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Filgotinib fares well in RA trial of inadequate methotrexate responders
MADRID – (cDMARD) in a phase 3 study.
The primary outcome results of the FINCH 1 study, which were presented at the European Congress of Rheumatology, showed that significantly more patients treated with filgotinib than placebo were able to achieve 20% improvement in American College of Rheumatology response criteria (ACR20).
At week 12, an ACR20 response was achieved by 69.8% of 480 patients treated with filgotinib 100 mg/day, 76.6% of 475 treated with filgotinib 200 mg/day, and 49.9% of 475 given a matching daily placebo (P less than .0001 for both comparisons). Adalimumab (Humira; 40 mg every 2 weeks) was used as an active comparator in the trial, and 70.8% of 325 patients treated with this biologic drug achieved an ACR20.
Similar patterns were seen for the ACR50 and ACR70 responses: more than 50% of patients treated with filgotinib or adalimumab achieved an ACR50 versus 33.3% of patients treated with placebo. The ACR70 response rate was more than 30% in patients treated with either biologic, compared against 14.9% with placebo.
The percentages of patients in the filgotinib 100-mg, filgotinib 200-mg, adalimumab, and placebo arms who achieved a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) of 3.2 or less at 12 weeks were 38.8%, 49.9%, 43.4%, and 23.4%. At 24 weeks, the rates were 53.1%, 60.6%, 50.5%, and 33.7%.
At 12 weeks, analysis showed that filgotinib 200 mg was noninferior to adalimumab in achieving a DAS28-CRP of 3.2 or less.
These study data, together with the results of two other phase 3 studies – FINCH 2 and FINCH 3 – will be used to submit a new drug application to the Food and Drug Administration for the use of filgotinib in the treatment of RA later this year, the drug’s developer, Gilead Sciences, announced on July 1. Each of the trials has addressed a different population of RA patients; while FINCH 1 looked at inadequate responders to methotrexate, FINCH 2 looked at those with an inadequate response to biologic DMARDs, and FINCH 3 recruited RA patients who were naive to methotrexate therapy.
FINCH 1 was a 1-year study, said presenting study investigator Bernard Combe, MD, PhD, professor of rheumatology at Montpellier (France) University and head of the bone and joint diseases department at the university. A total of 1,759 patients were randomized and 1,755 received study treatment with filgotinib, adalimumab, or placebo in addition to methotrexate. Data for the first 24 weeks were presented.
Dr. Combe and coauthors used hierarchical statistical testing to first compare the 200-mg dose versus placebo for the primary endpoint, and then, if positive, the percentage of patients at 12 weeks achieving a DAS28-CRP score of 3.2 or less and the score at 12 weeks on the Health Assessment Questionnaire – Disability Index (HAQ-DI), and then the DAS28-CRP again at 24 weeks. This was repeated with the 100-mg dose until finally noninferiority of the 200-mg dose versus adalimumab in DAS28-CRP at 12 weeks was tested.
Other findings included a significant reduction in radiographic progression at week 24 with both doses of filgotinib versus placebo; improvements in HAQ-DI and Functional Assessment of Chronic Illness Therapy-Fatigue scores also were seen at 12 and 24 weeks.
“The selective JAK1 inhibitor filgotinib, at doses of 200 and 100 mg per day, led to significant improvement in symptoms of RA patients with inadequate response to methotrexate,” Dr. Combe concluded. It “prevented radiographic progression, and improved physical function compared to placebo.”
Importantly, the drug was “well tolerated” and “a low frequency of venous thrombotic events, serious infections, and other adverse events of interest was observed.”
Commenting on the study during the Q&A session that followed Dr. Combe’s presentation, Roy M. Fleischmann, MD, clinical professor of medicine at the University of Texas Southwestern Medical Center in Dallas, noted that the choice of DAS28-CRP was “very unusual” as an endpoint after the ACR20 as it’s “almost always an ACR50 or 70.” There was also a “very high placebo response.”
Dr. Combe responded that he “wasn’t so surprised by the high placebo response. You know that this has been shown previously in some other trials.” As to why, he noted that there was an ongoing analysis but also proposed two reasons: First, the geographic region – with more than 1,700 patients from all over the world included in the trial, there could be variation in the placebo responses. Second, methotrexate might still be having a minor effect when the trial started.
The study was sponsored by Gilead Sciences in collaboration with Galapagos NV. Dr. Combe has received honoraria from AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, UCB, Genzyme, Sanofi, Regeneron, Sun Pharma Advanced Research, Boehringer Ingelheim, and Flexion. Dr. Combe is a shareholder in Novartis.
SOURCE: Combe B et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):77-8. Abstract LB0001, doi: 10.1136/annrheumdis-2019-eular.8676
MADRID – (cDMARD) in a phase 3 study.
The primary outcome results of the FINCH 1 study, which were presented at the European Congress of Rheumatology, showed that significantly more patients treated with filgotinib than placebo were able to achieve 20% improvement in American College of Rheumatology response criteria (ACR20).
At week 12, an ACR20 response was achieved by 69.8% of 480 patients treated with filgotinib 100 mg/day, 76.6% of 475 treated with filgotinib 200 mg/day, and 49.9% of 475 given a matching daily placebo (P less than .0001 for both comparisons). Adalimumab (Humira; 40 mg every 2 weeks) was used as an active comparator in the trial, and 70.8% of 325 patients treated with this biologic drug achieved an ACR20.
Similar patterns were seen for the ACR50 and ACR70 responses: more than 50% of patients treated with filgotinib or adalimumab achieved an ACR50 versus 33.3% of patients treated with placebo. The ACR70 response rate was more than 30% in patients treated with either biologic, compared against 14.9% with placebo.
The percentages of patients in the filgotinib 100-mg, filgotinib 200-mg, adalimumab, and placebo arms who achieved a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) of 3.2 or less at 12 weeks were 38.8%, 49.9%, 43.4%, and 23.4%. At 24 weeks, the rates were 53.1%, 60.6%, 50.5%, and 33.7%.
At 12 weeks, analysis showed that filgotinib 200 mg was noninferior to adalimumab in achieving a DAS28-CRP of 3.2 or less.
These study data, together with the results of two other phase 3 studies – FINCH 2 and FINCH 3 – will be used to submit a new drug application to the Food and Drug Administration for the use of filgotinib in the treatment of RA later this year, the drug’s developer, Gilead Sciences, announced on July 1. Each of the trials has addressed a different population of RA patients; while FINCH 1 looked at inadequate responders to methotrexate, FINCH 2 looked at those with an inadequate response to biologic DMARDs, and FINCH 3 recruited RA patients who were naive to methotrexate therapy.
FINCH 1 was a 1-year study, said presenting study investigator Bernard Combe, MD, PhD, professor of rheumatology at Montpellier (France) University and head of the bone and joint diseases department at the university. A total of 1,759 patients were randomized and 1,755 received study treatment with filgotinib, adalimumab, or placebo in addition to methotrexate. Data for the first 24 weeks were presented.
Dr. Combe and coauthors used hierarchical statistical testing to first compare the 200-mg dose versus placebo for the primary endpoint, and then, if positive, the percentage of patients at 12 weeks achieving a DAS28-CRP score of 3.2 or less and the score at 12 weeks on the Health Assessment Questionnaire – Disability Index (HAQ-DI), and then the DAS28-CRP again at 24 weeks. This was repeated with the 100-mg dose until finally noninferiority of the 200-mg dose versus adalimumab in DAS28-CRP at 12 weeks was tested.
Other findings included a significant reduction in radiographic progression at week 24 with both doses of filgotinib versus placebo; improvements in HAQ-DI and Functional Assessment of Chronic Illness Therapy-Fatigue scores also were seen at 12 and 24 weeks.
“The selective JAK1 inhibitor filgotinib, at doses of 200 and 100 mg per day, led to significant improvement in symptoms of RA patients with inadequate response to methotrexate,” Dr. Combe concluded. It “prevented radiographic progression, and improved physical function compared to placebo.”
Importantly, the drug was “well tolerated” and “a low frequency of venous thrombotic events, serious infections, and other adverse events of interest was observed.”
Commenting on the study during the Q&A session that followed Dr. Combe’s presentation, Roy M. Fleischmann, MD, clinical professor of medicine at the University of Texas Southwestern Medical Center in Dallas, noted that the choice of DAS28-CRP was “very unusual” as an endpoint after the ACR20 as it’s “almost always an ACR50 or 70.” There was also a “very high placebo response.”
Dr. Combe responded that he “wasn’t so surprised by the high placebo response. You know that this has been shown previously in some other trials.” As to why, he noted that there was an ongoing analysis but also proposed two reasons: First, the geographic region – with more than 1,700 patients from all over the world included in the trial, there could be variation in the placebo responses. Second, methotrexate might still be having a minor effect when the trial started.
The study was sponsored by Gilead Sciences in collaboration with Galapagos NV. Dr. Combe has received honoraria from AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, UCB, Genzyme, Sanofi, Regeneron, Sun Pharma Advanced Research, Boehringer Ingelheim, and Flexion. Dr. Combe is a shareholder in Novartis.
SOURCE: Combe B et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):77-8. Abstract LB0001, doi: 10.1136/annrheumdis-2019-eular.8676
MADRID – (cDMARD) in a phase 3 study.
The primary outcome results of the FINCH 1 study, which were presented at the European Congress of Rheumatology, showed that significantly more patients treated with filgotinib than placebo were able to achieve 20% improvement in American College of Rheumatology response criteria (ACR20).
At week 12, an ACR20 response was achieved by 69.8% of 480 patients treated with filgotinib 100 mg/day, 76.6% of 475 treated with filgotinib 200 mg/day, and 49.9% of 475 given a matching daily placebo (P less than .0001 for both comparisons). Adalimumab (Humira; 40 mg every 2 weeks) was used as an active comparator in the trial, and 70.8% of 325 patients treated with this biologic drug achieved an ACR20.
Similar patterns were seen for the ACR50 and ACR70 responses: more than 50% of patients treated with filgotinib or adalimumab achieved an ACR50 versus 33.3% of patients treated with placebo. The ACR70 response rate was more than 30% in patients treated with either biologic, compared against 14.9% with placebo.
The percentages of patients in the filgotinib 100-mg, filgotinib 200-mg, adalimumab, and placebo arms who achieved a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) of 3.2 or less at 12 weeks were 38.8%, 49.9%, 43.4%, and 23.4%. At 24 weeks, the rates were 53.1%, 60.6%, 50.5%, and 33.7%.
At 12 weeks, analysis showed that filgotinib 200 mg was noninferior to adalimumab in achieving a DAS28-CRP of 3.2 or less.
These study data, together with the results of two other phase 3 studies – FINCH 2 and FINCH 3 – will be used to submit a new drug application to the Food and Drug Administration for the use of filgotinib in the treatment of RA later this year, the drug’s developer, Gilead Sciences, announced on July 1. Each of the trials has addressed a different population of RA patients; while FINCH 1 looked at inadequate responders to methotrexate, FINCH 2 looked at those with an inadequate response to biologic DMARDs, and FINCH 3 recruited RA patients who were naive to methotrexate therapy.
FINCH 1 was a 1-year study, said presenting study investigator Bernard Combe, MD, PhD, professor of rheumatology at Montpellier (France) University and head of the bone and joint diseases department at the university. A total of 1,759 patients were randomized and 1,755 received study treatment with filgotinib, adalimumab, or placebo in addition to methotrexate. Data for the first 24 weeks were presented.
Dr. Combe and coauthors used hierarchical statistical testing to first compare the 200-mg dose versus placebo for the primary endpoint, and then, if positive, the percentage of patients at 12 weeks achieving a DAS28-CRP score of 3.2 or less and the score at 12 weeks on the Health Assessment Questionnaire – Disability Index (HAQ-DI), and then the DAS28-CRP again at 24 weeks. This was repeated with the 100-mg dose until finally noninferiority of the 200-mg dose versus adalimumab in DAS28-CRP at 12 weeks was tested.
Other findings included a significant reduction in radiographic progression at week 24 with both doses of filgotinib versus placebo; improvements in HAQ-DI and Functional Assessment of Chronic Illness Therapy-Fatigue scores also were seen at 12 and 24 weeks.
“The selective JAK1 inhibitor filgotinib, at doses of 200 and 100 mg per day, led to significant improvement in symptoms of RA patients with inadequate response to methotrexate,” Dr. Combe concluded. It “prevented radiographic progression, and improved physical function compared to placebo.”
Importantly, the drug was “well tolerated” and “a low frequency of venous thrombotic events, serious infections, and other adverse events of interest was observed.”
Commenting on the study during the Q&A session that followed Dr. Combe’s presentation, Roy M. Fleischmann, MD, clinical professor of medicine at the University of Texas Southwestern Medical Center in Dallas, noted that the choice of DAS28-CRP was “very unusual” as an endpoint after the ACR20 as it’s “almost always an ACR50 or 70.” There was also a “very high placebo response.”
Dr. Combe responded that he “wasn’t so surprised by the high placebo response. You know that this has been shown previously in some other trials.” As to why, he noted that there was an ongoing analysis but also proposed two reasons: First, the geographic region – with more than 1,700 patients from all over the world included in the trial, there could be variation in the placebo responses. Second, methotrexate might still be having a minor effect when the trial started.
The study was sponsored by Gilead Sciences in collaboration with Galapagos NV. Dr. Combe has received honoraria from AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, UCB, Genzyme, Sanofi, Regeneron, Sun Pharma Advanced Research, Boehringer Ingelheim, and Flexion. Dr. Combe is a shareholder in Novartis.
SOURCE: Combe B et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):77-8. Abstract LB0001, doi: 10.1136/annrheumdis-2019-eular.8676
REPORTING FROM EULAR 2019 CONGRESS
First adult APS recommendations released by European society
MADRID – Low-dose aspirin is recommended for the primary prevention of antiphospholipid syndrome (APS) in patients at high risk for developing the condition, according to new recommendations developed by the European League Against Rheumatism (EULAR).
Indeed, the NSAID should be given at a dose of between 75 mg and 100 mg per day, in patients with a “high risk” antiphospholipid (aPL) antibody profile, including asymptomatic aPL antibody carriers, patients with systemic lupus erythematosus (SLE) without APS, and in women who are not pregnant but who have a history of obstetric APS.
The recommendations aim to help guide practice and ultimately to improve the quality of care for patients and their outcomes following treatment, Maria G. Tektonidou, MD, PhD, said at the European Congress of Rheumatology.
The guidance is necessary as “clinical practice in APS remains highly variable,” said Dr. Tektonidou of the National and Kapodistrian University of Athens. This is perhaps because APS is a “rare disease and also because it’s a newly recognized disease – it’s only 35 years old – and knowledge about the clinical spectrum, classification, and management is continuously advancing.”
Dr. Tektonidou, who was the convener of the EULAR Task Force that wrote the recommendations, noted that they were now published in Annals of the Rheumatic Diseases and considered three main groups of patients: those with thrombotic APS, those with obstetric APS, and those with catastrophic APS (CAPS). There are three overarching principles, 12 recommendations, and 29 graded statements, she said.
The three overarching principles concerned risk stratification, general measures for managing patients who test positive for aPL antibodies, and patient education and counseling on various topics, such as treatment adherence, therapeutic drug monitoring, contraceptive use, and lifestyle interventions.
Dr. Tektonidou highlighted how risk stratification was important and that a high-risk aPL profile was defined as the presence of lupus anticoagulant (LA) on at least two occasions, measured 12 weeks apart according to International Society on Thrombosis and Haemostasis guidelines, or the presence of two or even three aPL antibodies, or persistently high aPL antibody titers. By contrast, a low-risk aPL profile was defined as the isolated presence of anticardiolipin (aCL) or anti–beta-2 glycoprotein I antibodies at low-medium titers, particularly if transiently positive.
“Risk stratification should include the determination of the high-risk aPL profile; a prior history of thrombotic or obstetric [APS]; the coexistence of other systemic autoimmune diseases, and the presence of traditional cardiovascular risk factors,” Dr. Tektonidou said.
Four of the recommendations focus on the secondary prevention of APS, giving guidance on anticoagulant treatment with definite APS, first provoked or unprovoked venous thrombosis, and how to manage recurrent venous thrombosis. There also is a recommendation for the management of patients with definite APS and a first arterial thrombosis, outlining the type and intensity of anticoagulant therapy that should be given. Another four of the recommendations focus on the management of obstetric APS, with a focus on how to manage the various types of complications seen in pregnant women. Then the final recommendation concerns CAPS, it’s prevention and first-line treatment, and how to manage refractory patients.
With regards to CAPS, Ricard Cervera, MD, PhD, of the Hospital Clinic of Barcelona, this is “terrible” but “thankfully rare” form of APS that was first described in the early 1990s.
Although fewer than 1% of the APS adult population have CAPS (Arthritis Rheum. 2002;46[4]:1019-27), it’s a condition in which several thrombotic events occur simultaneously, affecting multiple systems or organs and which can be life threatening if not treated quickly.
New treatment guidelines for catastrophic APS
During a separate clinical science session at the conference, Dr. Cervera discussed the development of treatment guidelines for CAPS, noting that this had been one of the focus points of the McMaster RARE-Bestpractices project group in 2016. The group selected CAPS for a pilot exercise in guideline development for a rare disease and published their recommendations in 2018 (J Thromb Haemost. 2018;16:1656-64). Ten recommendations were developed, most of which were conditional, Dr. Cervera said, due to the lack of, or very low certainty, of the evidence.
The new EULAR 2019 adult APS recommendations now include CAPS and recommendation number 12 is split into two parts. The first, part A, states that prompt treatment of infections is needed in all patients positive for aPL antibodies and that anticoagulation should have minimal interruption or be used at level to help prevent the development of CAPS.
The second, part B, states that the first-line treatment of CAPS should be a triple combination therapy of glucocorticoids, heparin, and plasma exchange, or intravenous immunoglobulins, rather than single-agent treatment. Plus, it says that any triggering factor should be treated accordingly.
“Finally,” Dr. Cervera said, “in patients with refractory CAPS, B-cell depletion with rituximab or complement inhibitors, for example eculizumab, may be considered.”
The adult APS recommendations project was funded by EULAR. Dr. Tektonidou and Dr. Cervera reported having no relevant conflicts of interest.
SOURCES: Tektonidou M. Ann Rheum Dis. Jun 2019;78(Suppl 2):59-60. Abstract SP0191, doi: 0.1136/annrheumdis-2019-eular.8601; and Cervera R et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):62. Abstract SP0201. doi: 10.1136/annrheumdis-2019-eular.8444.
MADRID – Low-dose aspirin is recommended for the primary prevention of antiphospholipid syndrome (APS) in patients at high risk for developing the condition, according to new recommendations developed by the European League Against Rheumatism (EULAR).
Indeed, the NSAID should be given at a dose of between 75 mg and 100 mg per day, in patients with a “high risk” antiphospholipid (aPL) antibody profile, including asymptomatic aPL antibody carriers, patients with systemic lupus erythematosus (SLE) without APS, and in women who are not pregnant but who have a history of obstetric APS.
The recommendations aim to help guide practice and ultimately to improve the quality of care for patients and their outcomes following treatment, Maria G. Tektonidou, MD, PhD, said at the European Congress of Rheumatology.
The guidance is necessary as “clinical practice in APS remains highly variable,” said Dr. Tektonidou of the National and Kapodistrian University of Athens. This is perhaps because APS is a “rare disease and also because it’s a newly recognized disease – it’s only 35 years old – and knowledge about the clinical spectrum, classification, and management is continuously advancing.”
Dr. Tektonidou, who was the convener of the EULAR Task Force that wrote the recommendations, noted that they were now published in Annals of the Rheumatic Diseases and considered three main groups of patients: those with thrombotic APS, those with obstetric APS, and those with catastrophic APS (CAPS). There are three overarching principles, 12 recommendations, and 29 graded statements, she said.
The three overarching principles concerned risk stratification, general measures for managing patients who test positive for aPL antibodies, and patient education and counseling on various topics, such as treatment adherence, therapeutic drug monitoring, contraceptive use, and lifestyle interventions.
Dr. Tektonidou highlighted how risk stratification was important and that a high-risk aPL profile was defined as the presence of lupus anticoagulant (LA) on at least two occasions, measured 12 weeks apart according to International Society on Thrombosis and Haemostasis guidelines, or the presence of two or even three aPL antibodies, or persistently high aPL antibody titers. By contrast, a low-risk aPL profile was defined as the isolated presence of anticardiolipin (aCL) or anti–beta-2 glycoprotein I antibodies at low-medium titers, particularly if transiently positive.
“Risk stratification should include the determination of the high-risk aPL profile; a prior history of thrombotic or obstetric [APS]; the coexistence of other systemic autoimmune diseases, and the presence of traditional cardiovascular risk factors,” Dr. Tektonidou said.
Four of the recommendations focus on the secondary prevention of APS, giving guidance on anticoagulant treatment with definite APS, first provoked or unprovoked venous thrombosis, and how to manage recurrent venous thrombosis. There also is a recommendation for the management of patients with definite APS and a first arterial thrombosis, outlining the type and intensity of anticoagulant therapy that should be given. Another four of the recommendations focus on the management of obstetric APS, with a focus on how to manage the various types of complications seen in pregnant women. Then the final recommendation concerns CAPS, it’s prevention and first-line treatment, and how to manage refractory patients.
With regards to CAPS, Ricard Cervera, MD, PhD, of the Hospital Clinic of Barcelona, this is “terrible” but “thankfully rare” form of APS that was first described in the early 1990s.
Although fewer than 1% of the APS adult population have CAPS (Arthritis Rheum. 2002;46[4]:1019-27), it’s a condition in which several thrombotic events occur simultaneously, affecting multiple systems or organs and which can be life threatening if not treated quickly.
New treatment guidelines for catastrophic APS
During a separate clinical science session at the conference, Dr. Cervera discussed the development of treatment guidelines for CAPS, noting that this had been one of the focus points of the McMaster RARE-Bestpractices project group in 2016. The group selected CAPS for a pilot exercise in guideline development for a rare disease and published their recommendations in 2018 (J Thromb Haemost. 2018;16:1656-64). Ten recommendations were developed, most of which were conditional, Dr. Cervera said, due to the lack of, or very low certainty, of the evidence.
The new EULAR 2019 adult APS recommendations now include CAPS and recommendation number 12 is split into two parts. The first, part A, states that prompt treatment of infections is needed in all patients positive for aPL antibodies and that anticoagulation should have minimal interruption or be used at level to help prevent the development of CAPS.
The second, part B, states that the first-line treatment of CAPS should be a triple combination therapy of glucocorticoids, heparin, and plasma exchange, or intravenous immunoglobulins, rather than single-agent treatment. Plus, it says that any triggering factor should be treated accordingly.
“Finally,” Dr. Cervera said, “in patients with refractory CAPS, B-cell depletion with rituximab or complement inhibitors, for example eculizumab, may be considered.”
The adult APS recommendations project was funded by EULAR. Dr. Tektonidou and Dr. Cervera reported having no relevant conflicts of interest.
SOURCES: Tektonidou M. Ann Rheum Dis. Jun 2019;78(Suppl 2):59-60. Abstract SP0191, doi: 0.1136/annrheumdis-2019-eular.8601; and Cervera R et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):62. Abstract SP0201. doi: 10.1136/annrheumdis-2019-eular.8444.
MADRID – Low-dose aspirin is recommended for the primary prevention of antiphospholipid syndrome (APS) in patients at high risk for developing the condition, according to new recommendations developed by the European League Against Rheumatism (EULAR).
Indeed, the NSAID should be given at a dose of between 75 mg and 100 mg per day, in patients with a “high risk” antiphospholipid (aPL) antibody profile, including asymptomatic aPL antibody carriers, patients with systemic lupus erythematosus (SLE) without APS, and in women who are not pregnant but who have a history of obstetric APS.
The recommendations aim to help guide practice and ultimately to improve the quality of care for patients and their outcomes following treatment, Maria G. Tektonidou, MD, PhD, said at the European Congress of Rheumatology.
The guidance is necessary as “clinical practice in APS remains highly variable,” said Dr. Tektonidou of the National and Kapodistrian University of Athens. This is perhaps because APS is a “rare disease and also because it’s a newly recognized disease – it’s only 35 years old – and knowledge about the clinical spectrum, classification, and management is continuously advancing.”
Dr. Tektonidou, who was the convener of the EULAR Task Force that wrote the recommendations, noted that they were now published in Annals of the Rheumatic Diseases and considered three main groups of patients: those with thrombotic APS, those with obstetric APS, and those with catastrophic APS (CAPS). There are three overarching principles, 12 recommendations, and 29 graded statements, she said.
The three overarching principles concerned risk stratification, general measures for managing patients who test positive for aPL antibodies, and patient education and counseling on various topics, such as treatment adherence, therapeutic drug monitoring, contraceptive use, and lifestyle interventions.
Dr. Tektonidou highlighted how risk stratification was important and that a high-risk aPL profile was defined as the presence of lupus anticoagulant (LA) on at least two occasions, measured 12 weeks apart according to International Society on Thrombosis and Haemostasis guidelines, or the presence of two or even three aPL antibodies, or persistently high aPL antibody titers. By contrast, a low-risk aPL profile was defined as the isolated presence of anticardiolipin (aCL) or anti–beta-2 glycoprotein I antibodies at low-medium titers, particularly if transiently positive.
“Risk stratification should include the determination of the high-risk aPL profile; a prior history of thrombotic or obstetric [APS]; the coexistence of other systemic autoimmune diseases, and the presence of traditional cardiovascular risk factors,” Dr. Tektonidou said.
Four of the recommendations focus on the secondary prevention of APS, giving guidance on anticoagulant treatment with definite APS, first provoked or unprovoked venous thrombosis, and how to manage recurrent venous thrombosis. There also is a recommendation for the management of patients with definite APS and a first arterial thrombosis, outlining the type and intensity of anticoagulant therapy that should be given. Another four of the recommendations focus on the management of obstetric APS, with a focus on how to manage the various types of complications seen in pregnant women. Then the final recommendation concerns CAPS, it’s prevention and first-line treatment, and how to manage refractory patients.
With regards to CAPS, Ricard Cervera, MD, PhD, of the Hospital Clinic of Barcelona, this is “terrible” but “thankfully rare” form of APS that was first described in the early 1990s.
Although fewer than 1% of the APS adult population have CAPS (Arthritis Rheum. 2002;46[4]:1019-27), it’s a condition in which several thrombotic events occur simultaneously, affecting multiple systems or organs and which can be life threatening if not treated quickly.
New treatment guidelines for catastrophic APS
During a separate clinical science session at the conference, Dr. Cervera discussed the development of treatment guidelines for CAPS, noting that this had been one of the focus points of the McMaster RARE-Bestpractices project group in 2016. The group selected CAPS for a pilot exercise in guideline development for a rare disease and published their recommendations in 2018 (J Thromb Haemost. 2018;16:1656-64). Ten recommendations were developed, most of which were conditional, Dr. Cervera said, due to the lack of, or very low certainty, of the evidence.
The new EULAR 2019 adult APS recommendations now include CAPS and recommendation number 12 is split into two parts. The first, part A, states that prompt treatment of infections is needed in all patients positive for aPL antibodies and that anticoagulation should have minimal interruption or be used at level to help prevent the development of CAPS.
The second, part B, states that the first-line treatment of CAPS should be a triple combination therapy of glucocorticoids, heparin, and plasma exchange, or intravenous immunoglobulins, rather than single-agent treatment. Plus, it says that any triggering factor should be treated accordingly.
“Finally,” Dr. Cervera said, “in patients with refractory CAPS, B-cell depletion with rituximab or complement inhibitors, for example eculizumab, may be considered.”
The adult APS recommendations project was funded by EULAR. Dr. Tektonidou and Dr. Cervera reported having no relevant conflicts of interest.
SOURCES: Tektonidou M. Ann Rheum Dis. Jun 2019;78(Suppl 2):59-60. Abstract SP0191, doi: 0.1136/annrheumdis-2019-eular.8601; and Cervera R et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):62. Abstract SP0201. doi: 10.1136/annrheumdis-2019-eular.8444.
REPORTING FROM THE EULAR 2019 Congress
Abatacept response in seropositive RA may be linked to HLA gene
MADRID – according to results from the “exploratory” Early AMPLE study.
Clinical responses seen in the study were higher in the abatacept (Orencia) versus adalimumab group, study investigator Vivian P. Bykerk, MD, reported at the European Congress of Rheumatology. Indeed, a 20% improvement in American College of Rheumatology response criteria (ACR20), as well as ACR50 and ACR70 responses, were achieved by 83%, 70%, and 48% of abatacept-treated patients and by 63%, 45%, and 30% of adalimumab-treated patients.
Numerically higher percentages of patients who were treated with abatacept and had the shared epitope in the human leukocyte antigen (HLA) DRB1 (HLA-DRB1) allele achieved ACR20-level improvement when compared against treatment with adalimumab, and the same was seen for ACR50 and ACR70 response rates.
“The results we saw were clearly driven by the presence of the shared epitope, and there may be a differential benefit by treating the shared epitope in early RA patients with abatacept, compared with adalimumab,” said Dr. Bykerk, who is director of the Inflammatory Arthritis Center of Excellence at the Hospital for Special Surgery in New York.
The investigators also observed numerically higher responses on the Simplified Disease Activity Index and Clinical Disease Activity Index as well as the 28-joint Disease Activity Score using C-reactive protein.
The shared epitope is a major histocompatibility complex (MHC) class II protein receptor encoded by some alleles of the HLA-DRB1 gene. It’s found in the majority (70%–80%) of RA patients who are seropositive for anti-citrullinated protein antibodies (ACPAs), and it’s linked to joint destruction.
Prior work has suggested that abatacept may be more effective in RA patients who have the shared epitope than in those who do not, Dr. Bykerk explained.
Early AMPLE (Abatacept versus adalimumab comparison in biologic naive RA subjects with background methotrexate) was a prospective, randomized, single-blind, controlled study that ran for 24 weeks. It’s aim was to look at changes in immune cells and proteins in response to treatment with abatacept and adalimumab, which were both given in combination with methotrexate, and in relation to the presence or absence of the shared epitope.
Since abatacept works directly on T-cell activation, the investigators hypothesized that it should have a greater effect than other agents that work further downstream, such as the tumor necrosis factor (TNF) inhibitor adalimumab.
A total of 80 patients who had RA for less than 1 year and had not previously been treated with a biologic were recruited; all were positive for ACPA, specifically anti–cyclic citrullinated protein 2 (anti-CCP2) antibodies, and 76% had the shared epitope.
“Of note, we observed higher ACPA levels in the shared epitope group, and this requires further observation and understanding,” Dr. Bykerk said. The mean level of anti-CCP2 antibodies in patients with and without the shared epitope were a respective 1,216 U/mL and 368 U/mL.
Patients had been randomized 1:1 to receive either abatacept (125 mg given subcutaneously every week) or adalimumab (40 mg given subcutaneously every 2 weeks) on top of continuing weekly treatment with oral methotrexate.
“For a long time, we’ve wanted to try to match a therapy’s mechanism of action to what’s going on with the patient,” Dr. Bykerk commented in an interview. “Clinical phenotyping is usually not good enough, and we are always guessing,” she added. Plus, she noted, RA treatments tend to be used in the order in which they were approved rather than there being a rationale for using one over another based on their suitability in a particular situation.
The Early AMPLE data “are a first step towards the rational choice of therapy that might be more likely to be sustainable in a patient for a longer period of time and actually continue to modify the disease,” Dr. Bykerk suggested.
TNF inhibitors “work across the board in early disease,” she observed. “The problem is that after a year or two that only 44% of people are left on their first TNF, and why is that?” Reasons for the loss of effect are not known. Using a drug that works in a different way might prove to be the answer, such as seen here with abatacept in seropositive patients with the shared episode, but further studies will be needed to validate the Early AMPLE findings.
Bristol-Myers Squibb sponsored the study. Dr. Bykerk disclosed receiving grant or research support paid to her institution from BMS, as well as Amgen and UCB. She also disclosed acting as a consultant to BMS and multiple other pharmaceutical companies. Several coauthors were employees and shareholders in BMS, or had acted as consultants to BMS.
SOURCE: Rigby W et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):263-4. Abstract LB0008 , doi: 10.1136/annrheumdis-2019-eular.8668.
MADRID – according to results from the “exploratory” Early AMPLE study.
Clinical responses seen in the study were higher in the abatacept (Orencia) versus adalimumab group, study investigator Vivian P. Bykerk, MD, reported at the European Congress of Rheumatology. Indeed, a 20% improvement in American College of Rheumatology response criteria (ACR20), as well as ACR50 and ACR70 responses, were achieved by 83%, 70%, and 48% of abatacept-treated patients and by 63%, 45%, and 30% of adalimumab-treated patients.
Numerically higher percentages of patients who were treated with abatacept and had the shared epitope in the human leukocyte antigen (HLA) DRB1 (HLA-DRB1) allele achieved ACR20-level improvement when compared against treatment with adalimumab, and the same was seen for ACR50 and ACR70 response rates.
“The results we saw were clearly driven by the presence of the shared epitope, and there may be a differential benefit by treating the shared epitope in early RA patients with abatacept, compared with adalimumab,” said Dr. Bykerk, who is director of the Inflammatory Arthritis Center of Excellence at the Hospital for Special Surgery in New York.
The investigators also observed numerically higher responses on the Simplified Disease Activity Index and Clinical Disease Activity Index as well as the 28-joint Disease Activity Score using C-reactive protein.
The shared epitope is a major histocompatibility complex (MHC) class II protein receptor encoded by some alleles of the HLA-DRB1 gene. It’s found in the majority (70%–80%) of RA patients who are seropositive for anti-citrullinated protein antibodies (ACPAs), and it’s linked to joint destruction.
Prior work has suggested that abatacept may be more effective in RA patients who have the shared epitope than in those who do not, Dr. Bykerk explained.
Early AMPLE (Abatacept versus adalimumab comparison in biologic naive RA subjects with background methotrexate) was a prospective, randomized, single-blind, controlled study that ran for 24 weeks. It’s aim was to look at changes in immune cells and proteins in response to treatment with abatacept and adalimumab, which were both given in combination with methotrexate, and in relation to the presence or absence of the shared epitope.
Since abatacept works directly on T-cell activation, the investigators hypothesized that it should have a greater effect than other agents that work further downstream, such as the tumor necrosis factor (TNF) inhibitor adalimumab.
A total of 80 patients who had RA for less than 1 year and had not previously been treated with a biologic were recruited; all were positive for ACPA, specifically anti–cyclic citrullinated protein 2 (anti-CCP2) antibodies, and 76% had the shared epitope.
“Of note, we observed higher ACPA levels in the shared epitope group, and this requires further observation and understanding,” Dr. Bykerk said. The mean level of anti-CCP2 antibodies in patients with and without the shared epitope were a respective 1,216 U/mL and 368 U/mL.
Patients had been randomized 1:1 to receive either abatacept (125 mg given subcutaneously every week) or adalimumab (40 mg given subcutaneously every 2 weeks) on top of continuing weekly treatment with oral methotrexate.
“For a long time, we’ve wanted to try to match a therapy’s mechanism of action to what’s going on with the patient,” Dr. Bykerk commented in an interview. “Clinical phenotyping is usually not good enough, and we are always guessing,” she added. Plus, she noted, RA treatments tend to be used in the order in which they were approved rather than there being a rationale for using one over another based on their suitability in a particular situation.
The Early AMPLE data “are a first step towards the rational choice of therapy that might be more likely to be sustainable in a patient for a longer period of time and actually continue to modify the disease,” Dr. Bykerk suggested.
TNF inhibitors “work across the board in early disease,” she observed. “The problem is that after a year or two that only 44% of people are left on their first TNF, and why is that?” Reasons for the loss of effect are not known. Using a drug that works in a different way might prove to be the answer, such as seen here with abatacept in seropositive patients with the shared episode, but further studies will be needed to validate the Early AMPLE findings.
Bristol-Myers Squibb sponsored the study. Dr. Bykerk disclosed receiving grant or research support paid to her institution from BMS, as well as Amgen and UCB. She also disclosed acting as a consultant to BMS and multiple other pharmaceutical companies. Several coauthors were employees and shareholders in BMS, or had acted as consultants to BMS.
SOURCE: Rigby W et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):263-4. Abstract LB0008 , doi: 10.1136/annrheumdis-2019-eular.8668.
MADRID – according to results from the “exploratory” Early AMPLE study.
Clinical responses seen in the study were higher in the abatacept (Orencia) versus adalimumab group, study investigator Vivian P. Bykerk, MD, reported at the European Congress of Rheumatology. Indeed, a 20% improvement in American College of Rheumatology response criteria (ACR20), as well as ACR50 and ACR70 responses, were achieved by 83%, 70%, and 48% of abatacept-treated patients and by 63%, 45%, and 30% of adalimumab-treated patients.
Numerically higher percentages of patients who were treated with abatacept and had the shared epitope in the human leukocyte antigen (HLA) DRB1 (HLA-DRB1) allele achieved ACR20-level improvement when compared against treatment with adalimumab, and the same was seen for ACR50 and ACR70 response rates.
“The results we saw were clearly driven by the presence of the shared epitope, and there may be a differential benefit by treating the shared epitope in early RA patients with abatacept, compared with adalimumab,” said Dr. Bykerk, who is director of the Inflammatory Arthritis Center of Excellence at the Hospital for Special Surgery in New York.
The investigators also observed numerically higher responses on the Simplified Disease Activity Index and Clinical Disease Activity Index as well as the 28-joint Disease Activity Score using C-reactive protein.
The shared epitope is a major histocompatibility complex (MHC) class II protein receptor encoded by some alleles of the HLA-DRB1 gene. It’s found in the majority (70%–80%) of RA patients who are seropositive for anti-citrullinated protein antibodies (ACPAs), and it’s linked to joint destruction.
Prior work has suggested that abatacept may be more effective in RA patients who have the shared epitope than in those who do not, Dr. Bykerk explained.
Early AMPLE (Abatacept versus adalimumab comparison in biologic naive RA subjects with background methotrexate) was a prospective, randomized, single-blind, controlled study that ran for 24 weeks. It’s aim was to look at changes in immune cells and proteins in response to treatment with abatacept and adalimumab, which were both given in combination with methotrexate, and in relation to the presence or absence of the shared epitope.
Since abatacept works directly on T-cell activation, the investigators hypothesized that it should have a greater effect than other agents that work further downstream, such as the tumor necrosis factor (TNF) inhibitor adalimumab.
A total of 80 patients who had RA for less than 1 year and had not previously been treated with a biologic were recruited; all were positive for ACPA, specifically anti–cyclic citrullinated protein 2 (anti-CCP2) antibodies, and 76% had the shared epitope.
“Of note, we observed higher ACPA levels in the shared epitope group, and this requires further observation and understanding,” Dr. Bykerk said. The mean level of anti-CCP2 antibodies in patients with and without the shared epitope were a respective 1,216 U/mL and 368 U/mL.
Patients had been randomized 1:1 to receive either abatacept (125 mg given subcutaneously every week) or adalimumab (40 mg given subcutaneously every 2 weeks) on top of continuing weekly treatment with oral methotrexate.
“For a long time, we’ve wanted to try to match a therapy’s mechanism of action to what’s going on with the patient,” Dr. Bykerk commented in an interview. “Clinical phenotyping is usually not good enough, and we are always guessing,” she added. Plus, she noted, RA treatments tend to be used in the order in which they were approved rather than there being a rationale for using one over another based on their suitability in a particular situation.
The Early AMPLE data “are a first step towards the rational choice of therapy that might be more likely to be sustainable in a patient for a longer period of time and actually continue to modify the disease,” Dr. Bykerk suggested.
TNF inhibitors “work across the board in early disease,” she observed. “The problem is that after a year or two that only 44% of people are left on their first TNF, and why is that?” Reasons for the loss of effect are not known. Using a drug that works in a different way might prove to be the answer, such as seen here with abatacept in seropositive patients with the shared episode, but further studies will be needed to validate the Early AMPLE findings.
Bristol-Myers Squibb sponsored the study. Dr. Bykerk disclosed receiving grant or research support paid to her institution from BMS, as well as Amgen and UCB. She also disclosed acting as a consultant to BMS and multiple other pharmaceutical companies. Several coauthors were employees and shareholders in BMS, or had acted as consultants to BMS.
SOURCE: Rigby W et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):263-4. Abstract LB0008 , doi: 10.1136/annrheumdis-2019-eular.8668.
REPORTING FROM THE EULAR 2019 Congress
Recognize and assess RA fatigue routinely, rheumatology experts urge
MADRID – Fatigue is one of the most frequent features of rheumatoid arthritis, and it needs to be assessed and addressed, several leading rheumatology experts urged at the European Congress of Rheumatology.
“Fatigue is an outcome of outstanding importance for patients with rheumatoid arthritis, and therefore it should be an outcome of outstanding importance for clinicians who take care of these patients,” said José António Pereira da Silva, MD, PhD, a professor of rheumatology at the University of Coimbra (Portugal) during a clinical science session dedicated to the topic.
“Fatigue is described as being significant by as many as 40%-80% of all patients with rheumatoid arthritis, and described as being severe by 41%-49% of these patients according to different studies,” Dr. da Silva said.
“The impact upon the quality of life from the patients’ perspective is quite varied but always rather important, if not ‘dramatic,’ ” Dr. da Silva said. Fatigue needs to be part of treatment targets alongside disease activity and thus regularly measured, he added.
The problem of fatigue
The problem, however, is that fatigue is such a complex construct, observed James Galloway, MBChB, PhD, of the Centre for Rheumatic Diseases at King’s College London. “It’s definitely multifactorial in origin; it’s a combination of inflammatory disease, psychosocial situations, and comorbidity.”
Moreover, said Dr. Galloway, “what people describe as fatigue is multidimensional; it’s not just how well you sleep, but how much energy you have, and it’s also how motivated you are.” The fatigue that accompanies RA is different from the fatigue that is experienced in daily life, he noted, and it has a huge impact on patients’ lives.
Determining the cause of fatigue can be challenging, said Wan-Fai Ng, MBChB, PhD, professor of rheumatology at the Institute of Cellular Medicine at Newcastle (England) University.
“Fatigue is a syndrome that often coexists with other symptoms, and there may be different type of fatigue,” Dr. Ng said. He noted that there were many potential underlying biological mechanisms, but the most studied so far is inflammation. Fatigue is probably driven, at least in part, by “sickness behavior” and there are frequent associations between fatigue and chronic inflammatory conditions such as RA and Sjögren’s syndrome.
“I think the role of conventional inflammatory mechanisms, at least in chronic fatigue in chronic conditions, remains unclear,” Dr. Ng added. “The biological systems, for example the vagus nerve, that regulate the immune system may play key roles in fatigue, especially in chronic inflammatory states.”
Whatever the underlying mechanism, it’s clear that there are multiple factors at play that need addressing if fatigue is to be properly addressed in the clinic. Dr. da Silva unveiled a new path analysis model that will be published in a future issue of Clinical and Experimental Rheumatology that showed how disease activity, pain, disability, sleep disturbance, and depression might all interlink to account for fatigue in patients with RA.
Young or old, fatigue is a prominent, persistent symptom
Fatigue is not just a problem in older adults with rheumatic and musculoskeletal diseases, as Ellen Dalen Arnstad, MD, pointed out in a separate session at the congress. Younger adults and adolescents are also often affected, as demonstrated by data she presented from an 18-year follow-up study of individuals with juvenile idiopathic arthritis (JIA).
An oft-used definition of fatigue, she said was “a persistent, overwhelming sense of tiredness, weakness, and exhaustion.” This results in “decreased capacity of physical function or mental work and is unrelieved by sleep or rests.”
Dr. Arnstad, a pediatric rheumatologist at the Hospital of Levanger in Norway and PhD student at the Norwegian University of Science and Technology in Trondheim, presented data from the Nordic JIA study of 377 subjects who were assessed for fatigue. These showed that there were higher levels of fatigue among participants with active disease, pain, and self-reported health problems. The mean Fatigue Severity Scale score was 3.2 overall, with a higher score in females (3.5) versus males (2.5).
“We found highest mean fatigue scores among those with bad physical and mental health,” Dr. Arnstad reported. Just over a quarter (26%) of patients had severe fatigue, which was defined as a score of 4 or more.
“Fatigue is a prominent symptom in JIA after 18 years of disease duration,” and it “should be measured in a long-term follow-up, both in clinical and research settings,” Dr. Arnstad said.
How should fatigue in RA be assessed?
“Fatigue is recognized by OMERACT [Outcome Measures in Rheumatology Clinical Trials group] as being one of the measured outcome factors in rheumatoid arthritis, one that we should all be taking care of,” Dr. da Silva said. It was added alongside the core set of measures that should be used in all trials “wherever possible.”
So how should fatigue be measured in practice? There are lots of instruments available. Indeed, Dr. da Silva and associates recently counted more than 12, but there is no consensus and no guidelines on which should be used.
“We propose to use a single-item instrument as a screening tool, like the BRAF NRS [Bristol Rheumatoid Arthritis Fatigue Numerical Rating Scale] or RAID-F [Rheumatoid Arthritis Impact of Disease–Fatigue domain], which would be supplemented by additional multidimensional assessments if significant levels of fatigue are identified,” he said in an interview. “This will be particularly useful when the aims are to explore causality of fatigue or the efficacy of an intervention.”
Dr. da Silva noted after his presentation that the RAID-F score is routinely used at his practice. “It’s an extremely useful instrument in trying to assess how the patient is dealing with rheumatoid arthritis,” he said. He emphasized that fatigue needed to be considered separately from disease activity and that “it should be part of treatment targets and it should be regularly measured in both research and clinical practice.”
How can fatigue in RA be treated?
When faced with a patient with RA who is experiencing fatigue, it’s important to take a full history and try to determine the cause or contributing factors, Dr. Galloway advised. “I think it’s really important to [take a history of this] specific symptom in the same way you take a history of articular pain.” Consider the onset of fatigue, for example. Is it sudden or linked to a particular stressor or life event, or has its development been more gradual? What’s been the clinical course, duration, and daily pattern? Are there any factors that might alleviate it or exacerbate it? What’s the impact on the patient’s daily life – both in terms of work and social participation?
Treating RA more effectively might help, “but that is unlikely to be sufficient,” Dr. Galloway said, observing that “leaving uncontrolled inflammation is bad, but, in 2019, more inflammation is probably not the solution to fatigue.” Instead, he suggested looking for and treating comorbidities that might be contributing to the fatigue, such as anemia, endocrine or cardiac disease, or perhaps sleep apnea or depression, among others.
“I would discourage the prescribing, for the large part, of drugs for fatigue; that’s because that’s where the evidence is probably the least strong,” Dr. Galloway said. However, there is much better evidence for the use of exercise training in RA and for combining exercise and psychosocial approaches. Improving sleep hygiene may also be beneficial for some patients.
The bottom line is that “fatigue matters” and should be “talked about more with our patients,” Dr. Galloway said.
Dr. da Silva and Dr. Arnstad had no financial conflicts of interest. Dr. Ng disclosed research collaborations with Resolve Therapeutics, electroCore, GlaxoSmithKline, and AbbVie. He also disclosed acting as a consultant for Novartis, GlaxoSmithKline, AbbVie, MedImmune, Pfizer, and Bristol-Myers Squibb. Dr. Galloway disclosed receiving honoraria for speaking at meetings, support for conference travel, or both from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Pfizer, and UCB.
SOURCES: da Silva J. Ann Rheum Dis. Jun 2019;78(Suppl 2):15. Abstract SP0052, doi: 10.1136/annrheumdis-2019-eular.8454; Galloway J. Ann Rheum Dis. Jun 2019;78(Suppl 2):15. Abstract SP0053, doi: 10.1136/annrheumdis-2019-eular.8483; Arnstad ED et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):176. Abstract OP201, doi: 10.1136/annrheumdis-2019-eular.4006
MADRID – Fatigue is one of the most frequent features of rheumatoid arthritis, and it needs to be assessed and addressed, several leading rheumatology experts urged at the European Congress of Rheumatology.
“Fatigue is an outcome of outstanding importance for patients with rheumatoid arthritis, and therefore it should be an outcome of outstanding importance for clinicians who take care of these patients,” said José António Pereira da Silva, MD, PhD, a professor of rheumatology at the University of Coimbra (Portugal) during a clinical science session dedicated to the topic.
“Fatigue is described as being significant by as many as 40%-80% of all patients with rheumatoid arthritis, and described as being severe by 41%-49% of these patients according to different studies,” Dr. da Silva said.
“The impact upon the quality of life from the patients’ perspective is quite varied but always rather important, if not ‘dramatic,’ ” Dr. da Silva said. Fatigue needs to be part of treatment targets alongside disease activity and thus regularly measured, he added.
The problem of fatigue
The problem, however, is that fatigue is such a complex construct, observed James Galloway, MBChB, PhD, of the Centre for Rheumatic Diseases at King’s College London. “It’s definitely multifactorial in origin; it’s a combination of inflammatory disease, psychosocial situations, and comorbidity.”
Moreover, said Dr. Galloway, “what people describe as fatigue is multidimensional; it’s not just how well you sleep, but how much energy you have, and it’s also how motivated you are.” The fatigue that accompanies RA is different from the fatigue that is experienced in daily life, he noted, and it has a huge impact on patients’ lives.
Determining the cause of fatigue can be challenging, said Wan-Fai Ng, MBChB, PhD, professor of rheumatology at the Institute of Cellular Medicine at Newcastle (England) University.
“Fatigue is a syndrome that often coexists with other symptoms, and there may be different type of fatigue,” Dr. Ng said. He noted that there were many potential underlying biological mechanisms, but the most studied so far is inflammation. Fatigue is probably driven, at least in part, by “sickness behavior” and there are frequent associations between fatigue and chronic inflammatory conditions such as RA and Sjögren’s syndrome.
“I think the role of conventional inflammatory mechanisms, at least in chronic fatigue in chronic conditions, remains unclear,” Dr. Ng added. “The biological systems, for example the vagus nerve, that regulate the immune system may play key roles in fatigue, especially in chronic inflammatory states.”
Whatever the underlying mechanism, it’s clear that there are multiple factors at play that need addressing if fatigue is to be properly addressed in the clinic. Dr. da Silva unveiled a new path analysis model that will be published in a future issue of Clinical and Experimental Rheumatology that showed how disease activity, pain, disability, sleep disturbance, and depression might all interlink to account for fatigue in patients with RA.
Young or old, fatigue is a prominent, persistent symptom
Fatigue is not just a problem in older adults with rheumatic and musculoskeletal diseases, as Ellen Dalen Arnstad, MD, pointed out in a separate session at the congress. Younger adults and adolescents are also often affected, as demonstrated by data she presented from an 18-year follow-up study of individuals with juvenile idiopathic arthritis (JIA).
An oft-used definition of fatigue, she said was “a persistent, overwhelming sense of tiredness, weakness, and exhaustion.” This results in “decreased capacity of physical function or mental work and is unrelieved by sleep or rests.”
Dr. Arnstad, a pediatric rheumatologist at the Hospital of Levanger in Norway and PhD student at the Norwegian University of Science and Technology in Trondheim, presented data from the Nordic JIA study of 377 subjects who were assessed for fatigue. These showed that there were higher levels of fatigue among participants with active disease, pain, and self-reported health problems. The mean Fatigue Severity Scale score was 3.2 overall, with a higher score in females (3.5) versus males (2.5).
“We found highest mean fatigue scores among those with bad physical and mental health,” Dr. Arnstad reported. Just over a quarter (26%) of patients had severe fatigue, which was defined as a score of 4 or more.
“Fatigue is a prominent symptom in JIA after 18 years of disease duration,” and it “should be measured in a long-term follow-up, both in clinical and research settings,” Dr. Arnstad said.
How should fatigue in RA be assessed?
“Fatigue is recognized by OMERACT [Outcome Measures in Rheumatology Clinical Trials group] as being one of the measured outcome factors in rheumatoid arthritis, one that we should all be taking care of,” Dr. da Silva said. It was added alongside the core set of measures that should be used in all trials “wherever possible.”
So how should fatigue be measured in practice? There are lots of instruments available. Indeed, Dr. da Silva and associates recently counted more than 12, but there is no consensus and no guidelines on which should be used.
“We propose to use a single-item instrument as a screening tool, like the BRAF NRS [Bristol Rheumatoid Arthritis Fatigue Numerical Rating Scale] or RAID-F [Rheumatoid Arthritis Impact of Disease–Fatigue domain], which would be supplemented by additional multidimensional assessments if significant levels of fatigue are identified,” he said in an interview. “This will be particularly useful when the aims are to explore causality of fatigue or the efficacy of an intervention.”
Dr. da Silva noted after his presentation that the RAID-F score is routinely used at his practice. “It’s an extremely useful instrument in trying to assess how the patient is dealing with rheumatoid arthritis,” he said. He emphasized that fatigue needed to be considered separately from disease activity and that “it should be part of treatment targets and it should be regularly measured in both research and clinical practice.”
How can fatigue in RA be treated?
When faced with a patient with RA who is experiencing fatigue, it’s important to take a full history and try to determine the cause or contributing factors, Dr. Galloway advised. “I think it’s really important to [take a history of this] specific symptom in the same way you take a history of articular pain.” Consider the onset of fatigue, for example. Is it sudden or linked to a particular stressor or life event, or has its development been more gradual? What’s been the clinical course, duration, and daily pattern? Are there any factors that might alleviate it or exacerbate it? What’s the impact on the patient’s daily life – both in terms of work and social participation?
Treating RA more effectively might help, “but that is unlikely to be sufficient,” Dr. Galloway said, observing that “leaving uncontrolled inflammation is bad, but, in 2019, more inflammation is probably not the solution to fatigue.” Instead, he suggested looking for and treating comorbidities that might be contributing to the fatigue, such as anemia, endocrine or cardiac disease, or perhaps sleep apnea or depression, among others.
“I would discourage the prescribing, for the large part, of drugs for fatigue; that’s because that’s where the evidence is probably the least strong,” Dr. Galloway said. However, there is much better evidence for the use of exercise training in RA and for combining exercise and psychosocial approaches. Improving sleep hygiene may also be beneficial for some patients.
The bottom line is that “fatigue matters” and should be “talked about more with our patients,” Dr. Galloway said.
Dr. da Silva and Dr. Arnstad had no financial conflicts of interest. Dr. Ng disclosed research collaborations with Resolve Therapeutics, electroCore, GlaxoSmithKline, and AbbVie. He also disclosed acting as a consultant for Novartis, GlaxoSmithKline, AbbVie, MedImmune, Pfizer, and Bristol-Myers Squibb. Dr. Galloway disclosed receiving honoraria for speaking at meetings, support for conference travel, or both from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Pfizer, and UCB.
SOURCES: da Silva J. Ann Rheum Dis. Jun 2019;78(Suppl 2):15. Abstract SP0052, doi: 10.1136/annrheumdis-2019-eular.8454; Galloway J. Ann Rheum Dis. Jun 2019;78(Suppl 2):15. Abstract SP0053, doi: 10.1136/annrheumdis-2019-eular.8483; Arnstad ED et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):176. Abstract OP201, doi: 10.1136/annrheumdis-2019-eular.4006
MADRID – Fatigue is one of the most frequent features of rheumatoid arthritis, and it needs to be assessed and addressed, several leading rheumatology experts urged at the European Congress of Rheumatology.
“Fatigue is an outcome of outstanding importance for patients with rheumatoid arthritis, and therefore it should be an outcome of outstanding importance for clinicians who take care of these patients,” said José António Pereira da Silva, MD, PhD, a professor of rheumatology at the University of Coimbra (Portugal) during a clinical science session dedicated to the topic.
“Fatigue is described as being significant by as many as 40%-80% of all patients with rheumatoid arthritis, and described as being severe by 41%-49% of these patients according to different studies,” Dr. da Silva said.
“The impact upon the quality of life from the patients’ perspective is quite varied but always rather important, if not ‘dramatic,’ ” Dr. da Silva said. Fatigue needs to be part of treatment targets alongside disease activity and thus regularly measured, he added.
The problem of fatigue
The problem, however, is that fatigue is such a complex construct, observed James Galloway, MBChB, PhD, of the Centre for Rheumatic Diseases at King’s College London. “It’s definitely multifactorial in origin; it’s a combination of inflammatory disease, psychosocial situations, and comorbidity.”
Moreover, said Dr. Galloway, “what people describe as fatigue is multidimensional; it’s not just how well you sleep, but how much energy you have, and it’s also how motivated you are.” The fatigue that accompanies RA is different from the fatigue that is experienced in daily life, he noted, and it has a huge impact on patients’ lives.
Determining the cause of fatigue can be challenging, said Wan-Fai Ng, MBChB, PhD, professor of rheumatology at the Institute of Cellular Medicine at Newcastle (England) University.
“Fatigue is a syndrome that often coexists with other symptoms, and there may be different type of fatigue,” Dr. Ng said. He noted that there were many potential underlying biological mechanisms, but the most studied so far is inflammation. Fatigue is probably driven, at least in part, by “sickness behavior” and there are frequent associations between fatigue and chronic inflammatory conditions such as RA and Sjögren’s syndrome.
“I think the role of conventional inflammatory mechanisms, at least in chronic fatigue in chronic conditions, remains unclear,” Dr. Ng added. “The biological systems, for example the vagus nerve, that regulate the immune system may play key roles in fatigue, especially in chronic inflammatory states.”
Whatever the underlying mechanism, it’s clear that there are multiple factors at play that need addressing if fatigue is to be properly addressed in the clinic. Dr. da Silva unveiled a new path analysis model that will be published in a future issue of Clinical and Experimental Rheumatology that showed how disease activity, pain, disability, sleep disturbance, and depression might all interlink to account for fatigue in patients with RA.
Young or old, fatigue is a prominent, persistent symptom
Fatigue is not just a problem in older adults with rheumatic and musculoskeletal diseases, as Ellen Dalen Arnstad, MD, pointed out in a separate session at the congress. Younger adults and adolescents are also often affected, as demonstrated by data she presented from an 18-year follow-up study of individuals with juvenile idiopathic arthritis (JIA).
An oft-used definition of fatigue, she said was “a persistent, overwhelming sense of tiredness, weakness, and exhaustion.” This results in “decreased capacity of physical function or mental work and is unrelieved by sleep or rests.”
Dr. Arnstad, a pediatric rheumatologist at the Hospital of Levanger in Norway and PhD student at the Norwegian University of Science and Technology in Trondheim, presented data from the Nordic JIA study of 377 subjects who were assessed for fatigue. These showed that there were higher levels of fatigue among participants with active disease, pain, and self-reported health problems. The mean Fatigue Severity Scale score was 3.2 overall, with a higher score in females (3.5) versus males (2.5).
“We found highest mean fatigue scores among those with bad physical and mental health,” Dr. Arnstad reported. Just over a quarter (26%) of patients had severe fatigue, which was defined as a score of 4 or more.
“Fatigue is a prominent symptom in JIA after 18 years of disease duration,” and it “should be measured in a long-term follow-up, both in clinical and research settings,” Dr. Arnstad said.
How should fatigue in RA be assessed?
“Fatigue is recognized by OMERACT [Outcome Measures in Rheumatology Clinical Trials group] as being one of the measured outcome factors in rheumatoid arthritis, one that we should all be taking care of,” Dr. da Silva said. It was added alongside the core set of measures that should be used in all trials “wherever possible.”
So how should fatigue be measured in practice? There are lots of instruments available. Indeed, Dr. da Silva and associates recently counted more than 12, but there is no consensus and no guidelines on which should be used.
“We propose to use a single-item instrument as a screening tool, like the BRAF NRS [Bristol Rheumatoid Arthritis Fatigue Numerical Rating Scale] or RAID-F [Rheumatoid Arthritis Impact of Disease–Fatigue domain], which would be supplemented by additional multidimensional assessments if significant levels of fatigue are identified,” he said in an interview. “This will be particularly useful when the aims are to explore causality of fatigue or the efficacy of an intervention.”
Dr. da Silva noted after his presentation that the RAID-F score is routinely used at his practice. “It’s an extremely useful instrument in trying to assess how the patient is dealing with rheumatoid arthritis,” he said. He emphasized that fatigue needed to be considered separately from disease activity and that “it should be part of treatment targets and it should be regularly measured in both research and clinical practice.”
How can fatigue in RA be treated?
When faced with a patient with RA who is experiencing fatigue, it’s important to take a full history and try to determine the cause or contributing factors, Dr. Galloway advised. “I think it’s really important to [take a history of this] specific symptom in the same way you take a history of articular pain.” Consider the onset of fatigue, for example. Is it sudden or linked to a particular stressor or life event, or has its development been more gradual? What’s been the clinical course, duration, and daily pattern? Are there any factors that might alleviate it or exacerbate it? What’s the impact on the patient’s daily life – both in terms of work and social participation?
Treating RA more effectively might help, “but that is unlikely to be sufficient,” Dr. Galloway said, observing that “leaving uncontrolled inflammation is bad, but, in 2019, more inflammation is probably not the solution to fatigue.” Instead, he suggested looking for and treating comorbidities that might be contributing to the fatigue, such as anemia, endocrine or cardiac disease, or perhaps sleep apnea or depression, among others.
“I would discourage the prescribing, for the large part, of drugs for fatigue; that’s because that’s where the evidence is probably the least strong,” Dr. Galloway said. However, there is much better evidence for the use of exercise training in RA and for combining exercise and psychosocial approaches. Improving sleep hygiene may also be beneficial for some patients.
The bottom line is that “fatigue matters” and should be “talked about more with our patients,” Dr. Galloway said.
Dr. da Silva and Dr. Arnstad had no financial conflicts of interest. Dr. Ng disclosed research collaborations with Resolve Therapeutics, electroCore, GlaxoSmithKline, and AbbVie. He also disclosed acting as a consultant for Novartis, GlaxoSmithKline, AbbVie, MedImmune, Pfizer, and Bristol-Myers Squibb. Dr. Galloway disclosed receiving honoraria for speaking at meetings, support for conference travel, or both from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Pfizer, and UCB.
SOURCES: da Silva J. Ann Rheum Dis. Jun 2019;78(Suppl 2):15. Abstract SP0052, doi: 10.1136/annrheumdis-2019-eular.8454; Galloway J. Ann Rheum Dis. Jun 2019;78(Suppl 2):15. Abstract SP0053, doi: 10.1136/annrheumdis-2019-eular.8483; Arnstad ED et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):176. Abstract OP201, doi: 10.1136/annrheumdis-2019-eular.4006
REPORTING FROM EULAR 2019 CONGRESS
After prior TNFi in axSpA, taking secukinumab or another TNFi appear equivalent
MADRID – In axial spondyloarthritis patients who discontinue a tumor necrosis factor inhibitor (TNFi), there does not appear to be any advantage for using the anti–interleukin-17 biologic secukinumab over a different tumor necrosis factor inhibitor for next therapy, according to an analysis presented at the European Congress of Rheumatology.
“Switching to secukinumab [Cosentyx] might even be inferior in many patients,” according to Adrian Ciurea, MD, of the clinic for rheumatology at University Hospital Zürich.
This conclusion was reached in a retrospective analysis of axial spondyloarthritis (axSpA) patients enrolled in the Swiss Clinical Quality Management Cohort. Although Dr. Ciurea said that a prospective trial is needed to confirm the findings, this study was conducted because there have been, up until now, “no data to choose between options” to guide this choice.
In this study of 382 axSpA patients who were candidates for a new biologic after discontinuing a previous TNFi, 275 were started on a different TNFi and 107 were started on secukinumab. Although about 60% of patients in both groups were HLAB27-positive, there were many other characteristics, including those related to disease severity, that were different, Dr. Ciurea acknowledged.
Specifically, the proportion of patients starting secukinumab treated with two or more TNF inhibitors was greater than that of patients switching to another TNFi (77.6% vs. 37.8%; P less than .001). In addition, patients in the secukinumab group had a higher baseline disease activity, more enthesitis, and greater axial impairment.
These were reflected in higher average Bath Ankylosing Spondylitis Disease Activity Index scores (6.1 vs. 4.8; P less than .001) as well as other baseline clinical scoring methods, such as the Bath Ankylosing Spondylitis Functional Index and the Maastricht Ankylosing Spondylitis Enthesitis Score.
However, baseline high-sensitivity C-reactive protein levels, number of swollen joints, or years of symptom duration were not significantly different between the groups, although all were numerically higher in the secukinumab group. The proportion of patients with uveitis was higher in the TNFi group. About 70% of patients in both groups had discontinued their prior TNFi for inadequate response.
For the primary assessment of drug survival on the new therapy, the median time was 1.1 years in the secukinumab group and 2.0 years in the group switched to a new TNFi, without adjustment for baseline characteristics and disease severity. After risk adjustment, this difference was no statistically significant.
“There was an interaction with gender, indicating a significantly higher risk of discontinuing secukinumab than a new TNFi in men,” according to Dr. Ciurea. This was not seen in women.
Previous studies have shown the response rate to a second TNFi is typically lower than for an initial TNFi therapy. Previous studies have also shown that response to secukinumab is lower in patients with previous TNFi experience than in those who are naive to biologics, Dr. Ciurea said. This analysis suggests that the likelihood of sustained disease control is not greater in TNFi-experienced patients who start secukinumab relative to a different TNFi.
When asked if the data had been analyzed to compare response in patients exposed to only one prior TNFi, Dr. Ciurea replied that this could not be done because the sample size was too small.
Although Dr. Ciurea acknowledged the limitations of retrospective studies with risk adjustments, he concluded that there does not appear to be an advantage for initiating secukinumab over starting a different TNFi in axSpA patients who require a switch from their current TNFi,
Even though he said that this is the first study to address this question objectively, Dr. Ciurea said, “A sufficiently powered, prospective, head-to-head trial is needed.”
Dr. Ciurea reported multiple financial relationships with pharmaceutical companies but received no funding for this study.
SOURCE: Tellenbach C et al. Ann Rheum Dis. 2019;78(Suppl 2):197. Abstract OPO237, doi: 10.1136/annrheumdis-2019-eular.2427
MADRID – In axial spondyloarthritis patients who discontinue a tumor necrosis factor inhibitor (TNFi), there does not appear to be any advantage for using the anti–interleukin-17 biologic secukinumab over a different tumor necrosis factor inhibitor for next therapy, according to an analysis presented at the European Congress of Rheumatology.
“Switching to secukinumab [Cosentyx] might even be inferior in many patients,” according to Adrian Ciurea, MD, of the clinic for rheumatology at University Hospital Zürich.
This conclusion was reached in a retrospective analysis of axial spondyloarthritis (axSpA) patients enrolled in the Swiss Clinical Quality Management Cohort. Although Dr. Ciurea said that a prospective trial is needed to confirm the findings, this study was conducted because there have been, up until now, “no data to choose between options” to guide this choice.
In this study of 382 axSpA patients who were candidates for a new biologic after discontinuing a previous TNFi, 275 were started on a different TNFi and 107 were started on secukinumab. Although about 60% of patients in both groups were HLAB27-positive, there were many other characteristics, including those related to disease severity, that were different, Dr. Ciurea acknowledged.
Specifically, the proportion of patients starting secukinumab treated with two or more TNF inhibitors was greater than that of patients switching to another TNFi (77.6% vs. 37.8%; P less than .001). In addition, patients in the secukinumab group had a higher baseline disease activity, more enthesitis, and greater axial impairment.
These were reflected in higher average Bath Ankylosing Spondylitis Disease Activity Index scores (6.1 vs. 4.8; P less than .001) as well as other baseline clinical scoring methods, such as the Bath Ankylosing Spondylitis Functional Index and the Maastricht Ankylosing Spondylitis Enthesitis Score.
However, baseline high-sensitivity C-reactive protein levels, number of swollen joints, or years of symptom duration were not significantly different between the groups, although all were numerically higher in the secukinumab group. The proportion of patients with uveitis was higher in the TNFi group. About 70% of patients in both groups had discontinued their prior TNFi for inadequate response.
For the primary assessment of drug survival on the new therapy, the median time was 1.1 years in the secukinumab group and 2.0 years in the group switched to a new TNFi, without adjustment for baseline characteristics and disease severity. After risk adjustment, this difference was no statistically significant.
“There was an interaction with gender, indicating a significantly higher risk of discontinuing secukinumab than a new TNFi in men,” according to Dr. Ciurea. This was not seen in women.
Previous studies have shown the response rate to a second TNFi is typically lower than for an initial TNFi therapy. Previous studies have also shown that response to secukinumab is lower in patients with previous TNFi experience than in those who are naive to biologics, Dr. Ciurea said. This analysis suggests that the likelihood of sustained disease control is not greater in TNFi-experienced patients who start secukinumab relative to a different TNFi.
When asked if the data had been analyzed to compare response in patients exposed to only one prior TNFi, Dr. Ciurea replied that this could not be done because the sample size was too small.
Although Dr. Ciurea acknowledged the limitations of retrospective studies with risk adjustments, he concluded that there does not appear to be an advantage for initiating secukinumab over starting a different TNFi in axSpA patients who require a switch from their current TNFi,
Even though he said that this is the first study to address this question objectively, Dr. Ciurea said, “A sufficiently powered, prospective, head-to-head trial is needed.”
Dr. Ciurea reported multiple financial relationships with pharmaceutical companies but received no funding for this study.
SOURCE: Tellenbach C et al. Ann Rheum Dis. 2019;78(Suppl 2):197. Abstract OPO237, doi: 10.1136/annrheumdis-2019-eular.2427
MADRID – In axial spondyloarthritis patients who discontinue a tumor necrosis factor inhibitor (TNFi), there does not appear to be any advantage for using the anti–interleukin-17 biologic secukinumab over a different tumor necrosis factor inhibitor for next therapy, according to an analysis presented at the European Congress of Rheumatology.
“Switching to secukinumab [Cosentyx] might even be inferior in many patients,” according to Adrian Ciurea, MD, of the clinic for rheumatology at University Hospital Zürich.
This conclusion was reached in a retrospective analysis of axial spondyloarthritis (axSpA) patients enrolled in the Swiss Clinical Quality Management Cohort. Although Dr. Ciurea said that a prospective trial is needed to confirm the findings, this study was conducted because there have been, up until now, “no data to choose between options” to guide this choice.
In this study of 382 axSpA patients who were candidates for a new biologic after discontinuing a previous TNFi, 275 were started on a different TNFi and 107 were started on secukinumab. Although about 60% of patients in both groups were HLAB27-positive, there were many other characteristics, including those related to disease severity, that were different, Dr. Ciurea acknowledged.
Specifically, the proportion of patients starting secukinumab treated with two or more TNF inhibitors was greater than that of patients switching to another TNFi (77.6% vs. 37.8%; P less than .001). In addition, patients in the secukinumab group had a higher baseline disease activity, more enthesitis, and greater axial impairment.
These were reflected in higher average Bath Ankylosing Spondylitis Disease Activity Index scores (6.1 vs. 4.8; P less than .001) as well as other baseline clinical scoring methods, such as the Bath Ankylosing Spondylitis Functional Index and the Maastricht Ankylosing Spondylitis Enthesitis Score.
However, baseline high-sensitivity C-reactive protein levels, number of swollen joints, or years of symptom duration were not significantly different between the groups, although all were numerically higher in the secukinumab group. The proportion of patients with uveitis was higher in the TNFi group. About 70% of patients in both groups had discontinued their prior TNFi for inadequate response.
For the primary assessment of drug survival on the new therapy, the median time was 1.1 years in the secukinumab group and 2.0 years in the group switched to a new TNFi, without adjustment for baseline characteristics and disease severity. After risk adjustment, this difference was no statistically significant.
“There was an interaction with gender, indicating a significantly higher risk of discontinuing secukinumab than a new TNFi in men,” according to Dr. Ciurea. This was not seen in women.
Previous studies have shown the response rate to a second TNFi is typically lower than for an initial TNFi therapy. Previous studies have also shown that response to secukinumab is lower in patients with previous TNFi experience than in those who are naive to biologics, Dr. Ciurea said. This analysis suggests that the likelihood of sustained disease control is not greater in TNFi-experienced patients who start secukinumab relative to a different TNFi.
When asked if the data had been analyzed to compare response in patients exposed to only one prior TNFi, Dr. Ciurea replied that this could not be done because the sample size was too small.
Although Dr. Ciurea acknowledged the limitations of retrospective studies with risk adjustments, he concluded that there does not appear to be an advantage for initiating secukinumab over starting a different TNFi in axSpA patients who require a switch from their current TNFi,
Even though he said that this is the first study to address this question objectively, Dr. Ciurea said, “A sufficiently powered, prospective, head-to-head trial is needed.”
Dr. Ciurea reported multiple financial relationships with pharmaceutical companies but received no funding for this study.
SOURCE: Tellenbach C et al. Ann Rheum Dis. 2019;78(Suppl 2):197. Abstract OPO237, doi: 10.1136/annrheumdis-2019-eular.2427
REPORTING FROM EULAR 2019 CONGRESS
Mechanism does not matter for second-line biologic choice in JIA
MADRID – When biologic treatment is indicated after initial tumor necrosis factor (TNF) inhibitor therapy for juvenile idiopathic arthritis (JIA) has failed, the mechanism of action of the second biologic does not appear to matter, according to data presented at the European Congress of Rheumatology.
“There appears to be no difference in effectiveness outcomes or drug survival in patients starting a second TNF inhibitor versus an alternative class of biologic,” said Lianne Kearsley-Fleet, an epidemiologist at the Centre for Epidemiology Versus Arthritis at the University of Manchester (England).
Indeed, at 6 months, there were no significant differences among patients who had switched from a TNF inhibitor to another TNF inhibitor or to a biologic with an alternative mechanism of action in terms of:
- The change in Juvenile Arthritis Disease Activity Score (JADAS)-71 from baseline (mean score change, 7.3 with second TNF inhibitor vs. 8.5 with an alternative biologic class).
- The percentage of patients achieving an American College of Rheumatology Pediatric 90% response (22% vs. 15%).
- The proportion of patients achieving minimal disease activity (30% vs. 23%).
- The percentage reaching a minimal clinically important difference (MCID; 44% vs. 43%).
There was also no difference between switching to a TNF inhibitor or alternative biologic in terms of the duration of time patients remained treated with the second-line agent.
“After 1 year, 62% of patients remained on their biologic therapy, and when we looked at drug survival over the course of that year, there was no difference between the two cohorts,” Mrs. Kearsley-Fleet reported. There was no difference also in the reasons for stopping the second biologic.
“We now have a wide range of biologic therapies available; however, there is no evidence regarding which biologic should be prescribed [in JIA], and if patients switch, which order this should be,” Mrs. Kearsley-Fleet stated. Current NHS England guidelines recommend that most patients with JIA should start a TNF inhibitor (unless they are rheumatoid factor positive, in which case they should be treated with rituximab [Rituxan]), and if the first fails, to switch to a second TNF inhibitor rather than to change class. The evidence for this is limited, she noted, adding that adult guidelines for rheumatoid arthritis now recommended a change of class if not contraindicated.
Using data from two pediatric biologics registers – the British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study (BSPAR-ETN) and Biologics for Children with Rheumatic Diseases (BCRD) – Mrs. Kearsley-Fleet and her associates looked at data on 241 children and adolescents with polyarticular JIA (or oligoarticular-extended JIA) starting a second biologic. The aim was to compare the effectiveness of starting a second TNF inhibitor versus switching to an alternative class of agent, such as a B-cell depleting agent such as rituximab, in routine clinical practice.
A majority (n = 188; 78%) of patients had etanercept (Enbrel) as their starting TNF inhibitor and those switching to a second TNF inhibitor (n = 196) were most likely to be given adalimumab (Humira; 58%). Patients starting a biologic with another mode of action (n = 45) were most likely to be given the interleukin-6 inhibitor tocilizumab (73%), followed by rituximab in 13%, and abatacept (Orencia) in 11%. The main reasons for switching to another biologic – TNF inhibitor or otherwise – were ineffectiveness (60% with a second TNF inhibitor vs. 62% with another biologic drug class) or adverse events or intolerance (19% vs. 13%, respectively).
The strength of these data are that they come from a very large cohort of children and adolescents starting biologics for JIA, with systematic follow-up and robust statistical methods, Mrs. Kearsley-Fleet said. However, she noted that JIA was rare and that only one-fifth of patients would start a biologic, and just 30% of those patients would then switch to a second biologic.
“We don’t see any reason that the guidelines should be changed,” Mrs. Kearsley-Fleet observed. “However, repeat analysis with a larger sample size is required to reinforce whether there is any advantage of switching or not.”
Versus Arthritis (formerly Arthritis Research UK) and The British Society for Rheumatology provided funding support. Mrs. Kearsley-Fleet had no financial conflicts of interest to disclose.
SOURCE: Kearsley-Fleet L et al. Ann Rheum Dis, Jun 2019;8(Suppl 2):74-5. Abstract OP0016. doi: 10.1136/annrheumdis-2019-eular.415.
MADRID – When biologic treatment is indicated after initial tumor necrosis factor (TNF) inhibitor therapy for juvenile idiopathic arthritis (JIA) has failed, the mechanism of action of the second biologic does not appear to matter, according to data presented at the European Congress of Rheumatology.
“There appears to be no difference in effectiveness outcomes or drug survival in patients starting a second TNF inhibitor versus an alternative class of biologic,” said Lianne Kearsley-Fleet, an epidemiologist at the Centre for Epidemiology Versus Arthritis at the University of Manchester (England).
Indeed, at 6 months, there were no significant differences among patients who had switched from a TNF inhibitor to another TNF inhibitor or to a biologic with an alternative mechanism of action in terms of:
- The change in Juvenile Arthritis Disease Activity Score (JADAS)-71 from baseline (mean score change, 7.3 with second TNF inhibitor vs. 8.5 with an alternative biologic class).
- The percentage of patients achieving an American College of Rheumatology Pediatric 90% response (22% vs. 15%).
- The proportion of patients achieving minimal disease activity (30% vs. 23%).
- The percentage reaching a minimal clinically important difference (MCID; 44% vs. 43%).
There was also no difference between switching to a TNF inhibitor or alternative biologic in terms of the duration of time patients remained treated with the second-line agent.
“After 1 year, 62% of patients remained on their biologic therapy, and when we looked at drug survival over the course of that year, there was no difference between the two cohorts,” Mrs. Kearsley-Fleet reported. There was no difference also in the reasons for stopping the second biologic.
“We now have a wide range of biologic therapies available; however, there is no evidence regarding which biologic should be prescribed [in JIA], and if patients switch, which order this should be,” Mrs. Kearsley-Fleet stated. Current NHS England guidelines recommend that most patients with JIA should start a TNF inhibitor (unless they are rheumatoid factor positive, in which case they should be treated with rituximab [Rituxan]), and if the first fails, to switch to a second TNF inhibitor rather than to change class. The evidence for this is limited, she noted, adding that adult guidelines for rheumatoid arthritis now recommended a change of class if not contraindicated.
Using data from two pediatric biologics registers – the British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study (BSPAR-ETN) and Biologics for Children with Rheumatic Diseases (BCRD) – Mrs. Kearsley-Fleet and her associates looked at data on 241 children and adolescents with polyarticular JIA (or oligoarticular-extended JIA) starting a second biologic. The aim was to compare the effectiveness of starting a second TNF inhibitor versus switching to an alternative class of agent, such as a B-cell depleting agent such as rituximab, in routine clinical practice.
A majority (n = 188; 78%) of patients had etanercept (Enbrel) as their starting TNF inhibitor and those switching to a second TNF inhibitor (n = 196) were most likely to be given adalimumab (Humira; 58%). Patients starting a biologic with another mode of action (n = 45) were most likely to be given the interleukin-6 inhibitor tocilizumab (73%), followed by rituximab in 13%, and abatacept (Orencia) in 11%. The main reasons for switching to another biologic – TNF inhibitor or otherwise – were ineffectiveness (60% with a second TNF inhibitor vs. 62% with another biologic drug class) or adverse events or intolerance (19% vs. 13%, respectively).
The strength of these data are that they come from a very large cohort of children and adolescents starting biologics for JIA, with systematic follow-up and robust statistical methods, Mrs. Kearsley-Fleet said. However, she noted that JIA was rare and that only one-fifth of patients would start a biologic, and just 30% of those patients would then switch to a second biologic.
“We don’t see any reason that the guidelines should be changed,” Mrs. Kearsley-Fleet observed. “However, repeat analysis with a larger sample size is required to reinforce whether there is any advantage of switching or not.”
Versus Arthritis (formerly Arthritis Research UK) and The British Society for Rheumatology provided funding support. Mrs. Kearsley-Fleet had no financial conflicts of interest to disclose.
SOURCE: Kearsley-Fleet L et al. Ann Rheum Dis, Jun 2019;8(Suppl 2):74-5. Abstract OP0016. doi: 10.1136/annrheumdis-2019-eular.415.
MADRID – When biologic treatment is indicated after initial tumor necrosis factor (TNF) inhibitor therapy for juvenile idiopathic arthritis (JIA) has failed, the mechanism of action of the second biologic does not appear to matter, according to data presented at the European Congress of Rheumatology.
“There appears to be no difference in effectiveness outcomes or drug survival in patients starting a second TNF inhibitor versus an alternative class of biologic,” said Lianne Kearsley-Fleet, an epidemiologist at the Centre for Epidemiology Versus Arthritis at the University of Manchester (England).
Indeed, at 6 months, there were no significant differences among patients who had switched from a TNF inhibitor to another TNF inhibitor or to a biologic with an alternative mechanism of action in terms of:
- The change in Juvenile Arthritis Disease Activity Score (JADAS)-71 from baseline (mean score change, 7.3 with second TNF inhibitor vs. 8.5 with an alternative biologic class).
- The percentage of patients achieving an American College of Rheumatology Pediatric 90% response (22% vs. 15%).
- The proportion of patients achieving minimal disease activity (30% vs. 23%).
- The percentage reaching a minimal clinically important difference (MCID; 44% vs. 43%).
There was also no difference between switching to a TNF inhibitor or alternative biologic in terms of the duration of time patients remained treated with the second-line agent.
“After 1 year, 62% of patients remained on their biologic therapy, and when we looked at drug survival over the course of that year, there was no difference between the two cohorts,” Mrs. Kearsley-Fleet reported. There was no difference also in the reasons for stopping the second biologic.
“We now have a wide range of biologic therapies available; however, there is no evidence regarding which biologic should be prescribed [in JIA], and if patients switch, which order this should be,” Mrs. Kearsley-Fleet stated. Current NHS England guidelines recommend that most patients with JIA should start a TNF inhibitor (unless they are rheumatoid factor positive, in which case they should be treated with rituximab [Rituxan]), and if the first fails, to switch to a second TNF inhibitor rather than to change class. The evidence for this is limited, she noted, adding that adult guidelines for rheumatoid arthritis now recommended a change of class if not contraindicated.
Using data from two pediatric biologics registers – the British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study (BSPAR-ETN) and Biologics for Children with Rheumatic Diseases (BCRD) – Mrs. Kearsley-Fleet and her associates looked at data on 241 children and adolescents with polyarticular JIA (or oligoarticular-extended JIA) starting a second biologic. The aim was to compare the effectiveness of starting a second TNF inhibitor versus switching to an alternative class of agent, such as a B-cell depleting agent such as rituximab, in routine clinical practice.
A majority (n = 188; 78%) of patients had etanercept (Enbrel) as their starting TNF inhibitor and those switching to a second TNF inhibitor (n = 196) were most likely to be given adalimumab (Humira; 58%). Patients starting a biologic with another mode of action (n = 45) were most likely to be given the interleukin-6 inhibitor tocilizumab (73%), followed by rituximab in 13%, and abatacept (Orencia) in 11%. The main reasons for switching to another biologic – TNF inhibitor or otherwise – were ineffectiveness (60% with a second TNF inhibitor vs. 62% with another biologic drug class) or adverse events or intolerance (19% vs. 13%, respectively).
The strength of these data are that they come from a very large cohort of children and adolescents starting biologics for JIA, with systematic follow-up and robust statistical methods, Mrs. Kearsley-Fleet said. However, she noted that JIA was rare and that only one-fifth of patients would start a biologic, and just 30% of those patients would then switch to a second biologic.
“We don’t see any reason that the guidelines should be changed,” Mrs. Kearsley-Fleet observed. “However, repeat analysis with a larger sample size is required to reinforce whether there is any advantage of switching or not.”
Versus Arthritis (formerly Arthritis Research UK) and The British Society for Rheumatology provided funding support. Mrs. Kearsley-Fleet had no financial conflicts of interest to disclose.
SOURCE: Kearsley-Fleet L et al. Ann Rheum Dis, Jun 2019;8(Suppl 2):74-5. Abstract OP0016. doi: 10.1136/annrheumdis-2019-eular.415.
REPORTING FROM EULAR 2019 Congress
Flurry of new anti–IL-17 monoclonal antibodies show efficacy in axSpA
MADRID – Trial results presented at the European Congress of Rheumatology for three anti–interleukin-17 receptor monoclonal antibodies under investigation for the treatment of axial spondyloarthritis (axSpA), including one for ankylosing spondylitis (AS), appear to support further clinical development and regulatory review to potentially join secukinumab (Cosentyx) and ixekizumab (Taltz) as the only IL-17 inhibitors to be licensed for rheumatic diseases.
Both netakimab and brodalumab (Siliq) achieved positive results in separate phase 3 trials for the treatment of axSpA, while new data from a phase 2b trial of bimekizumab was associated with improvement in the quality of life of patients with AS. Brodalumab is already approved by the Food and Drug Administration for treating moderate to severe plaque psoriasis.
Netakimab
The multinational, double-blind, phase 3 trial with netakimab, called the ASTERA trial, randomized 228 patients with radiographic axSpA to either 120 mg of the experimental agent or placebo, each administered subcutaneously in weekly doses in the first 2 weeks and then every other week thereafter. The primary endpoint was a 40% improvement in Assessment of SpondyloArthritis International Society response criteria (ASAS40) at week 16.
A larger proportion of patients in the netakimab arm met the primary endpoint, compared with those in the placebo arm (40.4% vs. 2.63%, respectively; P less than .0001), reported Inna Gaydukova, MD, of Mechnikov North-Western State Medical University, St. Petersburg, Russia.
“Most of the secondary efficacy endpoints also showed a significant advantage for netakimab relative to placebo by week 4, and these advantages remained significant for the remainder of the study,” she said.
The one serious adverse event in the study occurred in the placebo arm. Although mild to moderate anemia and neutropenia were associated with treatment, the drug was well tolerated overall.
“We did observe a significant reduction in inflammatory activity in the spine with MRI at week 16,” Dr. Gaydukova added. Functional improvements in the experimental arm relative to the placebo arm were also observed, although Dr. Gaydukova acknowledged that longer trials are needed to show that these benefits are durable.
Brodalumab
The results of a multinational, double-blind, phase 3 trial with brodalumab proved similar to those with netakimab. Conducted in Taiwan, Japan, and South Korea, the trial randomized 159 patients to 210 mg of brodalumab or placebo administered subcutaneously. The therapies were administered on the same schedule as in the netakimab trial. The primary outcome was also the same.
At week 16, 43.8% of those on the experimental agent versus 24.1% of those randomized to placebo achieved ASAS40 (P = .018). As in the netakimab study, greater activity with brodalumab than placebo was also seen on several secondary outcomes, such as ASAS20 (67.5% vs. 41.8%).
“In a subgroup analysis, there was an advantage for brodalumab over placebo whether or not patients had prior experience with a TNF [tumor necrosis factor] inhibitor, regardless of baseline hs-CRP [high sensitivity C-reactive protein] level and independent of HLA type,” reported James Cheng-Chung Wei, MD, of Chung Shan Medical University Hospital, Taichung, Taiwan.
There were no significant differences in the types or rates of adverse events, including serious adverse events, in patients assigned to brodalumab relative to placebo. Suicide ideation, which has been associated with some biologics targeting other immunologic mediators, was evaluated but not seen.
“We think brodalumab has the potential to be a new therapeutic option in axSpA,” said Dr. Wei, who reported that studies in AS are also planned.
Bimekizumab
Additional 12-week outcome data from the multinational, double-blind, phase 2b BE AGILE trial of bimekizumab in patients with active AS were presented by Désirée van der Heijde, MD, PhD, of Leiden (the Netherlands) University Medical Center.
Unlike secukinumab and most of the other anti–IL-17 receptor monoclonal antibodies in development, bimekizumab inhibits IL-17F in addition to IL-17A, according to Dr. van der Heijde. She cited experimental evidence suggesting that inhibition of both forms of IL-17 results in greater anti-inflammatory response.
In the initial and previously reported data from this dose-ranging study of 303 AS patients, all four doses of bimekizumab (16 mg, 64 mg, 160 mg, or 320 mg) were superior to placebo for the primary endpoint of ASAS40. However, greater relative benefit was observed for the three highest doses.
In the new analysis, symptoms were evaluated with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). At 12 weeks, 47.5% of patients on the highest dose of bimekizumab versus only 11.9% of patients randomized to placebo achieved a 50% or greater level of improvement on the BASDAI, called BASDAI 50 (P less than .001).
The greater clinical activity of bimekizumab relative to placebo translated into improvement from baseline in Ankylosing Spondylitis Quality of Life scores. Greater reductions in Ankylosing Spondylitis Quality of Life scores relative to placebo, signaling an improved quality of life, were achieved with all doses, but they reached 4.6 points for the highest dose versus only 1.3 for placebo.
When evaluated with Patient Global Assessment of Disease Activity, another tool that reflects perception of disease burden, the score reduction was 3.3 points for the highest dose versus 1.0 points for placebo. Dr. van der Heijde characterized the reductions at the highest doses versus placebo as “significant” although she did not provide P values.
Like the data presented on the other newer anti–IL-17 therapies, bimekizumab was well tolerated with relatively low rates of adverse events, most of which were mild to moderate in severity, according to Dr. van der Heijde.
“The data from the BE AGILE trial supports phase 3 development in AS,” Dr. van der Heijde said. She noted that trials are also being planned in axSpA.
All three presenting authors reported multiple financial relationships with pharmaceutical companies, including, in each case, the pharmaceutical company that sponsored the trial they presented.
SOURCES: Gaydukova I et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):193-4, Abstract OP0232. doi: 10.1136/annrheumdis-2019-eular.6633; Wei JC et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):195, Abstract OP0234. doi: 10.1136/annrheumdis-2019-eular.6888; van der Heijde D et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):193, Abstract OP0231. doi: 10.1136/annrheumdis-2019-eular.6607.
MADRID – Trial results presented at the European Congress of Rheumatology for three anti–interleukin-17 receptor monoclonal antibodies under investigation for the treatment of axial spondyloarthritis (axSpA), including one for ankylosing spondylitis (AS), appear to support further clinical development and regulatory review to potentially join secukinumab (Cosentyx) and ixekizumab (Taltz) as the only IL-17 inhibitors to be licensed for rheumatic diseases.
Both netakimab and brodalumab (Siliq) achieved positive results in separate phase 3 trials for the treatment of axSpA, while new data from a phase 2b trial of bimekizumab was associated with improvement in the quality of life of patients with AS. Brodalumab is already approved by the Food and Drug Administration for treating moderate to severe plaque psoriasis.
Netakimab
The multinational, double-blind, phase 3 trial with netakimab, called the ASTERA trial, randomized 228 patients with radiographic axSpA to either 120 mg of the experimental agent or placebo, each administered subcutaneously in weekly doses in the first 2 weeks and then every other week thereafter. The primary endpoint was a 40% improvement in Assessment of SpondyloArthritis International Society response criteria (ASAS40) at week 16.
A larger proportion of patients in the netakimab arm met the primary endpoint, compared with those in the placebo arm (40.4% vs. 2.63%, respectively; P less than .0001), reported Inna Gaydukova, MD, of Mechnikov North-Western State Medical University, St. Petersburg, Russia.
“Most of the secondary efficacy endpoints also showed a significant advantage for netakimab relative to placebo by week 4, and these advantages remained significant for the remainder of the study,” she said.
The one serious adverse event in the study occurred in the placebo arm. Although mild to moderate anemia and neutropenia were associated with treatment, the drug was well tolerated overall.
“We did observe a significant reduction in inflammatory activity in the spine with MRI at week 16,” Dr. Gaydukova added. Functional improvements in the experimental arm relative to the placebo arm were also observed, although Dr. Gaydukova acknowledged that longer trials are needed to show that these benefits are durable.
Brodalumab
The results of a multinational, double-blind, phase 3 trial with brodalumab proved similar to those with netakimab. Conducted in Taiwan, Japan, and South Korea, the trial randomized 159 patients to 210 mg of brodalumab or placebo administered subcutaneously. The therapies were administered on the same schedule as in the netakimab trial. The primary outcome was also the same.
At week 16, 43.8% of those on the experimental agent versus 24.1% of those randomized to placebo achieved ASAS40 (P = .018). As in the netakimab study, greater activity with brodalumab than placebo was also seen on several secondary outcomes, such as ASAS20 (67.5% vs. 41.8%).
“In a subgroup analysis, there was an advantage for brodalumab over placebo whether or not patients had prior experience with a TNF [tumor necrosis factor] inhibitor, regardless of baseline hs-CRP [high sensitivity C-reactive protein] level and independent of HLA type,” reported James Cheng-Chung Wei, MD, of Chung Shan Medical University Hospital, Taichung, Taiwan.
There were no significant differences in the types or rates of adverse events, including serious adverse events, in patients assigned to brodalumab relative to placebo. Suicide ideation, which has been associated with some biologics targeting other immunologic mediators, was evaluated but not seen.
“We think brodalumab has the potential to be a new therapeutic option in axSpA,” said Dr. Wei, who reported that studies in AS are also planned.
Bimekizumab
Additional 12-week outcome data from the multinational, double-blind, phase 2b BE AGILE trial of bimekizumab in patients with active AS were presented by Désirée van der Heijde, MD, PhD, of Leiden (the Netherlands) University Medical Center.
Unlike secukinumab and most of the other anti–IL-17 receptor monoclonal antibodies in development, bimekizumab inhibits IL-17F in addition to IL-17A, according to Dr. van der Heijde. She cited experimental evidence suggesting that inhibition of both forms of IL-17 results in greater anti-inflammatory response.
In the initial and previously reported data from this dose-ranging study of 303 AS patients, all four doses of bimekizumab (16 mg, 64 mg, 160 mg, or 320 mg) were superior to placebo for the primary endpoint of ASAS40. However, greater relative benefit was observed for the three highest doses.
In the new analysis, symptoms were evaluated with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). At 12 weeks, 47.5% of patients on the highest dose of bimekizumab versus only 11.9% of patients randomized to placebo achieved a 50% or greater level of improvement on the BASDAI, called BASDAI 50 (P less than .001).
The greater clinical activity of bimekizumab relative to placebo translated into improvement from baseline in Ankylosing Spondylitis Quality of Life scores. Greater reductions in Ankylosing Spondylitis Quality of Life scores relative to placebo, signaling an improved quality of life, were achieved with all doses, but they reached 4.6 points for the highest dose versus only 1.3 for placebo.
When evaluated with Patient Global Assessment of Disease Activity, another tool that reflects perception of disease burden, the score reduction was 3.3 points for the highest dose versus 1.0 points for placebo. Dr. van der Heijde characterized the reductions at the highest doses versus placebo as “significant” although she did not provide P values.
Like the data presented on the other newer anti–IL-17 therapies, bimekizumab was well tolerated with relatively low rates of adverse events, most of which were mild to moderate in severity, according to Dr. van der Heijde.
“The data from the BE AGILE trial supports phase 3 development in AS,” Dr. van der Heijde said. She noted that trials are also being planned in axSpA.
All three presenting authors reported multiple financial relationships with pharmaceutical companies, including, in each case, the pharmaceutical company that sponsored the trial they presented.
SOURCES: Gaydukova I et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):193-4, Abstract OP0232. doi: 10.1136/annrheumdis-2019-eular.6633; Wei JC et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):195, Abstract OP0234. doi: 10.1136/annrheumdis-2019-eular.6888; van der Heijde D et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):193, Abstract OP0231. doi: 10.1136/annrheumdis-2019-eular.6607.
MADRID – Trial results presented at the European Congress of Rheumatology for three anti–interleukin-17 receptor monoclonal antibodies under investigation for the treatment of axial spondyloarthritis (axSpA), including one for ankylosing spondylitis (AS), appear to support further clinical development and regulatory review to potentially join secukinumab (Cosentyx) and ixekizumab (Taltz) as the only IL-17 inhibitors to be licensed for rheumatic diseases.
Both netakimab and brodalumab (Siliq) achieved positive results in separate phase 3 trials for the treatment of axSpA, while new data from a phase 2b trial of bimekizumab was associated with improvement in the quality of life of patients with AS. Brodalumab is already approved by the Food and Drug Administration for treating moderate to severe plaque psoriasis.
Netakimab
The multinational, double-blind, phase 3 trial with netakimab, called the ASTERA trial, randomized 228 patients with radiographic axSpA to either 120 mg of the experimental agent or placebo, each administered subcutaneously in weekly doses in the first 2 weeks and then every other week thereafter. The primary endpoint was a 40% improvement in Assessment of SpondyloArthritis International Society response criteria (ASAS40) at week 16.
A larger proportion of patients in the netakimab arm met the primary endpoint, compared with those in the placebo arm (40.4% vs. 2.63%, respectively; P less than .0001), reported Inna Gaydukova, MD, of Mechnikov North-Western State Medical University, St. Petersburg, Russia.
“Most of the secondary efficacy endpoints also showed a significant advantage for netakimab relative to placebo by week 4, and these advantages remained significant for the remainder of the study,” she said.
The one serious adverse event in the study occurred in the placebo arm. Although mild to moderate anemia and neutropenia were associated with treatment, the drug was well tolerated overall.
“We did observe a significant reduction in inflammatory activity in the spine with MRI at week 16,” Dr. Gaydukova added. Functional improvements in the experimental arm relative to the placebo arm were also observed, although Dr. Gaydukova acknowledged that longer trials are needed to show that these benefits are durable.
Brodalumab
The results of a multinational, double-blind, phase 3 trial with brodalumab proved similar to those with netakimab. Conducted in Taiwan, Japan, and South Korea, the trial randomized 159 patients to 210 mg of brodalumab or placebo administered subcutaneously. The therapies were administered on the same schedule as in the netakimab trial. The primary outcome was also the same.
At week 16, 43.8% of those on the experimental agent versus 24.1% of those randomized to placebo achieved ASAS40 (P = .018). As in the netakimab study, greater activity with brodalumab than placebo was also seen on several secondary outcomes, such as ASAS20 (67.5% vs. 41.8%).
“In a subgroup analysis, there was an advantage for brodalumab over placebo whether or not patients had prior experience with a TNF [tumor necrosis factor] inhibitor, regardless of baseline hs-CRP [high sensitivity C-reactive protein] level and independent of HLA type,” reported James Cheng-Chung Wei, MD, of Chung Shan Medical University Hospital, Taichung, Taiwan.
There were no significant differences in the types or rates of adverse events, including serious adverse events, in patients assigned to brodalumab relative to placebo. Suicide ideation, which has been associated with some biologics targeting other immunologic mediators, was evaluated but not seen.
“We think brodalumab has the potential to be a new therapeutic option in axSpA,” said Dr. Wei, who reported that studies in AS are also planned.
Bimekizumab
Additional 12-week outcome data from the multinational, double-blind, phase 2b BE AGILE trial of bimekizumab in patients with active AS were presented by Désirée van der Heijde, MD, PhD, of Leiden (the Netherlands) University Medical Center.
Unlike secukinumab and most of the other anti–IL-17 receptor monoclonal antibodies in development, bimekizumab inhibits IL-17F in addition to IL-17A, according to Dr. van der Heijde. She cited experimental evidence suggesting that inhibition of both forms of IL-17 results in greater anti-inflammatory response.
In the initial and previously reported data from this dose-ranging study of 303 AS patients, all four doses of bimekizumab (16 mg, 64 mg, 160 mg, or 320 mg) were superior to placebo for the primary endpoint of ASAS40. However, greater relative benefit was observed for the three highest doses.
In the new analysis, symptoms were evaluated with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). At 12 weeks, 47.5% of patients on the highest dose of bimekizumab versus only 11.9% of patients randomized to placebo achieved a 50% or greater level of improvement on the BASDAI, called BASDAI 50 (P less than .001).
The greater clinical activity of bimekizumab relative to placebo translated into improvement from baseline in Ankylosing Spondylitis Quality of Life scores. Greater reductions in Ankylosing Spondylitis Quality of Life scores relative to placebo, signaling an improved quality of life, were achieved with all doses, but they reached 4.6 points for the highest dose versus only 1.3 for placebo.
When evaluated with Patient Global Assessment of Disease Activity, another tool that reflects perception of disease burden, the score reduction was 3.3 points for the highest dose versus 1.0 points for placebo. Dr. van der Heijde characterized the reductions at the highest doses versus placebo as “significant” although she did not provide P values.
Like the data presented on the other newer anti–IL-17 therapies, bimekizumab was well tolerated with relatively low rates of adverse events, most of which were mild to moderate in severity, according to Dr. van der Heijde.
“The data from the BE AGILE trial supports phase 3 development in AS,” Dr. van der Heijde said. She noted that trials are also being planned in axSpA.
All three presenting authors reported multiple financial relationships with pharmaceutical companies, including, in each case, the pharmaceutical company that sponsored the trial they presented.
SOURCES: Gaydukova I et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):193-4, Abstract OP0232. doi: 10.1136/annrheumdis-2019-eular.6633; Wei JC et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):195, Abstract OP0234. doi: 10.1136/annrheumdis-2019-eular.6888; van der Heijde D et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):193, Abstract OP0231. doi: 10.1136/annrheumdis-2019-eular.6607.
REPORTING FROM EULAR 2019 CONGRESS
Secukinumab reduced joint pain of psoriatic arthritis in early data from phase 3b trial
MADRID – Secukinumab was superior to placebo for the primary endpoint of 20% improvement in Assessment of SpondyloArthritis international Society criteria (ASAS20), based on the initial 12-week data from the ongoing phase 3b MAXIMISE trial, the first randomized, controlled trial to evaluate a biologic therapy for the treatment of the axial manifestations of psoriatic arthritis (PsA).
“There was rapid and significant clinical improvement as measured with ASAS20 with both of the study doses of secukinumab,” an anti–interleukin-17 monoclonal antibody, reported Xenofon Baraliakos, MD, of Rheumazentrum Ruhrgebliet, Ruhr-University Bochum in Herne, Germany.
At the European Congress of Rheumatology, Dr. Baraliakos said that the 1-year data will be complete before the end of 2019.
In this primary analysis, 498 patients with established PsA were randomized to 150 mg secukinumab, 300 mg secukinumab, or placebo. For enrollment, all patients were required to have substantial axial pain and a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score greater than 4 despite treatment with at least two NSAIDs.
For the first 4 weeks of the trial, patients received their assigned therapies weekly by subcutaneous administration. Treatment thereafter was every 4 weeks.
Almost all patients had active psoriasis and axial symptoms of at least several years duration. The median patient age was 46 years. Approximately one-third were HLA B27 positive.
At baseline, the median back pain score on a visual analog scale of 100 was 73, and the median BASDAI score was greater than 7.0. More than 90% of patients reported back pain worsening with rest.
The proportion of patients achieving ASAS20 at 12 weeks was 63.1% in the group assigned to 300 mg secukinumab, 66.3% in those assigned 150 mg, and 31.1% for those assigned placebo (P less than .0001 for either active therapy versus placebo).
Analyses conducted with multiple imputations and comparing those who were and were not taking methotrexate produced almost the same relative advantage for secukinumab. ASAS20 responses in patients using concomitant methotrexate were 65.1% with 300 mg secukinumab, 67.3% with 150 mg secukinumab, and 33.9% with placebo. Corresponding values in the no-methotrexate group were 60.5%, 64.4%, and 27.1%, respectively.
“There was a good response from either dose of secukinumab no matter what analysis was employed,” reported Dr. Baraliakos, citing an odds ratio of 3.81 for reaching the primary endpoint with secukinumab versus placebo. There were no significant differences in efficacy between the doses of secukinumab.
There was “not much to say about safety,” according to Dr. Baraliakos, as no significant differences in any adverse events were observed between study arms. However, he did caution that longer-term exposure is needed for a more complete analysis of tolerability and safety.
Most patients with PsA are thought to eventually develop axial involvement, which has a major adverse affect on quality of life, according to Dr. Baraliakos. He considers this primary 12-week analysis encouraging, but said the 1-year data will provide more information about whether this therapy should be considered routinely in PsA patients with persistent axial symptoms.
Axial imaging was conducted at study entry even though it was not a criterion for enrollment. Dr. Baraliakos reported that the impact of secukinumab on objective imaging measures of disease activity, if any, is forthcoming.
Imaging data might be needed to establish benefit objectively, judging from a criticism of the study design that arose during discussion after the data were presented. Specifically, it was pointed out that improvement in ASAS20 and BASDAI could occur as a result of improvement in peripheral symptoms, such as enthesitis. The lack of axial-specific outcomes was called a potential weakness of this study.
Dr. Baraliakos countered that BASDAI evaluations did include axial-specific questions, but also confirmed that spine-specific outcomes are included among outcomes to be presented with longer-term analyses.
“These data will come,” said Dr. Baraliakos, referring to imaging as well as other outcomes that will provide more information on the impact of secukinumab in treating the axial involvement of PsA.
Dr. Baraliakos reported multiple financial relationships with pharmaceutical companies, including Novartis, which sponsored this trial.
SOURCE: Ann Rheum Dis. Jun 2019;78(Suppl2):195-6. Abstract OPO235. doi: 10.1136/annrheumdis-2019-eular.2932.
MADRID – Secukinumab was superior to placebo for the primary endpoint of 20% improvement in Assessment of SpondyloArthritis international Society criteria (ASAS20), based on the initial 12-week data from the ongoing phase 3b MAXIMISE trial, the first randomized, controlled trial to evaluate a biologic therapy for the treatment of the axial manifestations of psoriatic arthritis (PsA).
“There was rapid and significant clinical improvement as measured with ASAS20 with both of the study doses of secukinumab,” an anti–interleukin-17 monoclonal antibody, reported Xenofon Baraliakos, MD, of Rheumazentrum Ruhrgebliet, Ruhr-University Bochum in Herne, Germany.
At the European Congress of Rheumatology, Dr. Baraliakos said that the 1-year data will be complete before the end of 2019.
In this primary analysis, 498 patients with established PsA were randomized to 150 mg secukinumab, 300 mg secukinumab, or placebo. For enrollment, all patients were required to have substantial axial pain and a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score greater than 4 despite treatment with at least two NSAIDs.
For the first 4 weeks of the trial, patients received their assigned therapies weekly by subcutaneous administration. Treatment thereafter was every 4 weeks.
Almost all patients had active psoriasis and axial symptoms of at least several years duration. The median patient age was 46 years. Approximately one-third were HLA B27 positive.
At baseline, the median back pain score on a visual analog scale of 100 was 73, and the median BASDAI score was greater than 7.0. More than 90% of patients reported back pain worsening with rest.
The proportion of patients achieving ASAS20 at 12 weeks was 63.1% in the group assigned to 300 mg secukinumab, 66.3% in those assigned 150 mg, and 31.1% for those assigned placebo (P less than .0001 for either active therapy versus placebo).
Analyses conducted with multiple imputations and comparing those who were and were not taking methotrexate produced almost the same relative advantage for secukinumab. ASAS20 responses in patients using concomitant methotrexate were 65.1% with 300 mg secukinumab, 67.3% with 150 mg secukinumab, and 33.9% with placebo. Corresponding values in the no-methotrexate group were 60.5%, 64.4%, and 27.1%, respectively.
“There was a good response from either dose of secukinumab no matter what analysis was employed,” reported Dr. Baraliakos, citing an odds ratio of 3.81 for reaching the primary endpoint with secukinumab versus placebo. There were no significant differences in efficacy between the doses of secukinumab.
There was “not much to say about safety,” according to Dr. Baraliakos, as no significant differences in any adverse events were observed between study arms. However, he did caution that longer-term exposure is needed for a more complete analysis of tolerability and safety.
Most patients with PsA are thought to eventually develop axial involvement, which has a major adverse affect on quality of life, according to Dr. Baraliakos. He considers this primary 12-week analysis encouraging, but said the 1-year data will provide more information about whether this therapy should be considered routinely in PsA patients with persistent axial symptoms.
Axial imaging was conducted at study entry even though it was not a criterion for enrollment. Dr. Baraliakos reported that the impact of secukinumab on objective imaging measures of disease activity, if any, is forthcoming.
Imaging data might be needed to establish benefit objectively, judging from a criticism of the study design that arose during discussion after the data were presented. Specifically, it was pointed out that improvement in ASAS20 and BASDAI could occur as a result of improvement in peripheral symptoms, such as enthesitis. The lack of axial-specific outcomes was called a potential weakness of this study.
Dr. Baraliakos countered that BASDAI evaluations did include axial-specific questions, but also confirmed that spine-specific outcomes are included among outcomes to be presented with longer-term analyses.
“These data will come,” said Dr. Baraliakos, referring to imaging as well as other outcomes that will provide more information on the impact of secukinumab in treating the axial involvement of PsA.
Dr. Baraliakos reported multiple financial relationships with pharmaceutical companies, including Novartis, which sponsored this trial.
SOURCE: Ann Rheum Dis. Jun 2019;78(Suppl2):195-6. Abstract OPO235. doi: 10.1136/annrheumdis-2019-eular.2932.
MADRID – Secukinumab was superior to placebo for the primary endpoint of 20% improvement in Assessment of SpondyloArthritis international Society criteria (ASAS20), based on the initial 12-week data from the ongoing phase 3b MAXIMISE trial, the first randomized, controlled trial to evaluate a biologic therapy for the treatment of the axial manifestations of psoriatic arthritis (PsA).
“There was rapid and significant clinical improvement as measured with ASAS20 with both of the study doses of secukinumab,” an anti–interleukin-17 monoclonal antibody, reported Xenofon Baraliakos, MD, of Rheumazentrum Ruhrgebliet, Ruhr-University Bochum in Herne, Germany.
At the European Congress of Rheumatology, Dr. Baraliakos said that the 1-year data will be complete before the end of 2019.
In this primary analysis, 498 patients with established PsA were randomized to 150 mg secukinumab, 300 mg secukinumab, or placebo. For enrollment, all patients were required to have substantial axial pain and a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score greater than 4 despite treatment with at least two NSAIDs.
For the first 4 weeks of the trial, patients received their assigned therapies weekly by subcutaneous administration. Treatment thereafter was every 4 weeks.
Almost all patients had active psoriasis and axial symptoms of at least several years duration. The median patient age was 46 years. Approximately one-third were HLA B27 positive.
At baseline, the median back pain score on a visual analog scale of 100 was 73, and the median BASDAI score was greater than 7.0. More than 90% of patients reported back pain worsening with rest.
The proportion of patients achieving ASAS20 at 12 weeks was 63.1% in the group assigned to 300 mg secukinumab, 66.3% in those assigned 150 mg, and 31.1% for those assigned placebo (P less than .0001 for either active therapy versus placebo).
Analyses conducted with multiple imputations and comparing those who were and were not taking methotrexate produced almost the same relative advantage for secukinumab. ASAS20 responses in patients using concomitant methotrexate were 65.1% with 300 mg secukinumab, 67.3% with 150 mg secukinumab, and 33.9% with placebo. Corresponding values in the no-methotrexate group were 60.5%, 64.4%, and 27.1%, respectively.
“There was a good response from either dose of secukinumab no matter what analysis was employed,” reported Dr. Baraliakos, citing an odds ratio of 3.81 for reaching the primary endpoint with secukinumab versus placebo. There were no significant differences in efficacy between the doses of secukinumab.
There was “not much to say about safety,” according to Dr. Baraliakos, as no significant differences in any adverse events were observed between study arms. However, he did caution that longer-term exposure is needed for a more complete analysis of tolerability and safety.
Most patients with PsA are thought to eventually develop axial involvement, which has a major adverse affect on quality of life, according to Dr. Baraliakos. He considers this primary 12-week analysis encouraging, but said the 1-year data will provide more information about whether this therapy should be considered routinely in PsA patients with persistent axial symptoms.
Axial imaging was conducted at study entry even though it was not a criterion for enrollment. Dr. Baraliakos reported that the impact of secukinumab on objective imaging measures of disease activity, if any, is forthcoming.
Imaging data might be needed to establish benefit objectively, judging from a criticism of the study design that arose during discussion after the data were presented. Specifically, it was pointed out that improvement in ASAS20 and BASDAI could occur as a result of improvement in peripheral symptoms, such as enthesitis. The lack of axial-specific outcomes was called a potential weakness of this study.
Dr. Baraliakos countered that BASDAI evaluations did include axial-specific questions, but also confirmed that spine-specific outcomes are included among outcomes to be presented with longer-term analyses.
“These data will come,” said Dr. Baraliakos, referring to imaging as well as other outcomes that will provide more information on the impact of secukinumab in treating the axial involvement of PsA.
Dr. Baraliakos reported multiple financial relationships with pharmaceutical companies, including Novartis, which sponsored this trial.
SOURCE: Ann Rheum Dis. Jun 2019;78(Suppl2):195-6. Abstract OPO235. doi: 10.1136/annrheumdis-2019-eular.2932.
REPORTING FROM EULAR 2019 CONGRESS
Overreliance on DAS scores undermines rheumatoid arthritis management
MADRID – Two major changes that improved RA management in recent years – the introduction of potent biologic and targeted synthetic drugs to control inflammatory disease, and the treat-to-target strategy – have also produced an unanticipated snag in the care patients receive. Their persistent comorbidities and their more atypical rheumatoid manifestations often go overlooked and untreated.
The situation has been dubbed “DAS blindness,” when clinicians caring for patients with RA are so focused on a patient’s disease activity score (DAS), measured by counting their swollen and tender joints (usually 28 joints to tally the DAS28 score), that they lose sight of other important features of a RA patient’s disease such as pain and fatigue, Ruth Williams, MBChB, said in an invited talk at the European Congress of Rheumatology.
“There is so much focus on the DAS28 that people are blinded by it. Clinicians concentrate too much on the primary physical condition” of RA, “and they miss important functional, psychological, and social impacts of the disease,” said Dr. Williams, a general-practice physician who is also a long-time RA patient who works as a patient representative and RA researcher at King’s College London.
In Dr. William’s extended personal experience as an RA patient (she was first diagnosed in 1966 as a child), management of the disease changed dramatically with the relatively recent, widespread adoption of the DAS28 score in routine clinical practice in Europe and the United States, migrating from its initial use in research studies. Once her clinicians began to use the DAS28 “I felt that perhaps I wasn’t being seen anymore. It was just the biology of my disease being noted rather than me as an individual,” Dr. Williams said in an interview. Clinicians “need to discuss with patients what remission means to them, and their objectives” from treatment, because a patient’s treatment goals may go beyond just reducing the number of swollen or tender joints they total in the DAS28 assessment.
Rheumatologists also have begun to recognize this common disconnect between both the assessment and the antirheumatoid treatment that RA patients routinely receive, and the symptoms that cause problems for RA patients that are not directly tied to their inflammatory disease. Patients can present with remission-level responses in their tender and swollen joint counts and in their serum level of C-reactive protein or erythrocyte sedimentation rate but still score high on the patient global assessment (PGA) scale, a residual consequence of RA that places them out of remission range based on the 2011 “Boolean” criteria for RA remission in trials endorsed by the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) (Arthritis Rheum. 2011 Mar;63[3]:373-86).
In a review of 411 RA patients who met three of the four ACR/EULAR criteria that collectively define remission, 61% missed on the PGA measure (Ann Rheum Dis. 2012 Oct;71[10]:1702-5), noted Joan M. Bathon, MD, professor of medicine and director of rheumatology at Columbia University, New York, in a talk during the Congress. Another review of 273 RA patients who missed on one of the four criteria showed 80% missing because of their PGA score (Arthritis Res Ther. 2013;15:R221). The specific clinical features that triggered high PGAs in these patients were things like fibromyalgia, back pain, anxiety, depression, and rheumatoid activity in joints not included in the DAS28 score, Dr. Bathon noted. The PGA can have poor correlation with the other three measures, but that is a strength because it reflects different dimensions of RA that are important to patients. When the PGA is discordant with the other three measures of remission, it may not make sense to try to improve it by simply using more immunosuppressive treatment.
The solution to the dilemma of what remission target to aim for when treating to target is to apply common sense to existing guidelines and recommendations and tailor management to each patient, she concluded. “The worst thing we can do is to take criteria meant for clinical rials and for patients with average scores and apply them to every individual patient,” she said. Remission guidelines are good for large populations, “but we shouldn’t apply them to every single patient without thinking.”
A similar plea for thoughtful use of the treat-to-target model and immunomodulatory treatment came in a separate talk from Laure Gossec, MD, a professor of rheumatology at Pitie-Salpétriere Hospital and Sorbonne University in Paris.
The challenge of DAS28 is that it was a remission criteria developed by the ACR and EULAR to use in clinical trials that was coopted for use in routine practice. Despite that, Dr. Gossec believes that DAS28 largely succeeded in this transition. “The DAS28 performs well, it has good prognostic capacity and is widely used.” In her practice, Dr. Gossec relies on the DAS28 score as her primary tool to track disease status in RA patients. “It’s not perfect, but I’m familiar with it, and I work with it,” she said.
It’s undeniable, she acknowledged, that a high PGA often stands between a patient and remission. PGA “is hard to use to guide anti-inflammatory treatment. Many patients have high PGA scores even though they have no inflammation.” Discrepancies like this create a case for dual-treatment targets, both a low swollen and tender joint count and low PGA, as separate and equal treatment goals, Dr. Gossec said, an approach she and her associates proposed in a recent article (Arthritis Care Res. 2018 Mar;709[3]:369-78).
Dr. Williams had no disclosures. Dr. Bathon has been a consultant to AbbVie and has received research funding from Bristol-Myers Squibb and Pfizer. Dr. Gossec has been a consultant to and has received research funding from several companies.
MADRID – Two major changes that improved RA management in recent years – the introduction of potent biologic and targeted synthetic drugs to control inflammatory disease, and the treat-to-target strategy – have also produced an unanticipated snag in the care patients receive. Their persistent comorbidities and their more atypical rheumatoid manifestations often go overlooked and untreated.
The situation has been dubbed “DAS blindness,” when clinicians caring for patients with RA are so focused on a patient’s disease activity score (DAS), measured by counting their swollen and tender joints (usually 28 joints to tally the DAS28 score), that they lose sight of other important features of a RA patient’s disease such as pain and fatigue, Ruth Williams, MBChB, said in an invited talk at the European Congress of Rheumatology.
“There is so much focus on the DAS28 that people are blinded by it. Clinicians concentrate too much on the primary physical condition” of RA, “and they miss important functional, psychological, and social impacts of the disease,” said Dr. Williams, a general-practice physician who is also a long-time RA patient who works as a patient representative and RA researcher at King’s College London.
In Dr. William’s extended personal experience as an RA patient (she was first diagnosed in 1966 as a child), management of the disease changed dramatically with the relatively recent, widespread adoption of the DAS28 score in routine clinical practice in Europe and the United States, migrating from its initial use in research studies. Once her clinicians began to use the DAS28 “I felt that perhaps I wasn’t being seen anymore. It was just the biology of my disease being noted rather than me as an individual,” Dr. Williams said in an interview. Clinicians “need to discuss with patients what remission means to them, and their objectives” from treatment, because a patient’s treatment goals may go beyond just reducing the number of swollen or tender joints they total in the DAS28 assessment.
Rheumatologists also have begun to recognize this common disconnect between both the assessment and the antirheumatoid treatment that RA patients routinely receive, and the symptoms that cause problems for RA patients that are not directly tied to their inflammatory disease. Patients can present with remission-level responses in their tender and swollen joint counts and in their serum level of C-reactive protein or erythrocyte sedimentation rate but still score high on the patient global assessment (PGA) scale, a residual consequence of RA that places them out of remission range based on the 2011 “Boolean” criteria for RA remission in trials endorsed by the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) (Arthritis Rheum. 2011 Mar;63[3]:373-86).
In a review of 411 RA patients who met three of the four ACR/EULAR criteria that collectively define remission, 61% missed on the PGA measure (Ann Rheum Dis. 2012 Oct;71[10]:1702-5), noted Joan M. Bathon, MD, professor of medicine and director of rheumatology at Columbia University, New York, in a talk during the Congress. Another review of 273 RA patients who missed on one of the four criteria showed 80% missing because of their PGA score (Arthritis Res Ther. 2013;15:R221). The specific clinical features that triggered high PGAs in these patients were things like fibromyalgia, back pain, anxiety, depression, and rheumatoid activity in joints not included in the DAS28 score, Dr. Bathon noted. The PGA can have poor correlation with the other three measures, but that is a strength because it reflects different dimensions of RA that are important to patients. When the PGA is discordant with the other three measures of remission, it may not make sense to try to improve it by simply using more immunosuppressive treatment.
The solution to the dilemma of what remission target to aim for when treating to target is to apply common sense to existing guidelines and recommendations and tailor management to each patient, she concluded. “The worst thing we can do is to take criteria meant for clinical rials and for patients with average scores and apply them to every individual patient,” she said. Remission guidelines are good for large populations, “but we shouldn’t apply them to every single patient without thinking.”
A similar plea for thoughtful use of the treat-to-target model and immunomodulatory treatment came in a separate talk from Laure Gossec, MD, a professor of rheumatology at Pitie-Salpétriere Hospital and Sorbonne University in Paris.
The challenge of DAS28 is that it was a remission criteria developed by the ACR and EULAR to use in clinical trials that was coopted for use in routine practice. Despite that, Dr. Gossec believes that DAS28 largely succeeded in this transition. “The DAS28 performs well, it has good prognostic capacity and is widely used.” In her practice, Dr. Gossec relies on the DAS28 score as her primary tool to track disease status in RA patients. “It’s not perfect, but I’m familiar with it, and I work with it,” she said.
It’s undeniable, she acknowledged, that a high PGA often stands between a patient and remission. PGA “is hard to use to guide anti-inflammatory treatment. Many patients have high PGA scores even though they have no inflammation.” Discrepancies like this create a case for dual-treatment targets, both a low swollen and tender joint count and low PGA, as separate and equal treatment goals, Dr. Gossec said, an approach she and her associates proposed in a recent article (Arthritis Care Res. 2018 Mar;709[3]:369-78).
Dr. Williams had no disclosures. Dr. Bathon has been a consultant to AbbVie and has received research funding from Bristol-Myers Squibb and Pfizer. Dr. Gossec has been a consultant to and has received research funding from several companies.
MADRID – Two major changes that improved RA management in recent years – the introduction of potent biologic and targeted synthetic drugs to control inflammatory disease, and the treat-to-target strategy – have also produced an unanticipated snag in the care patients receive. Their persistent comorbidities and their more atypical rheumatoid manifestations often go overlooked and untreated.
The situation has been dubbed “DAS blindness,” when clinicians caring for patients with RA are so focused on a patient’s disease activity score (DAS), measured by counting their swollen and tender joints (usually 28 joints to tally the DAS28 score), that they lose sight of other important features of a RA patient’s disease such as pain and fatigue, Ruth Williams, MBChB, said in an invited talk at the European Congress of Rheumatology.
“There is so much focus on the DAS28 that people are blinded by it. Clinicians concentrate too much on the primary physical condition” of RA, “and they miss important functional, psychological, and social impacts of the disease,” said Dr. Williams, a general-practice physician who is also a long-time RA patient who works as a patient representative and RA researcher at King’s College London.
In Dr. William’s extended personal experience as an RA patient (she was first diagnosed in 1966 as a child), management of the disease changed dramatically with the relatively recent, widespread adoption of the DAS28 score in routine clinical practice in Europe and the United States, migrating from its initial use in research studies. Once her clinicians began to use the DAS28 “I felt that perhaps I wasn’t being seen anymore. It was just the biology of my disease being noted rather than me as an individual,” Dr. Williams said in an interview. Clinicians “need to discuss with patients what remission means to them, and their objectives” from treatment, because a patient’s treatment goals may go beyond just reducing the number of swollen or tender joints they total in the DAS28 assessment.
Rheumatologists also have begun to recognize this common disconnect between both the assessment and the antirheumatoid treatment that RA patients routinely receive, and the symptoms that cause problems for RA patients that are not directly tied to their inflammatory disease. Patients can present with remission-level responses in their tender and swollen joint counts and in their serum level of C-reactive protein or erythrocyte sedimentation rate but still score high on the patient global assessment (PGA) scale, a residual consequence of RA that places them out of remission range based on the 2011 “Boolean” criteria for RA remission in trials endorsed by the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) (Arthritis Rheum. 2011 Mar;63[3]:373-86).
In a review of 411 RA patients who met three of the four ACR/EULAR criteria that collectively define remission, 61% missed on the PGA measure (Ann Rheum Dis. 2012 Oct;71[10]:1702-5), noted Joan M. Bathon, MD, professor of medicine and director of rheumatology at Columbia University, New York, in a talk during the Congress. Another review of 273 RA patients who missed on one of the four criteria showed 80% missing because of their PGA score (Arthritis Res Ther. 2013;15:R221). The specific clinical features that triggered high PGAs in these patients were things like fibromyalgia, back pain, anxiety, depression, and rheumatoid activity in joints not included in the DAS28 score, Dr. Bathon noted. The PGA can have poor correlation with the other three measures, but that is a strength because it reflects different dimensions of RA that are important to patients. When the PGA is discordant with the other three measures of remission, it may not make sense to try to improve it by simply using more immunosuppressive treatment.
The solution to the dilemma of what remission target to aim for when treating to target is to apply common sense to existing guidelines and recommendations and tailor management to each patient, she concluded. “The worst thing we can do is to take criteria meant for clinical rials and for patients with average scores and apply them to every individual patient,” she said. Remission guidelines are good for large populations, “but we shouldn’t apply them to every single patient without thinking.”
A similar plea for thoughtful use of the treat-to-target model and immunomodulatory treatment came in a separate talk from Laure Gossec, MD, a professor of rheumatology at Pitie-Salpétriere Hospital and Sorbonne University in Paris.
The challenge of DAS28 is that it was a remission criteria developed by the ACR and EULAR to use in clinical trials that was coopted for use in routine practice. Despite that, Dr. Gossec believes that DAS28 largely succeeded in this transition. “The DAS28 performs well, it has good prognostic capacity and is widely used.” In her practice, Dr. Gossec relies on the DAS28 score as her primary tool to track disease status in RA patients. “It’s not perfect, but I’m familiar with it, and I work with it,” she said.
It’s undeniable, she acknowledged, that a high PGA often stands between a patient and remission. PGA “is hard to use to guide anti-inflammatory treatment. Many patients have high PGA scores even though they have no inflammation.” Discrepancies like this create a case for dual-treatment targets, both a low swollen and tender joint count and low PGA, as separate and equal treatment goals, Dr. Gossec said, an approach she and her associates proposed in a recent article (Arthritis Care Res. 2018 Mar;709[3]:369-78).
Dr. Williams had no disclosures. Dr. Bathon has been a consultant to AbbVie and has received research funding from Bristol-Myers Squibb and Pfizer. Dr. Gossec has been a consultant to and has received research funding from several companies.
REPORTING FROM EULAR 2019 CONGRESS
Tocilizumab linked to refractory uveitis improvements in some JIA patients
MADRID – Tocilizumab was associated with improved vision in about half of 22 enrolled children with juvenile idiopathic arthritis (JIA) and uveitis refractory to tumor necrosis factor inhibitor (TNFi) therapy, based on results from an investigator-initiated phase 2 trial presented at the European Congress of Rheumatology.
At 12 weeks of treatment, 11 children in the study had some improvement in uveitis and 7 of them had achieved the primary study outcome, which was a two-step decrease in the level of inflammation as measured by the Standard of the Uveitis Nomenclature (SUN) criteria, Athimalaipet V. Ramanan, MBBS, of the department of paediatric rheumatology at the University Hospitals Bristol (England) NHS Foundation Trust, said. Ten of the 21 evaluable patients had no apparent response to tocilizumab. One study participant could not be included in the final analysis because of a violation in study protocol that involved use of disallowed concomitant medications.
“Although this study did not meet the prespecified criterion for efficacy (for most of those treated) ... almost half of those enrolled achieved some benefit,” reported Dr. Ramanan.
The multicenter investigator-initiated phase 2 trial conducted in the United Kingdom enrolled children with JIA and uveitis that was refractory to methotrexate and TNFi therapy. The study participants received methotrexate as well as 162 mg of tocilizumab administered subcutaneously every 2 weeks (those weighing less than 30 kg received tocilizumab treatment every 3 weeks).
Seven of 21 evaluable patients achieved the two-step reduction in inflammation that was the prespecified criterion for a response. For the study population overall, this fell short of statistical significance (P = .11).
However, Dr. Ramanan emphasized that another three patients achieved a one-step improvement, which he believes merits consideration as a sign of efficacy in a “very refractory group.” Moreover, three of four patients with macular edema at baseline had total resolution of this complication.
Other outcomes of interest monitored during the study included the safety and tolerability of tocilizumab and change in use of topical corticosteroids. There were no serious adverse events associated with tocilizumab in this study, according to Dr. Ramanan.
SOURCE: Ann Rheum Dis. Jun 2019;78(Suppl2)265, Abstract LB0011.
MADRID – Tocilizumab was associated with improved vision in about half of 22 enrolled children with juvenile idiopathic arthritis (JIA) and uveitis refractory to tumor necrosis factor inhibitor (TNFi) therapy, based on results from an investigator-initiated phase 2 trial presented at the European Congress of Rheumatology.
At 12 weeks of treatment, 11 children in the study had some improvement in uveitis and 7 of them had achieved the primary study outcome, which was a two-step decrease in the level of inflammation as measured by the Standard of the Uveitis Nomenclature (SUN) criteria, Athimalaipet V. Ramanan, MBBS, of the department of paediatric rheumatology at the University Hospitals Bristol (England) NHS Foundation Trust, said. Ten of the 21 evaluable patients had no apparent response to tocilizumab. One study participant could not be included in the final analysis because of a violation in study protocol that involved use of disallowed concomitant medications.
“Although this study did not meet the prespecified criterion for efficacy (for most of those treated) ... almost half of those enrolled achieved some benefit,” reported Dr. Ramanan.
The multicenter investigator-initiated phase 2 trial conducted in the United Kingdom enrolled children with JIA and uveitis that was refractory to methotrexate and TNFi therapy. The study participants received methotrexate as well as 162 mg of tocilizumab administered subcutaneously every 2 weeks (those weighing less than 30 kg received tocilizumab treatment every 3 weeks).
Seven of 21 evaluable patients achieved the two-step reduction in inflammation that was the prespecified criterion for a response. For the study population overall, this fell short of statistical significance (P = .11).
However, Dr. Ramanan emphasized that another three patients achieved a one-step improvement, which he believes merits consideration as a sign of efficacy in a “very refractory group.” Moreover, three of four patients with macular edema at baseline had total resolution of this complication.
Other outcomes of interest monitored during the study included the safety and tolerability of tocilizumab and change in use of topical corticosteroids. There were no serious adverse events associated with tocilizumab in this study, according to Dr. Ramanan.
SOURCE: Ann Rheum Dis. Jun 2019;78(Suppl2)265, Abstract LB0011.
MADRID – Tocilizumab was associated with improved vision in about half of 22 enrolled children with juvenile idiopathic arthritis (JIA) and uveitis refractory to tumor necrosis factor inhibitor (TNFi) therapy, based on results from an investigator-initiated phase 2 trial presented at the European Congress of Rheumatology.
At 12 weeks of treatment, 11 children in the study had some improvement in uveitis and 7 of them had achieved the primary study outcome, which was a two-step decrease in the level of inflammation as measured by the Standard of the Uveitis Nomenclature (SUN) criteria, Athimalaipet V. Ramanan, MBBS, of the department of paediatric rheumatology at the University Hospitals Bristol (England) NHS Foundation Trust, said. Ten of the 21 evaluable patients had no apparent response to tocilizumab. One study participant could not be included in the final analysis because of a violation in study protocol that involved use of disallowed concomitant medications.
“Although this study did not meet the prespecified criterion for efficacy (for most of those treated) ... almost half of those enrolled achieved some benefit,” reported Dr. Ramanan.
The multicenter investigator-initiated phase 2 trial conducted in the United Kingdom enrolled children with JIA and uveitis that was refractory to methotrexate and TNFi therapy. The study participants received methotrexate as well as 162 mg of tocilizumab administered subcutaneously every 2 weeks (those weighing less than 30 kg received tocilizumab treatment every 3 weeks).
Seven of 21 evaluable patients achieved the two-step reduction in inflammation that was the prespecified criterion for a response. For the study population overall, this fell short of statistical significance (P = .11).
However, Dr. Ramanan emphasized that another three patients achieved a one-step improvement, which he believes merits consideration as a sign of efficacy in a “very refractory group.” Moreover, three of four patients with macular edema at baseline had total resolution of this complication.
Other outcomes of interest monitored during the study included the safety and tolerability of tocilizumab and change in use of topical corticosteroids. There were no serious adverse events associated with tocilizumab in this study, according to Dr. Ramanan.
SOURCE: Ann Rheum Dis. Jun 2019;78(Suppl2)265, Abstract LB0011.
REPORTING FROM EULAR 2019 Congress