular characteristics of the synovium in RA,” they wrote, concluding that incorporation of synovial assessments into clinical management of patients is “the next step in empowering clinicians to apply advances in molecular immunology to better tailor treatment decisions.”
Indeed, an important goal is empowering rheumatologists to become adept in obtaining synovial biopsies in clinical practice, much like gastroenterologists collect tissue for biopsy via colonoscopy, Dr. Pitzalis said in an interview following his R4-RA presentation at the ACR meeting.
Dr. Hughes predicts that a subset will embrace the concept, but not all rheumatologists are interested and not all use musculoskeletal US in their practice.
“It requires a lot of training, there is a credentialing exam, and it’s not necessary for practicing rheumatology, but there is a lot of growth,” she said, noting that training is being promoted through the ACR and other organizations, and Europeans who are well-versed in US-guided STB have served as mentors. “It’s been a nice collaboration, and I think it’s just going to push the field forward ... it really is exciting – I think synovial biopsies will yield a lot of information and really, hopefully, help us target therapy and find new therapeutic targets that we haven’t even thought of.”
However, Dr. Pitzalis stressed that there remains much work to do.
“It’s important to understand this is early data and will require validation in larger and target-driven and biopsy-driven treatment clinical trials,” he said of the R4-RA findings.
Those efforts are underway; the REASON study, for example, is moving forward, having recently been awarded a National Institutes of Health Research Project Grant, Dr. Perlman said, explaining that the latest goal is to determine whether the transcription modules the investigators have identified to date can be predictive of treatment response.
He expects to report outcomes at ACR 2020, and noted that preliminary findings suggest that “we can tell, by 4 weeks, which patients will respond or not.”
Dr. Pitzalis and his colleagues are also working on their “next set of trials,” which are using biopsies for treatment allocation (B cell–poor patients get one drug, B cell–rich patients, another, for example), and he, too said he expects to have additional data to present at ACR 2020.
“If we are to demonstrate clinical utility, I think rheumatology will be ready to implement this methodology in clinical practice,” he said.
The authors interviewed for this article reported having no relevant financial disclosures.
Low-dose methotrexate trial pins down adverse event rates
A new study has found an elevated risk of some adverse events in patients treated with low-dose methotrexate, compared with patients treated with placebo.
“The data presented here provide an important source of new evidence to improve the monitoring guidelines and safe prescribing of LD-MTX [low-dose methotrexate],” wrote Daniel H. Solomon, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, and coauthors. The study was published in Annals of Internal Medicine.
To determine the rates of adverse events (AEs) among LD-MTX users, along with assessing the risks of certain predefined AEs, the researchers enrolled 6,158 patients in the Cardiovascular Inflammation Reduction Trial (CIRT) and randomized 4,786 of those patients to two groups: those receiving LD-MTX (n = 2,391) and those receiving placebo (n = 2,395). The median dose was 15 mg per week, and median follow-up was 23 months. All participants in CIRT had a history of cardiovascular disease, along with diabetes or metabolic syndrome. Just over 81% of the participants were male, and nearly 85% were white. Their median age was nearly 66 years.
Of the participants in the LD-MTX group, 2,156 (90.2%) had an AE and 2,080 (87.0%) had an AE of interest, which included infectious, hematologic, pulmonary, hepatic, cancerous, and gastrointestinal AEs. Of the participants in the placebo group, 2,076 (86.7%) had an AE and 1,951 (81.5%) had an AE of interest. As such, the relative rate of an AE of interest was 17% higher in the LD-MTX group (hazard ratio, 1.17; 95% confidence interval, 1.10-1.25).
In regard to specific types of AEs, the rates of gastrointestinal (HR, 1.23; 95% CI, 1.03-1.47), pulmonary (HR, 1.42; 95% CI, 1.14-1.77), infectious (HR, 1.15; 95% CI, 1.01-1.30) and hematologic (HR, 1.22; 95% CI, 1.11-1.34) were higher for participants in the LD-MTX group. Five cases of cirrhosis were found in the LD-MTX group, compared with none in the placebo group; none of the patients with cirrhosis had severe liver test abnormalities before their diagnosis. While the risk of cancer overall was not elevated in the LD-MTX group, 53 participants in that group developed skin cancer, compared with 26 in the placebo group (HR, 2.04; 95% CI, 1.28-3.26). Renal AEs were among the few that decreased in LD-MTX users (HR, 0.85; 95% CI, 0.78-0.93).
“Methotrexate has become the standard of care for RA patients,” Dr. Solomon said in an interview, “and because it worked so well, we accepted it without large placebo-controlled trials and without a precise understanding of the risk factors for AEs. Until this study, our evidence basis for the side-effect profile was relatively weak.
“We had a limited data set but decades of experience,” he added. “Now we have better evidence, for example, that methotrexate is associated with elevations in liver function tests. We even found five cases of cirrhosis. And the people who developed cirrhosis didn’t have severe test abnormalities; just minor ones over many months. So now we have a better understanding of the potential impact of minor, yet chronic abnormalities.”
Dr. Solomon and coauthors acknowledged their study’s limitations, including CIRT not including patients with systemic rheumatic disease and the possibility that participants did not report AEs that occurred in between routine study visits. In addition, although the median follow-up of nearly 2 years was longer than in other LD-MTX trials, they noted that “it may still be too short to observe some AEs that require long-term exposure.”
Dr. Solomon and colleagues should be commended for undertaking a long-awaited randomized, placebo-controlled trial that adds much-needed insight into how and when to monitor patients being treated with MTX, Vivian P. Bykerk, MD, of the Hospital for Special Surgery and Weill Cornell Medical College in New York, wrote in an editorial (Ann Intern Med. 2020 Feb 17. doi: 10.7326/M20-0435).
Dr. Bykerk noted that although the results may not be applicable to patients with RA and other inflammatory arthritides who are treated with MTX – RA patients in particular are younger, more often female, have lower rates of diabetes, and usually receive higher doses than those used in CIRT — the risk estimates from the CIRT study are “largely congruent with those expected in MTX-treated patients with rheumatic diseases.”
Regardless, she emphasized that this is a step in a much-needed direction, reminding physicians that “MTX use has inherent risks” and that its AEs, although infrequent, are clinically serious.
The National Institutes of Health funded the study. Various authors reported receiving grants from the National Heart, Lung, and Blood Institute, along with grants, research support, and personal fees from numerous pharmaceutical companies before and during the study. Dr. Bykerk reported receiving personal fees, grants, and nonfinancial support from pharmaceutical companies, foundations, and the NIH.
SOURCE: Solomon DH et al. Ann Intern Med. 2020 Feb 17. doi: 10.7326/M19-3369.
A new study has found an elevated risk of some adverse events in patients treated with low-dose methotrexate, compared with patients treated with placebo.
“The data presented here provide an important source of new evidence to improve the monitoring guidelines and safe prescribing of LD-MTX [low-dose methotrexate],” wrote Daniel H. Solomon, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, and coauthors. The study was published in Annals of Internal Medicine.
To determine the rates of adverse events (AEs) among LD-MTX users, along with assessing the risks of certain predefined AEs, the researchers enrolled 6,158 patients in the Cardiovascular Inflammation Reduction Trial (CIRT) and randomized 4,786 of those patients to two groups: those receiving LD-MTX (n = 2,391) and those receiving placebo (n = 2,395). The median dose was 15 mg per week, and median follow-up was 23 months. All participants in CIRT had a history of cardiovascular disease, along with diabetes or metabolic syndrome. Just over 81% of the participants were male, and nearly 85% were white. Their median age was nearly 66 years.
Of the participants in the LD-MTX group, 2,156 (90.2%) had an AE and 2,080 (87.0%) had an AE of interest, which included infectious, hematologic, pulmonary, hepatic, cancerous, and gastrointestinal AEs. Of the participants in the placebo group, 2,076 (86.7%) had an AE and 1,951 (81.5%) had an AE of interest. As such, the relative rate of an AE of interest was 17% higher in the LD-MTX group (hazard ratio, 1.17; 95% confidence interval, 1.10-1.25).
In regard to specific types of AEs, the rates of gastrointestinal (HR, 1.23; 95% CI, 1.03-1.47), pulmonary (HR, 1.42; 95% CI, 1.14-1.77), infectious (HR, 1.15; 95% CI, 1.01-1.30) and hematologic (HR, 1.22; 95% CI, 1.11-1.34) were higher for participants in the LD-MTX group. Five cases of cirrhosis were found in the LD-MTX group, compared with none in the placebo group; none of the patients with cirrhosis had severe liver test abnormalities before their diagnosis. While the risk of cancer overall was not elevated in the LD-MTX group, 53 participants in that group developed skin cancer, compared with 26 in the placebo group (HR, 2.04; 95% CI, 1.28-3.26). Renal AEs were among the few that decreased in LD-MTX users (HR, 0.85; 95% CI, 0.78-0.93).
“Methotrexate has become the standard of care for RA patients,” Dr. Solomon said in an interview, “and because it worked so well, we accepted it without large placebo-controlled trials and without a precise understanding of the risk factors for AEs. Until this study, our evidence basis for the side-effect profile was relatively weak.
“We had a limited data set but decades of experience,” he added. “Now we have better evidence, for example, that methotrexate is associated with elevations in liver function tests. We even found five cases of cirrhosis. And the people who developed cirrhosis didn’t have severe test abnormalities; just minor ones over many months. So now we have a better understanding of the potential impact of minor, yet chronic abnormalities.”
Dr. Solomon and coauthors acknowledged their study’s limitations, including CIRT not including patients with systemic rheumatic disease and the possibility that participants did not report AEs that occurred in between routine study visits. In addition, although the median follow-up of nearly 2 years was longer than in other LD-MTX trials, they noted that “it may still be too short to observe some AEs that require long-term exposure.”
Dr. Solomon and colleagues should be commended for undertaking a long-awaited randomized, placebo-controlled trial that adds much-needed insight into how and when to monitor patients being treated with MTX, Vivian P. Bykerk, MD, of the Hospital for Special Surgery and Weill Cornell Medical College in New York, wrote in an editorial (Ann Intern Med. 2020 Feb 17. doi: 10.7326/M20-0435).
Dr. Bykerk noted that although the results may not be applicable to patients with RA and other inflammatory arthritides who are treated with MTX – RA patients in particular are younger, more often female, have lower rates of diabetes, and usually receive higher doses than those used in CIRT — the risk estimates from the CIRT study are “largely congruent with those expected in MTX-treated patients with rheumatic diseases.”
Regardless, she emphasized that this is a step in a much-needed direction, reminding physicians that “MTX use has inherent risks” and that its AEs, although infrequent, are clinically serious.
The National Institutes of Health funded the study. Various authors reported receiving grants from the National Heart, Lung, and Blood Institute, along with grants, research support, and personal fees from numerous pharmaceutical companies before and during the study. Dr. Bykerk reported receiving personal fees, grants, and nonfinancial support from pharmaceutical companies, foundations, and the NIH.
SOURCE: Solomon DH et al. Ann Intern Med. 2020 Feb 17. doi: 10.7326/M19-3369.
A new study has found an elevated risk of some adverse events in patients treated with low-dose methotrexate, compared with patients treated with placebo.
“The data presented here provide an important source of new evidence to improve the monitoring guidelines and safe prescribing of LD-MTX [low-dose methotrexate],” wrote Daniel H. Solomon, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, and coauthors. The study was published in Annals of Internal Medicine.
To determine the rates of adverse events (AEs) among LD-MTX users, along with assessing the risks of certain predefined AEs, the researchers enrolled 6,158 patients in the Cardiovascular Inflammation Reduction Trial (CIRT) and randomized 4,786 of those patients to two groups: those receiving LD-MTX (n = 2,391) and those receiving placebo (n = 2,395). The median dose was 15 mg per week, and median follow-up was 23 months. All participants in CIRT had a history of cardiovascular disease, along with diabetes or metabolic syndrome. Just over 81% of the participants were male, and nearly 85% were white. Their median age was nearly 66 years.
Of the participants in the LD-MTX group, 2,156 (90.2%) had an AE and 2,080 (87.0%) had an AE of interest, which included infectious, hematologic, pulmonary, hepatic, cancerous, and gastrointestinal AEs. Of the participants in the placebo group, 2,076 (86.7%) had an AE and 1,951 (81.5%) had an AE of interest. As such, the relative rate of an AE of interest was 17% higher in the LD-MTX group (hazard ratio, 1.17; 95% confidence interval, 1.10-1.25).
In regard to specific types of AEs, the rates of gastrointestinal (HR, 1.23; 95% CI, 1.03-1.47), pulmonary (HR, 1.42; 95% CI, 1.14-1.77), infectious (HR, 1.15; 95% CI, 1.01-1.30) and hematologic (HR, 1.22; 95% CI, 1.11-1.34) were higher for participants in the LD-MTX group. Five cases of cirrhosis were found in the LD-MTX group, compared with none in the placebo group; none of the patients with cirrhosis had severe liver test abnormalities before their diagnosis. While the risk of cancer overall was not elevated in the LD-MTX group, 53 participants in that group developed skin cancer, compared with 26 in the placebo group (HR, 2.04; 95% CI, 1.28-3.26). Renal AEs were among the few that decreased in LD-MTX users (HR, 0.85; 95% CI, 0.78-0.93).
“Methotrexate has become the standard of care for RA patients,” Dr. Solomon said in an interview, “and because it worked so well, we accepted it without large placebo-controlled trials and without a precise understanding of the risk factors for AEs. Until this study, our evidence basis for the side-effect profile was relatively weak.
“We had a limited data set but decades of experience,” he added. “Now we have better evidence, for example, that methotrexate is associated with elevations in liver function tests. We even found five cases of cirrhosis. And the people who developed cirrhosis didn’t have severe test abnormalities; just minor ones over many months. So now we have a better understanding of the potential impact of minor, yet chronic abnormalities.”
Dr. Solomon and coauthors acknowledged their study’s limitations, including CIRT not including patients with systemic rheumatic disease and the possibility that participants did not report AEs that occurred in between routine study visits. In addition, although the median follow-up of nearly 2 years was longer than in other LD-MTX trials, they noted that “it may still be too short to observe some AEs that require long-term exposure.”
Dr. Solomon and colleagues should be commended for undertaking a long-awaited randomized, placebo-controlled trial that adds much-needed insight into how and when to monitor patients being treated with MTX, Vivian P. Bykerk, MD, of the Hospital for Special Surgery and Weill Cornell Medical College in New York, wrote in an editorial (Ann Intern Med. 2020 Feb 17. doi: 10.7326/M20-0435).
Dr. Bykerk noted that although the results may not be applicable to patients with RA and other inflammatory arthritides who are treated with MTX – RA patients in particular are younger, more often female, have lower rates of diabetes, and usually receive higher doses than those used in CIRT — the risk estimates from the CIRT study are “largely congruent with those expected in MTX-treated patients with rheumatic diseases.”
Regardless, she emphasized that this is a step in a much-needed direction, reminding physicians that “MTX use has inherent risks” and that its AEs, although infrequent, are clinically serious.
The National Institutes of Health funded the study. Various authors reported receiving grants from the National Heart, Lung, and Blood Institute, along with grants, research support, and personal fees from numerous pharmaceutical companies before and during the study. Dr. Bykerk reported receiving personal fees, grants, and nonfinancial support from pharmaceutical companies, foundations, and the NIH.
SOURCE: Solomon DH et al. Ann Intern Med. 2020 Feb 17. doi: 10.7326/M19-3369.
FROM ANNALS OF INTERNAL MEDICINE
Value of very early etanercept plus methotrexate not confirmed in real-world RA trial
, investigators say.
A remission rate of 52% was seen with first-line etanercept plus methotrexate, compared with 38% for a strategy of methotrexate escalated to add etanercept in patients not in remission at 24 weeks in the study, known as VEDERA (Very Early Versus Delayed Etanercept in Patients With RA).
Investigators said a difference of 14 percentage points between remission rates was comparable to what was seen among patients with early RA in an earlier randomized trial of etanercept plus methotrexate versus methotrexate monotherapy.
However, the difference was not on par with the “larger than standard” effect of about 30% seen in an exploratory analysis of the very early RA subset in that previous study, according to VEDERA study authors, led by Paul Emery, MD, of the University of Leeds (England).
Taken together, the results highlight a “ceiling effect” in achieving remission in this real-life, treatment-naive cohort, Dr. Emery and coauthors noted in their report, which appears in Annals of the Rheumatic Diseases.
The study population aligned with real-world clinical practice, according to the investigators, who noted that half the cohort had at least one comorbidity.
“This may have partly driven the generally poorer than expected performance, the exact mechanisms for which are unclear,” they wrote in their discussion of results.
Delaying etanercept until failure of methotrexate, instead of giving both drugs up front, was linked to poorer etanercept response in an exploratory analysis of VEDERA. However, Dr. Emery and coinvestigators noted that this finding “requires validation and further investigation.”
While first-line etanercept plus methotrexate is a “clinically appropriate approach” in early RA, results of the VEDERA study don’t help to inform clinicians as to when it would be prudent to select that therapeutic approach, said Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles.
“Whether you’re treating with methotrexate or methotrexate plus etanercept, they do pretty well,” Dr. Furst said in an interview. “What that says to me is when you have patients with very early RA and the disease is moderately active, you should really try methotrexate before you add expensive other drugs.”
The phase 4, open-label, randomized VEDERA trial included 120 adult patients with new-onset early RA with symptom duration of less than 12 months. All patients in VEDERA had a 28-joint disease activity score based on erythrocyte sedimentation rate (DAS28-ESR) of 3.2 or greater and clinical evidence of synovitis. They were all positive for anti-citrullinated peptide antibody or rheumatoid factor, or had evidence of disease activity in at least one joint by power Doppler ultrasonography.
The patients were randomized to 48 weeks of treatment with either first-line etanercept plus methotrexate, or with methotrexate in a treat-to-target strategy that called for the addition of etanercept if the DAS28-ESR was still 2.6 or greater at 24 weeks.
Based on results of the earlier trial, known as COMET, a confirmatory remission rate in the etanercept plus methotrexate arm was anticipated to be 70%, versus 40% for the methotrexate treat-to-target arm, investigators said in a discussion of their statistical methods.
Study results did not confirm a large effect size, according to the investigators. By week 48, DAS28-ESR remission was achieved in 52% of patients in the first-line etanercept plus methotrexate arm, versus 38% in the methotrexate treat-to-target arm, for an absolute difference of 14 percentage points (odds ratio, 1.73; 95% confidence interval, 0.81-3.70; P = .160).
In early, new-onset RA, remission is the goal, Dr. Emery and coauthors said. The proportions of patients in remission in both arms are “suboptimal rates for the contemporary era,” they wrote.
The escalation to etanercept at week 24 did not improve remission rates appreciably, with about 60% still failing to achieve that endpoint. However, an exploratory analysis suggested the subsequent 24 weeks of etanercept exposure in those escalated patients was associated with a lower rate of remission, compared with 24 weeks of etanercept in the front-line approach, investigators said.
In that analysis, the adjusted odds ratio of achieving DAS28-ESR remission was 2.84 (95% CI, 0.84-9.60) in favor of the first-line etanercept approach.
Dr. Furst said in the interview that the VEDERA results are subject to the inherent biases of an open-label study. He also suggested that further investigations could compare the two first-line treatment approaches specifically in very early RA patients with markers of more severe disease.
“That’s the only way I would think we might gain a little bit more, but so far, these data don’t support getting terribly aggressive,” he said.
The study was funded through an investigator-sponsored research grant provided by Pfizer. Three authors disclosed financial relationships with multiple pharmaceutical companies that market drugs for RA, including Pfizer.
SOURCE: Emery P et al. Ann Rheum Dis. 2020 Jan 29. doi: 10.1136/annrheumdis-2019-216539.
, investigators say.
A remission rate of 52% was seen with first-line etanercept plus methotrexate, compared with 38% for a strategy of methotrexate escalated to add etanercept in patients not in remission at 24 weeks in the study, known as VEDERA (Very Early Versus Delayed Etanercept in Patients With RA).
Investigators said a difference of 14 percentage points between remission rates was comparable to what was seen among patients with early RA in an earlier randomized trial of etanercept plus methotrexate versus methotrexate monotherapy.
However, the difference was not on par with the “larger than standard” effect of about 30% seen in an exploratory analysis of the very early RA subset in that previous study, according to VEDERA study authors, led by Paul Emery, MD, of the University of Leeds (England).
Taken together, the results highlight a “ceiling effect” in achieving remission in this real-life, treatment-naive cohort, Dr. Emery and coauthors noted in their report, which appears in Annals of the Rheumatic Diseases.
The study population aligned with real-world clinical practice, according to the investigators, who noted that half the cohort had at least one comorbidity.
“This may have partly driven the generally poorer than expected performance, the exact mechanisms for which are unclear,” they wrote in their discussion of results.
Delaying etanercept until failure of methotrexate, instead of giving both drugs up front, was linked to poorer etanercept response in an exploratory analysis of VEDERA. However, Dr. Emery and coinvestigators noted that this finding “requires validation and further investigation.”
While first-line etanercept plus methotrexate is a “clinically appropriate approach” in early RA, results of the VEDERA study don’t help to inform clinicians as to when it would be prudent to select that therapeutic approach, said Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles.
“Whether you’re treating with methotrexate or methotrexate plus etanercept, they do pretty well,” Dr. Furst said in an interview. “What that says to me is when you have patients with very early RA and the disease is moderately active, you should really try methotrexate before you add expensive other drugs.”
The phase 4, open-label, randomized VEDERA trial included 120 adult patients with new-onset early RA with symptom duration of less than 12 months. All patients in VEDERA had a 28-joint disease activity score based on erythrocyte sedimentation rate (DAS28-ESR) of 3.2 or greater and clinical evidence of synovitis. They were all positive for anti-citrullinated peptide antibody or rheumatoid factor, or had evidence of disease activity in at least one joint by power Doppler ultrasonography.
The patients were randomized to 48 weeks of treatment with either first-line etanercept plus methotrexate, or with methotrexate in a treat-to-target strategy that called for the addition of etanercept if the DAS28-ESR was still 2.6 or greater at 24 weeks.
Based on results of the earlier trial, known as COMET, a confirmatory remission rate in the etanercept plus methotrexate arm was anticipated to be 70%, versus 40% for the methotrexate treat-to-target arm, investigators said in a discussion of their statistical methods.
Study results did not confirm a large effect size, according to the investigators. By week 48, DAS28-ESR remission was achieved in 52% of patients in the first-line etanercept plus methotrexate arm, versus 38% in the methotrexate treat-to-target arm, for an absolute difference of 14 percentage points (odds ratio, 1.73; 95% confidence interval, 0.81-3.70; P = .160).
In early, new-onset RA, remission is the goal, Dr. Emery and coauthors said. The proportions of patients in remission in both arms are “suboptimal rates for the contemporary era,” they wrote.
The escalation to etanercept at week 24 did not improve remission rates appreciably, with about 60% still failing to achieve that endpoint. However, an exploratory analysis suggested the subsequent 24 weeks of etanercept exposure in those escalated patients was associated with a lower rate of remission, compared with 24 weeks of etanercept in the front-line approach, investigators said.
In that analysis, the adjusted odds ratio of achieving DAS28-ESR remission was 2.84 (95% CI, 0.84-9.60) in favor of the first-line etanercept approach.
Dr. Furst said in the interview that the VEDERA results are subject to the inherent biases of an open-label study. He also suggested that further investigations could compare the two first-line treatment approaches specifically in very early RA patients with markers of more severe disease.
“That’s the only way I would think we might gain a little bit more, but so far, these data don’t support getting terribly aggressive,” he said.
The study was funded through an investigator-sponsored research grant provided by Pfizer. Three authors disclosed financial relationships with multiple pharmaceutical companies that market drugs for RA, including Pfizer.
SOURCE: Emery P et al. Ann Rheum Dis. 2020 Jan 29. doi: 10.1136/annrheumdis-2019-216539.
, investigators say.
A remission rate of 52% was seen with first-line etanercept plus methotrexate, compared with 38% for a strategy of methotrexate escalated to add etanercept in patients not in remission at 24 weeks in the study, known as VEDERA (Very Early Versus Delayed Etanercept in Patients With RA).
Investigators said a difference of 14 percentage points between remission rates was comparable to what was seen among patients with early RA in an earlier randomized trial of etanercept plus methotrexate versus methotrexate monotherapy.
However, the difference was not on par with the “larger than standard” effect of about 30% seen in an exploratory analysis of the very early RA subset in that previous study, according to VEDERA study authors, led by Paul Emery, MD, of the University of Leeds (England).
Taken together, the results highlight a “ceiling effect” in achieving remission in this real-life, treatment-naive cohort, Dr. Emery and coauthors noted in their report, which appears in Annals of the Rheumatic Diseases.
The study population aligned with real-world clinical practice, according to the investigators, who noted that half the cohort had at least one comorbidity.
“This may have partly driven the generally poorer than expected performance, the exact mechanisms for which are unclear,” they wrote in their discussion of results.
Delaying etanercept until failure of methotrexate, instead of giving both drugs up front, was linked to poorer etanercept response in an exploratory analysis of VEDERA. However, Dr. Emery and coinvestigators noted that this finding “requires validation and further investigation.”
While first-line etanercept plus methotrexate is a “clinically appropriate approach” in early RA, results of the VEDERA study don’t help to inform clinicians as to when it would be prudent to select that therapeutic approach, said Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles.
“Whether you’re treating with methotrexate or methotrexate plus etanercept, they do pretty well,” Dr. Furst said in an interview. “What that says to me is when you have patients with very early RA and the disease is moderately active, you should really try methotrexate before you add expensive other drugs.”
The phase 4, open-label, randomized VEDERA trial included 120 adult patients with new-onset early RA with symptom duration of less than 12 months. All patients in VEDERA had a 28-joint disease activity score based on erythrocyte sedimentation rate (DAS28-ESR) of 3.2 or greater and clinical evidence of synovitis. They were all positive for anti-citrullinated peptide antibody or rheumatoid factor, or had evidence of disease activity in at least one joint by power Doppler ultrasonography.
The patients were randomized to 48 weeks of treatment with either first-line etanercept plus methotrexate, or with methotrexate in a treat-to-target strategy that called for the addition of etanercept if the DAS28-ESR was still 2.6 or greater at 24 weeks.
Based on results of the earlier trial, known as COMET, a confirmatory remission rate in the etanercept plus methotrexate arm was anticipated to be 70%, versus 40% for the methotrexate treat-to-target arm, investigators said in a discussion of their statistical methods.
Study results did not confirm a large effect size, according to the investigators. By week 48, DAS28-ESR remission was achieved in 52% of patients in the first-line etanercept plus methotrexate arm, versus 38% in the methotrexate treat-to-target arm, for an absolute difference of 14 percentage points (odds ratio, 1.73; 95% confidence interval, 0.81-3.70; P = .160).
In early, new-onset RA, remission is the goal, Dr. Emery and coauthors said. The proportions of patients in remission in both arms are “suboptimal rates for the contemporary era,” they wrote.
The escalation to etanercept at week 24 did not improve remission rates appreciably, with about 60% still failing to achieve that endpoint. However, an exploratory analysis suggested the subsequent 24 weeks of etanercept exposure in those escalated patients was associated with a lower rate of remission, compared with 24 weeks of etanercept in the front-line approach, investigators said.
In that analysis, the adjusted odds ratio of achieving DAS28-ESR remission was 2.84 (95% CI, 0.84-9.60) in favor of the first-line etanercept approach.
Dr. Furst said in the interview that the VEDERA results are subject to the inherent biases of an open-label study. He also suggested that further investigations could compare the two first-line treatment approaches specifically in very early RA patients with markers of more severe disease.
“That’s the only way I would think we might gain a little bit more, but so far, these data don’t support getting terribly aggressive,” he said.
The study was funded through an investigator-sponsored research grant provided by Pfizer. Three authors disclosed financial relationships with multiple pharmaceutical companies that market drugs for RA, including Pfizer.
SOURCE: Emery P et al. Ann Rheum Dis. 2020 Jan 29. doi: 10.1136/annrheumdis-2019-216539.
FROM ANNALS OF THE RHEUMATIC DISEASES
Multiple assessment measures can hone RA treatment
Combining the measures of the Clinical Disease Activity Index and the Disease Activity Score in 28 joints provides an opportunity adjust treatment for patients with RA, based on data from a cross-sectional study of 1,585 adults.
Although the Clinical Disease Activity Index (CDAI) is considered more stringent, comparisons with the Disease Activity Score in 28 joints with erythrocyte sedimentation rate (DAS28-ESR) outside of clinical trials are limited, wrote Satoshi Takanashi, MD, of Keio University School of Medicine in Tokyo, and colleagues.
In a study published in Annals of the Rheumatic Diseases, the researchers reviewed data from 1,585 consecutive RA patients seen at Keio University Hospital in Tokyo. The average age of the patients was 64 years, 84% were women, and the average duration of disease was 12 years.
Overall, more patients met the CDAI remission criteria but not the DAS28-ESR criteria, with the exception of patients treated with an interleukin-6 inhibitor.
Of the patients in remission based on CDAI, the proportion who were not in DAS28-ESR remission was 19.4% for those treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), 18.2% for tumor necrosis factor inhibitors, 4.2% for IL-6 inhibitors, 27.6% for CTLA4-Ig fusion protein, and 33.3% for Janus kinase inhibitors.
Of the patients in DAS28-ESR remission, those not also in CDAI remission totaled 11.7% with csDMARDs, 15.4% with tumor necrosis factor inhibitors, 29.5% with IL-6 inhibitors, 16.0% with CTLA4-Ig, and 14.3% with Janus kinase inhibitors.
“The fact that many patients fulfilled the CDAI but not DAS28-ESR remission could be explained by several reasons including residual synovitis in joints that are not included in the main 28 joints, which could lead to an increase in acute phase reactants and elevate only DAS28-ESR, extra-articular involvement or other comorbidities that could elevate the C-reactive protein irrelevant to arthritis,” the researchers noted. The prevalence of complications was higher in patients in CDAI remission and DAS28-ESR nonremission independent of rheumatoid or nonrheumatoid comorbid conditions, they added.
The findings were limited by several factors, including the cross-sectional study design that did not evaluate longitudinal radiological and functional progression, the researchers wrote.
“However, patients in both CDAI and DAS28-ESR remission were apparently in better condition than those who met either criteria; therefore, in the management of rheumatoid arthritis, assessing patients with two composite measures can yield important opportunities to consider what causes the discrepancy between the measures and adjust treatment appropriately,” they concluded.
The authors did not report having a specific grant for this research. Two of the paper’s three authors disclosed relationships with multiple companies that market drugs for RA.
SOURCE: Takanashi S et al. Ann Rheum Dis. 2020 Jan 29. doi: 10.1136/annrheumdis-2019-216607.
Combining the measures of the Clinical Disease Activity Index and the Disease Activity Score in 28 joints provides an opportunity adjust treatment for patients with RA, based on data from a cross-sectional study of 1,585 adults.
Although the Clinical Disease Activity Index (CDAI) is considered more stringent, comparisons with the Disease Activity Score in 28 joints with erythrocyte sedimentation rate (DAS28-ESR) outside of clinical trials are limited, wrote Satoshi Takanashi, MD, of Keio University School of Medicine in Tokyo, and colleagues.
In a study published in Annals of the Rheumatic Diseases, the researchers reviewed data from 1,585 consecutive RA patients seen at Keio University Hospital in Tokyo. The average age of the patients was 64 years, 84% were women, and the average duration of disease was 12 years.
Overall, more patients met the CDAI remission criteria but not the DAS28-ESR criteria, with the exception of patients treated with an interleukin-6 inhibitor.
Of the patients in remission based on CDAI, the proportion who were not in DAS28-ESR remission was 19.4% for those treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), 18.2% for tumor necrosis factor inhibitors, 4.2% for IL-6 inhibitors, 27.6% for CTLA4-Ig fusion protein, and 33.3% for Janus kinase inhibitors.
Of the patients in DAS28-ESR remission, those not also in CDAI remission totaled 11.7% with csDMARDs, 15.4% with tumor necrosis factor inhibitors, 29.5% with IL-6 inhibitors, 16.0% with CTLA4-Ig, and 14.3% with Janus kinase inhibitors.
“The fact that many patients fulfilled the CDAI but not DAS28-ESR remission could be explained by several reasons including residual synovitis in joints that are not included in the main 28 joints, which could lead to an increase in acute phase reactants and elevate only DAS28-ESR, extra-articular involvement or other comorbidities that could elevate the C-reactive protein irrelevant to arthritis,” the researchers noted. The prevalence of complications was higher in patients in CDAI remission and DAS28-ESR nonremission independent of rheumatoid or nonrheumatoid comorbid conditions, they added.
The findings were limited by several factors, including the cross-sectional study design that did not evaluate longitudinal radiological and functional progression, the researchers wrote.
“However, patients in both CDAI and DAS28-ESR remission were apparently in better condition than those who met either criteria; therefore, in the management of rheumatoid arthritis, assessing patients with two composite measures can yield important opportunities to consider what causes the discrepancy between the measures and adjust treatment appropriately,” they concluded.
The authors did not report having a specific grant for this research. Two of the paper’s three authors disclosed relationships with multiple companies that market drugs for RA.
SOURCE: Takanashi S et al. Ann Rheum Dis. 2020 Jan 29. doi: 10.1136/annrheumdis-2019-216607.
Combining the measures of the Clinical Disease Activity Index and the Disease Activity Score in 28 joints provides an opportunity adjust treatment for patients with RA, based on data from a cross-sectional study of 1,585 adults.
Although the Clinical Disease Activity Index (CDAI) is considered more stringent, comparisons with the Disease Activity Score in 28 joints with erythrocyte sedimentation rate (DAS28-ESR) outside of clinical trials are limited, wrote Satoshi Takanashi, MD, of Keio University School of Medicine in Tokyo, and colleagues.
In a study published in Annals of the Rheumatic Diseases, the researchers reviewed data from 1,585 consecutive RA patients seen at Keio University Hospital in Tokyo. The average age of the patients was 64 years, 84% were women, and the average duration of disease was 12 years.
Overall, more patients met the CDAI remission criteria but not the DAS28-ESR criteria, with the exception of patients treated with an interleukin-6 inhibitor.
Of the patients in remission based on CDAI, the proportion who were not in DAS28-ESR remission was 19.4% for those treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), 18.2% for tumor necrosis factor inhibitors, 4.2% for IL-6 inhibitors, 27.6% for CTLA4-Ig fusion protein, and 33.3% for Janus kinase inhibitors.
Of the patients in DAS28-ESR remission, those not also in CDAI remission totaled 11.7% with csDMARDs, 15.4% with tumor necrosis factor inhibitors, 29.5% with IL-6 inhibitors, 16.0% with CTLA4-Ig, and 14.3% with Janus kinase inhibitors.
“The fact that many patients fulfilled the CDAI but not DAS28-ESR remission could be explained by several reasons including residual synovitis in joints that are not included in the main 28 joints, which could lead to an increase in acute phase reactants and elevate only DAS28-ESR, extra-articular involvement or other comorbidities that could elevate the C-reactive protein irrelevant to arthritis,” the researchers noted. The prevalence of complications was higher in patients in CDAI remission and DAS28-ESR nonremission independent of rheumatoid or nonrheumatoid comorbid conditions, they added.
The findings were limited by several factors, including the cross-sectional study design that did not evaluate longitudinal radiological and functional progression, the researchers wrote.
“However, patients in both CDAI and DAS28-ESR remission were apparently in better condition than those who met either criteria; therefore, in the management of rheumatoid arthritis, assessing patients with two composite measures can yield important opportunities to consider what causes the discrepancy between the measures and adjust treatment appropriately,” they concluded.
The authors did not report having a specific grant for this research. Two of the paper’s three authors disclosed relationships with multiple companies that market drugs for RA.
SOURCE: Takanashi S et al. Ann Rheum Dis. 2020 Jan 29. doi: 10.1136/annrheumdis-2019-216607.
FROM ANNALS OF THE RHEUMATIC DISEASES
In rheumatology, biosimilars are flatlining. Why?
Although biosimilar versions of tumor necrosis factor inhibitors (TNFis) have been available to U.S. rheumatologists and their patients for over 3 years, uptake has thus far been slow.
In an analysis of data from a large commercial payer, the two available biosimilars for infliximab (Remicade) accounted for less than 1% of TNFi prescribing since the first biosimilar to infliximab was approved in 2016.
The study, published in Arthritis & Rheumatology, involved a total of 1.1 million TNFi prescriptions or infusions received by 95,906 patients from 2016 to 2019. Investigators found that uptake of biosimilar infliximab was essentially flat, standing at 0.1% of prescribing in the second quarter of 2017, and topping out at 0.9% in the first quarter of 2019. For branded infliximab, prescribing was also stable, but accounted for about 20% of overall biologic dispensing in each quarter of the period studied.
There are currently two biosimilar medications to the originator infliximab, which is one of five originator biologics available to treat rheumatic diseases in the United States: infliximab-dyyb (Inflectra) and infliximab-abda (Renflexis). The former was approved in 2016 and the latter in 2017, said study author Seoyoung C. Kim, MD, ScD, of the division of pharmacoepidemiology and pharmacoeconomics, Brigham and Women’s Hospital, Boston, and her coauthors.
“Our paper reports a disappointingly low uptake of biosimilar infliximab since the first quarter of 2017 using claims data from a large private health plan. The main and maybe the only reason to consider using a biosimilar is cost saving,” said Dr. Kim in an interview. “Our results suggest that current modest cost savings from infliximab biosimilars in the U.S. are not sufficient to promote their widespread use.”
In the payer database study conducted by Dr. Kim and colleagues, the insurer paid similar mean amounts per patient per quarter for originator and biosimilar infliximab in mid-2017 ($8,322 versus $8,656). By the end of 2018, a gap appeared, with the insurer paying a mean quarterly per-patient sum of $8,111 for biosimilar infliximab compared with $9,535 for the branded biologic.
“The lack of market penetration and very modest price reductions for biosimilars have left policymakers, payers, physicians, and the public frustrated, particularly because sales in Europe continue to rapidly expand and robust cost-savings have materialized,” wrote Jinoos Yazdany, MD, MPH, in an editorial accompanying the study.
Dr. Yazdany, professor and chief of the division of rheumatology at the University of California, San Francisco, noted that increased spending on biologics in the United States – which increased by 50% from 2014 to 2018 – has been driven by rising prices as well as increased uptake of biologic therapies.
At least in part, Europe has been able to reap cost savings where the United States hasn’t because fundamental differences in health care reimbursement can ease sweeping biosimilar adoption, Dr. Yazdany noted. “Countries like Denmark and Sweden, using the negotiating and purchasing power of their single-payer systems have instituted a winner-takes-all bidding system,” with Denmark seeing cost savings of up to two-thirds when bidding was combined with mandatory switching, she said.
The continued market dominance of originator infliximab means that savings from biosimilars have thus far amounted to about $91 million, far short of the $1 billion that the Congressional Budget Office had projected for this date, Dr. Yazdany said.
One problem in the adoption of biosimilars by U.S. rheumatologists may have been uneven marketing and pricing across different types of practice, Colin C. Edgerton, MD, a rheumatologist at Low Country Rheumatology in South Carolina and chair of the American College of Rheumatology’s Committee on Rheumatologic Care, said in an interview.
“Rheumatologists have generally developed comfort with biosimilars, although this is not universal. The core message, that all biologics vary and that this is OK, is getting out. In general, rheumatologists also understand the problem with high drug prices and the threat to patient access,” Dr. Edgerton said. But “the early marketing and pricing focus for biosimilars seemed to be on hospitals and facilities, and this did not work effectively for community rheumatologists, where the majority of care is delivered. We have been pleased to see a manufacturer pivot toward community rheumatology where additional efforts need to be made to bend the curve on biosimilar adoption. It is critical for practices with experience using biosimilars to educate peers, and this is where networks of practicing rheumatologists are important.”
In Dr. Yazdany’s editorial, she cited four structural factors impeding biosimilar uptake and downstream savings.
First, she cites ongoing actions by pharmaceutical companies, which create a “patent thicket” that has the effect of fencing off originator biologics from biosimilars long beyond the original 12-year exclusivity period. Supporting the notion that “patent thickets” are a common strategy, Dr. Yazdany noted that almost half of the patent applications that AbbVie has filed for adalimumab (Humira) have come in after the original exclusivity period expired in 2014. Humira’s price has risen 18% yearly during this period.
The complicated role played by pharmacy benefit managers (PBMs) is another factor in slow adoption, said Dr. Yazdany: When manufacturers offer rebates to PBMs, the price of the originator biologic may be less than its biosimilar. Further, manufacturers may sign multiyear rebate agreements just before a biosimilar launch; PBMs are also sometimes threatened with the withdrawal of rebates if they offer biosimilars, she noted.
Third, prescriber inertia may also be at play, Dr. Yazdany noted, not least because patients often see little difference in out-of-pocket costs when they make the switch to a biosimilar – PBM rebates are not necessarily passed on to patients. Payers may not reimburse a biosimilar, or formularies can be built without them, influencing prescribing, and there’s usually no reimbursement incentive for biosimilar prescribing in the nonpublic sector, she said. To the contrary, infusing a drug with a higher price often means higher reimbursement for the administering clinician, since commercial insurance reimbursement is often calculated as a percent of the charge for the drug.
Further contributing to inertia is the extra time required for patient education and writing a new set of orders – all work that can’t be captured for extra reimbursement. Dr. Edgerton said that rheumatologists can talk with patients about the “nocebo effect” relating to biosimilars. “This is a phenomenon in which patients are thought to experience worsening symptoms associated with negative beliefs about biosimilars. There has been a study in Arthritis Care & Research addressing this concern. The authors found that positive framing of biosimilars led to more participants being willing to switch than negative framing. This suggests that clinicians have an important role in informing patients about biosimilars, and addressing hesitancy.”
Finally, Dr. Yazdany pointed out that for a pharmaceutical company pursuing biosimilar approval, the regulatory pathway itself can provide its own set of complications and confusion. Biosimilars are not exact molecular replicas of the originator biologic, and these differences can change efficacy and immunogenicity, and also affect stability. Hence, a company wishing to market a biosimilar has to show the Food and Drug Administration that safety and efficacy aren’t affected by a switch to biosimilar from an originator biologic. Extrapolation from one indication to another can be made – with scientific justification.
Rheumatologists are mindful of the potential differences between biosimilars and the originator biologic, as evinced in a recent position statement from the American College of Rheumatology. The position statement advises that “extrapolation should be pursued with caution,” and asks for clear labeling when biosimilars have been designated “interchangeable” with their biosimilar. Interchangeability can clear the way for pharmacy substitution of a prescribed biologic, though Dr. Yazdany noted that 40 states have passed legislation requiring prescriber notification.
The FDA is currently using postmarketing pharmacovigilance to monitor biosimilar performance in the real world, and a recent systematic review “should provide some reassurance,” wrote Dr. Yazdany, citing the study, which looked at 14,000 patients who had a total of 14 disease indications for biosimilar use. The 90-article review largely found no differences in safety, efficacy, or immunogenicity between originators and their biosimilars. Dr. Yazdany recommended greater openness to incorporating the European experience in the FDA’s ongoing reassessment.
A further way forward can come through tackling the patent thicket with the proposed bipartisan Biologic Patent Transparency Act, which would require publication of biologic patents in a one-stop publicly searchable database. Going further with legislation to address anticompetitive activity by pharmaceutical companies could shorten the runway to biosimilar launching considerably, she noted.
The complicated landscape of PBMs and rebates affects many sectors of health care, and new policy efforts are needed here as well, she said. Reimbursement strategies – and much-needed continuing medical education – can both ease prescriber unfamiliarity with biosimilars and provide incentives for their use, she concluded.
Dr. Kim concurred that change is needed before the United States is likely to reap significant economic benefit from biosimilars. “The uptake of biosimilars and their impact on overall health care cost needs to be reevaluated when we have more biosimilars available in the next 3-4 years. However, for now, it appears that substantial savings achieved in some European countries – for example, Denmark – may not be possible without systemic reform of the U.S. pharmaceutical market,” she said.
Dr. Yazdany is supported by the Alice Betts Endowed Chair in Arthritis Research, the Russel/Engleman Research Center at the University of California, San Francisco, and the National Institutes of Health. She has received independent research grants from Pfizer and Genentech and research consulting fees from Eli Lilly and AstraZeneca.
Dr. Kim’s study was supported by the division of pharmacoepidemiology and pharmacoeconomics, department of medicine, Brigham and Women’s Hospital, and Arnold Ventures. Dr. Kim has received research grants to Brigham and Women’s Hospital from Pfizer, AbbVie, Bristol-Myers Squibb, and Roche.
SOURCES: Kim SC et al. Arthritis Rheumatol. 2020 Jan 13. doi: 10.1002/art.41201; Yazdany J. Arthritis Rheumatol. 2020 Jan 10. doi: 10.1002/art.41203.
Although biosimilar versions of tumor necrosis factor inhibitors (TNFis) have been available to U.S. rheumatologists and their patients for over 3 years, uptake has thus far been slow.
In an analysis of data from a large commercial payer, the two available biosimilars for infliximab (Remicade) accounted for less than 1% of TNFi prescribing since the first biosimilar to infliximab was approved in 2016.
The study, published in Arthritis & Rheumatology, involved a total of 1.1 million TNFi prescriptions or infusions received by 95,906 patients from 2016 to 2019. Investigators found that uptake of biosimilar infliximab was essentially flat, standing at 0.1% of prescribing in the second quarter of 2017, and topping out at 0.9% in the first quarter of 2019. For branded infliximab, prescribing was also stable, but accounted for about 20% of overall biologic dispensing in each quarter of the period studied.
There are currently two biosimilar medications to the originator infliximab, which is one of five originator biologics available to treat rheumatic diseases in the United States: infliximab-dyyb (Inflectra) and infliximab-abda (Renflexis). The former was approved in 2016 and the latter in 2017, said study author Seoyoung C. Kim, MD, ScD, of the division of pharmacoepidemiology and pharmacoeconomics, Brigham and Women’s Hospital, Boston, and her coauthors.
“Our paper reports a disappointingly low uptake of biosimilar infliximab since the first quarter of 2017 using claims data from a large private health plan. The main and maybe the only reason to consider using a biosimilar is cost saving,” said Dr. Kim in an interview. “Our results suggest that current modest cost savings from infliximab biosimilars in the U.S. are not sufficient to promote their widespread use.”
In the payer database study conducted by Dr. Kim and colleagues, the insurer paid similar mean amounts per patient per quarter for originator and biosimilar infliximab in mid-2017 ($8,322 versus $8,656). By the end of 2018, a gap appeared, with the insurer paying a mean quarterly per-patient sum of $8,111 for biosimilar infliximab compared with $9,535 for the branded biologic.
“The lack of market penetration and very modest price reductions for biosimilars have left policymakers, payers, physicians, and the public frustrated, particularly because sales in Europe continue to rapidly expand and robust cost-savings have materialized,” wrote Jinoos Yazdany, MD, MPH, in an editorial accompanying the study.
Dr. Yazdany, professor and chief of the division of rheumatology at the University of California, San Francisco, noted that increased spending on biologics in the United States – which increased by 50% from 2014 to 2018 – has been driven by rising prices as well as increased uptake of biologic therapies.
At least in part, Europe has been able to reap cost savings where the United States hasn’t because fundamental differences in health care reimbursement can ease sweeping biosimilar adoption, Dr. Yazdany noted. “Countries like Denmark and Sweden, using the negotiating and purchasing power of their single-payer systems have instituted a winner-takes-all bidding system,” with Denmark seeing cost savings of up to two-thirds when bidding was combined with mandatory switching, she said.
The continued market dominance of originator infliximab means that savings from biosimilars have thus far amounted to about $91 million, far short of the $1 billion that the Congressional Budget Office had projected for this date, Dr. Yazdany said.
One problem in the adoption of biosimilars by U.S. rheumatologists may have been uneven marketing and pricing across different types of practice, Colin C. Edgerton, MD, a rheumatologist at Low Country Rheumatology in South Carolina and chair of the American College of Rheumatology’s Committee on Rheumatologic Care, said in an interview.
“Rheumatologists have generally developed comfort with biosimilars, although this is not universal. The core message, that all biologics vary and that this is OK, is getting out. In general, rheumatologists also understand the problem with high drug prices and the threat to patient access,” Dr. Edgerton said. But “the early marketing and pricing focus for biosimilars seemed to be on hospitals and facilities, and this did not work effectively for community rheumatologists, where the majority of care is delivered. We have been pleased to see a manufacturer pivot toward community rheumatology where additional efforts need to be made to bend the curve on biosimilar adoption. It is critical for practices with experience using biosimilars to educate peers, and this is where networks of practicing rheumatologists are important.”
In Dr. Yazdany’s editorial, she cited four structural factors impeding biosimilar uptake and downstream savings.
First, she cites ongoing actions by pharmaceutical companies, which create a “patent thicket” that has the effect of fencing off originator biologics from biosimilars long beyond the original 12-year exclusivity period. Supporting the notion that “patent thickets” are a common strategy, Dr. Yazdany noted that almost half of the patent applications that AbbVie has filed for adalimumab (Humira) have come in after the original exclusivity period expired in 2014. Humira’s price has risen 18% yearly during this period.
The complicated role played by pharmacy benefit managers (PBMs) is another factor in slow adoption, said Dr. Yazdany: When manufacturers offer rebates to PBMs, the price of the originator biologic may be less than its biosimilar. Further, manufacturers may sign multiyear rebate agreements just before a biosimilar launch; PBMs are also sometimes threatened with the withdrawal of rebates if they offer biosimilars, she noted.
Third, prescriber inertia may also be at play, Dr. Yazdany noted, not least because patients often see little difference in out-of-pocket costs when they make the switch to a biosimilar – PBM rebates are not necessarily passed on to patients. Payers may not reimburse a biosimilar, or formularies can be built without them, influencing prescribing, and there’s usually no reimbursement incentive for biosimilar prescribing in the nonpublic sector, she said. To the contrary, infusing a drug with a higher price often means higher reimbursement for the administering clinician, since commercial insurance reimbursement is often calculated as a percent of the charge for the drug.
Further contributing to inertia is the extra time required for patient education and writing a new set of orders – all work that can’t be captured for extra reimbursement. Dr. Edgerton said that rheumatologists can talk with patients about the “nocebo effect” relating to biosimilars. “This is a phenomenon in which patients are thought to experience worsening symptoms associated with negative beliefs about biosimilars. There has been a study in Arthritis Care & Research addressing this concern. The authors found that positive framing of biosimilars led to more participants being willing to switch than negative framing. This suggests that clinicians have an important role in informing patients about biosimilars, and addressing hesitancy.”
Finally, Dr. Yazdany pointed out that for a pharmaceutical company pursuing biosimilar approval, the regulatory pathway itself can provide its own set of complications and confusion. Biosimilars are not exact molecular replicas of the originator biologic, and these differences can change efficacy and immunogenicity, and also affect stability. Hence, a company wishing to market a biosimilar has to show the Food and Drug Administration that safety and efficacy aren’t affected by a switch to biosimilar from an originator biologic. Extrapolation from one indication to another can be made – with scientific justification.
Rheumatologists are mindful of the potential differences between biosimilars and the originator biologic, as evinced in a recent position statement from the American College of Rheumatology. The position statement advises that “extrapolation should be pursued with caution,” and asks for clear labeling when biosimilars have been designated “interchangeable” with their biosimilar. Interchangeability can clear the way for pharmacy substitution of a prescribed biologic, though Dr. Yazdany noted that 40 states have passed legislation requiring prescriber notification.
The FDA is currently using postmarketing pharmacovigilance to monitor biosimilar performance in the real world, and a recent systematic review “should provide some reassurance,” wrote Dr. Yazdany, citing the study, which looked at 14,000 patients who had a total of 14 disease indications for biosimilar use. The 90-article review largely found no differences in safety, efficacy, or immunogenicity between originators and their biosimilars. Dr. Yazdany recommended greater openness to incorporating the European experience in the FDA’s ongoing reassessment.
A further way forward can come through tackling the patent thicket with the proposed bipartisan Biologic Patent Transparency Act, which would require publication of biologic patents in a one-stop publicly searchable database. Going further with legislation to address anticompetitive activity by pharmaceutical companies could shorten the runway to biosimilar launching considerably, she noted.
The complicated landscape of PBMs and rebates affects many sectors of health care, and new policy efforts are needed here as well, she said. Reimbursement strategies – and much-needed continuing medical education – can both ease prescriber unfamiliarity with biosimilars and provide incentives for their use, she concluded.
Dr. Kim concurred that change is needed before the United States is likely to reap significant economic benefit from biosimilars. “The uptake of biosimilars and their impact on overall health care cost needs to be reevaluated when we have more biosimilars available in the next 3-4 years. However, for now, it appears that substantial savings achieved in some European countries – for example, Denmark – may not be possible without systemic reform of the U.S. pharmaceutical market,” she said.
Dr. Yazdany is supported by the Alice Betts Endowed Chair in Arthritis Research, the Russel/Engleman Research Center at the University of California, San Francisco, and the National Institutes of Health. She has received independent research grants from Pfizer and Genentech and research consulting fees from Eli Lilly and AstraZeneca.
Dr. Kim’s study was supported by the division of pharmacoepidemiology and pharmacoeconomics, department of medicine, Brigham and Women’s Hospital, and Arnold Ventures. Dr. Kim has received research grants to Brigham and Women’s Hospital from Pfizer, AbbVie, Bristol-Myers Squibb, and Roche.
SOURCES: Kim SC et al. Arthritis Rheumatol. 2020 Jan 13. doi: 10.1002/art.41201; Yazdany J. Arthritis Rheumatol. 2020 Jan 10. doi: 10.1002/art.41203.
Although biosimilar versions of tumor necrosis factor inhibitors (TNFis) have been available to U.S. rheumatologists and their patients for over 3 years, uptake has thus far been slow.
In an analysis of data from a large commercial payer, the two available biosimilars for infliximab (Remicade) accounted for less than 1% of TNFi prescribing since the first biosimilar to infliximab was approved in 2016.
The study, published in Arthritis & Rheumatology, involved a total of 1.1 million TNFi prescriptions or infusions received by 95,906 patients from 2016 to 2019. Investigators found that uptake of biosimilar infliximab was essentially flat, standing at 0.1% of prescribing in the second quarter of 2017, and topping out at 0.9% in the first quarter of 2019. For branded infliximab, prescribing was also stable, but accounted for about 20% of overall biologic dispensing in each quarter of the period studied.
There are currently two biosimilar medications to the originator infliximab, which is one of five originator biologics available to treat rheumatic diseases in the United States: infliximab-dyyb (Inflectra) and infliximab-abda (Renflexis). The former was approved in 2016 and the latter in 2017, said study author Seoyoung C. Kim, MD, ScD, of the division of pharmacoepidemiology and pharmacoeconomics, Brigham and Women’s Hospital, Boston, and her coauthors.
“Our paper reports a disappointingly low uptake of biosimilar infliximab since the first quarter of 2017 using claims data from a large private health plan. The main and maybe the only reason to consider using a biosimilar is cost saving,” said Dr. Kim in an interview. “Our results suggest that current modest cost savings from infliximab biosimilars in the U.S. are not sufficient to promote their widespread use.”
In the payer database study conducted by Dr. Kim and colleagues, the insurer paid similar mean amounts per patient per quarter for originator and biosimilar infliximab in mid-2017 ($8,322 versus $8,656). By the end of 2018, a gap appeared, with the insurer paying a mean quarterly per-patient sum of $8,111 for biosimilar infliximab compared with $9,535 for the branded biologic.
“The lack of market penetration and very modest price reductions for biosimilars have left policymakers, payers, physicians, and the public frustrated, particularly because sales in Europe continue to rapidly expand and robust cost-savings have materialized,” wrote Jinoos Yazdany, MD, MPH, in an editorial accompanying the study.
Dr. Yazdany, professor and chief of the division of rheumatology at the University of California, San Francisco, noted that increased spending on biologics in the United States – which increased by 50% from 2014 to 2018 – has been driven by rising prices as well as increased uptake of biologic therapies.
At least in part, Europe has been able to reap cost savings where the United States hasn’t because fundamental differences in health care reimbursement can ease sweeping biosimilar adoption, Dr. Yazdany noted. “Countries like Denmark and Sweden, using the negotiating and purchasing power of their single-payer systems have instituted a winner-takes-all bidding system,” with Denmark seeing cost savings of up to two-thirds when bidding was combined with mandatory switching, she said.
The continued market dominance of originator infliximab means that savings from biosimilars have thus far amounted to about $91 million, far short of the $1 billion that the Congressional Budget Office had projected for this date, Dr. Yazdany said.
One problem in the adoption of biosimilars by U.S. rheumatologists may have been uneven marketing and pricing across different types of practice, Colin C. Edgerton, MD, a rheumatologist at Low Country Rheumatology in South Carolina and chair of the American College of Rheumatology’s Committee on Rheumatologic Care, said in an interview.
“Rheumatologists have generally developed comfort with biosimilars, although this is not universal. The core message, that all biologics vary and that this is OK, is getting out. In general, rheumatologists also understand the problem with high drug prices and the threat to patient access,” Dr. Edgerton said. But “the early marketing and pricing focus for biosimilars seemed to be on hospitals and facilities, and this did not work effectively for community rheumatologists, where the majority of care is delivered. We have been pleased to see a manufacturer pivot toward community rheumatology where additional efforts need to be made to bend the curve on biosimilar adoption. It is critical for practices with experience using biosimilars to educate peers, and this is where networks of practicing rheumatologists are important.”
In Dr. Yazdany’s editorial, she cited four structural factors impeding biosimilar uptake and downstream savings.
First, she cites ongoing actions by pharmaceutical companies, which create a “patent thicket” that has the effect of fencing off originator biologics from biosimilars long beyond the original 12-year exclusivity period. Supporting the notion that “patent thickets” are a common strategy, Dr. Yazdany noted that almost half of the patent applications that AbbVie has filed for adalimumab (Humira) have come in after the original exclusivity period expired in 2014. Humira’s price has risen 18% yearly during this period.
The complicated role played by pharmacy benefit managers (PBMs) is another factor in slow adoption, said Dr. Yazdany: When manufacturers offer rebates to PBMs, the price of the originator biologic may be less than its biosimilar. Further, manufacturers may sign multiyear rebate agreements just before a biosimilar launch; PBMs are also sometimes threatened with the withdrawal of rebates if they offer biosimilars, she noted.
Third, prescriber inertia may also be at play, Dr. Yazdany noted, not least because patients often see little difference in out-of-pocket costs when they make the switch to a biosimilar – PBM rebates are not necessarily passed on to patients. Payers may not reimburse a biosimilar, or formularies can be built without them, influencing prescribing, and there’s usually no reimbursement incentive for biosimilar prescribing in the nonpublic sector, she said. To the contrary, infusing a drug with a higher price often means higher reimbursement for the administering clinician, since commercial insurance reimbursement is often calculated as a percent of the charge for the drug.
Further contributing to inertia is the extra time required for patient education and writing a new set of orders – all work that can’t be captured for extra reimbursement. Dr. Edgerton said that rheumatologists can talk with patients about the “nocebo effect” relating to biosimilars. “This is a phenomenon in which patients are thought to experience worsening symptoms associated with negative beliefs about biosimilars. There has been a study in Arthritis Care & Research addressing this concern. The authors found that positive framing of biosimilars led to more participants being willing to switch than negative framing. This suggests that clinicians have an important role in informing patients about biosimilars, and addressing hesitancy.”
Finally, Dr. Yazdany pointed out that for a pharmaceutical company pursuing biosimilar approval, the regulatory pathway itself can provide its own set of complications and confusion. Biosimilars are not exact molecular replicas of the originator biologic, and these differences can change efficacy and immunogenicity, and also affect stability. Hence, a company wishing to market a biosimilar has to show the Food and Drug Administration that safety and efficacy aren’t affected by a switch to biosimilar from an originator biologic. Extrapolation from one indication to another can be made – with scientific justification.
Rheumatologists are mindful of the potential differences between biosimilars and the originator biologic, as evinced in a recent position statement from the American College of Rheumatology. The position statement advises that “extrapolation should be pursued with caution,” and asks for clear labeling when biosimilars have been designated “interchangeable” with their biosimilar. Interchangeability can clear the way for pharmacy substitution of a prescribed biologic, though Dr. Yazdany noted that 40 states have passed legislation requiring prescriber notification.
The FDA is currently using postmarketing pharmacovigilance to monitor biosimilar performance in the real world, and a recent systematic review “should provide some reassurance,” wrote Dr. Yazdany, citing the study, which looked at 14,000 patients who had a total of 14 disease indications for biosimilar use. The 90-article review largely found no differences in safety, efficacy, or immunogenicity between originators and their biosimilars. Dr. Yazdany recommended greater openness to incorporating the European experience in the FDA’s ongoing reassessment.
A further way forward can come through tackling the patent thicket with the proposed bipartisan Biologic Patent Transparency Act, which would require publication of biologic patents in a one-stop publicly searchable database. Going further with legislation to address anticompetitive activity by pharmaceutical companies could shorten the runway to biosimilar launching considerably, she noted.
The complicated landscape of PBMs and rebates affects many sectors of health care, and new policy efforts are needed here as well, she said. Reimbursement strategies – and much-needed continuing medical education – can both ease prescriber unfamiliarity with biosimilars and provide incentives for their use, she concluded.
Dr. Kim concurred that change is needed before the United States is likely to reap significant economic benefit from biosimilars. “The uptake of biosimilars and their impact on overall health care cost needs to be reevaluated when we have more biosimilars available in the next 3-4 years. However, for now, it appears that substantial savings achieved in some European countries – for example, Denmark – may not be possible without systemic reform of the U.S. pharmaceutical market,” she said.
Dr. Yazdany is supported by the Alice Betts Endowed Chair in Arthritis Research, the Russel/Engleman Research Center at the University of California, San Francisco, and the National Institutes of Health. She has received independent research grants from Pfizer and Genentech and research consulting fees from Eli Lilly and AstraZeneca.
Dr. Kim’s study was supported by the division of pharmacoepidemiology and pharmacoeconomics, department of medicine, Brigham and Women’s Hospital, and Arnold Ventures. Dr. Kim has received research grants to Brigham and Women’s Hospital from Pfizer, AbbVie, Bristol-Myers Squibb, and Roche.
SOURCES: Kim SC et al. Arthritis Rheumatol. 2020 Jan 13. doi: 10.1002/art.41201; Yazdany J. Arthritis Rheumatol. 2020 Jan 10. doi: 10.1002/art.41203.
FROM ARTHRITIS & RHEUMATOLOGY