Objective. To report safety and efficacy of ixekizumab (IXE) from the COAST program at 3 years, including 1 year from the originating studies (COAST-V, COAST-W, and COAST-X), and 2 years from COAST... Show moreObjective. To report safety and efficacy of ixekizumab (IXE) from the COAST program at 3 years, including 1 year from the originating studies (COAST-V, COAST-W, and COAST-X), and 2 years from COAST-Y.Methods. In COAST-Y, patients continued with the dose received at the end of the originating study at week 52: 80 mg IXE either every 4 weeks (Q4W) or every 2 weeks (Q2W). Placebo-treated patients from COAST-X received IXE Q4W in COAST-Y. Starting at week 116 (week 64 of COAST-Y), patients receiving IXE Q4W could be escalated to Q2W. Safety for patients receiving >= 1 dose of IXE and efficacy for patients receiving >= 1 dose of IXE Q4W was assessed. Data are summarized as observed.Results. For the 932 patients who received >= 1 dose of IXE (Q2W or Q4W) through 3 years, treatment-emergent adverse events (TEAEs) occurred at an incidence rate (IR) of 38.0 per 100 patient-years (PYs). The most frequently reported were infections (IR 25.7 per 100 PYs) and injection site reactions (IR 7.4 per 100 PYs); the majority of TEAEs were mild or moderate in severity. In total, 7.1% of TEAEs led to discontinuation (IR 3.1 per 100 PYs). All patient groups receiving IXE Q4W assessed through 3 years saw sustained improvements in Ankylosing Spondylitis Disease Activity Score, clinically important improvement, and other efficacy end points.Conclusion. The 3-year safety profile of IXE in the COAST program is consistent with the previously established long-term safety profile. IXE Q4W provided sustained improvement of disease activity in patients who received treatment through 3 years. (ClinicalTrials.gov: NCT02696785 [COAST-V], NCT02696798 [COAST-W], NCT02757352 [COAST-X], and NCT03129100 [COAST-Y]) Show less
Objective: Our aim was to study the importance of baseline BMI, smoking, and alcohol consumption (AC) for disease activity (DA) over 1 year in early axial spondyloarthritis (axSpA), stratified by... Show moreObjective: Our aim was to study the importance of baseline BMI, smoking, and alcohol consumption (AC) for disease activity (DA) over 1 year in early axial spondyloarthritis (axSpA), stratified by sex. Methods: In the SPondyloArthritis Caught Early cohort ( patients with chronic back pain onset at age < 45 yrs, with pain for >= 3 months and >= 2 yrs), the Ankylosing Spondylitis Disease Activity Score (ASDAS) was recorded at inclusion, 3, and 12 months. All patients included in the analysis had axSpA based on a high physician's level of confidence at baseline. Differences in ASDAS over 1 year by BMI (normal < 25 kg/m(2), overweight 25-29.9 kg/m(2), and obese >= 30 kg/m(2)), smoking history (never/previous/current), and AC (none, 0.1-2 units/week, 3-5 units/week, and >= 6 units/week) at baseline were estimated using mixed linear regression models. Results: There were 344 subjects (mean age of 30.3 yrs; 49.4% men). In women, obesity was associated with 0.60 (95% CI 0.28-0.91) higher ASDAS compared to normal BMI. In both sexes, AC tended to be associated with lower DA over 1 year, with a significant association only in women with the highest AC (mean difference of -0.55, 95% CI -1.05 to -0.04). Smoking was associated with higher ASDAS over 1 year compared to never smoking in both sexes, although the difference reached statistical significance only in female former smokers. Results were similar in multivariable analysis, adjusted for all lifestyle factors and other confounders. Conclusion: In early axSpA, BMI and smoking are associated with higher DA over 1 year, and AC with lower DA. The magnitude of the modest associations may differ between men and women. Show less
Heijde, D. van der; Ostergaard, M.; Reveille, J.D.; Baraliakos, X.; Kronbergs, A.; Sandoval, D.M.; ... ; Maksymowych, W.P. 2022
Objective. To evaluate the long-term effect of ixekizumab (IXE) on radiographic changes in the spine in patients with radiographic axial spondyloarthritis (r-axSpA) by measuring change from... Show moreObjective. To evaluate the long-term effect of ixekizumab (IXE) on radiographic changes in the spine in patients with radiographic axial spondyloarthritis (r-axSpA) by measuring change from baseline through 2 years in modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS), and to identify potential predictors of progression. Methods. This study evaluates patients from COAST-V (ClinicalTrials.gov: NCT02696785, biologic disease-modifying antirheumatic drug-naive) and COAST-W (NCT02696798, tumor necrosis factor inhibitor-experienced) who had mSASSS data at baseline in the originating studies and 108 weeks after baseline in the extension study COAST-Y (NCT03129100). We examined the proportion of patients who did not have spinal radiographic progression through 2 years (108 weeks) of treatment with IXE (80 mg every 2 or 4 weeks) and the change from baseline to year 2 in mSASSS. Potential predictors of spinal radiographic progression were also evaluated. Results. Among patients with evaluable radiographs who were originally assigned to IXE (n = 230), mean (SD) change in mSASSS from baseline at year 2 was 0.3 (1.8). The proportion of nonprogressors over 2 years was 89.6% if defined as mSASSS change from baseline < 2 and 75.7% if defined as mSASSS change from baseline <= 0. Predictors of structural progression at year 2 (mSASSS change > 0) were age >= 40, baseline syndesmophytes, HLA-B27 positivity, and male sex. Week 52 inflammation in Spondyloarthritis Research Consortium of Canada spine was also a predictor of radiographic progression at year 2 in patients with magnetic resonance imaging data in COAST-V (n = 109). Conclusion. The majority of patients with r-axSpA receiving IXE had no radiographic progression in the spine through 2 years of treatment. Predictors were generally consistent with previous studies. Show less
Boel, A.; Navarro-Compan, V.; Boonen, A.; Mease, P.; Kiltz, U.; Dougados, M.; ... ; Heijde, D. van der 2021
Objective. Advances in the field of axial spondyloarthritis (axSpA) and the methodology to develop core sets have led the Assessment of SpondyloArthritis international Society (ASAS) group to... Show moreObjective. Advances in the field of axial spondyloarthritis (axSpA) and the methodology to develop core sets have led the Assessment of SpondyloArthritis international Society (ASAS) group to update the ASAS-Outcomes in Rheumatology (OMERACT) core set. An important aspect was to ensure it would be applicable to the entire spectrum of axSpA. The first step was to define the most relevant disease domains.Methods. A 3-round Delphi survey was conducted to gather opinions of 188 patients and 188 axSpA experts to define the most relevant disease domains to be included in the core set. The Delphi survey evaluated 2 separate research settings: (1) studies assessing symptom-modifying therapies; and (2) studies evaluating disease-modifying therapies. Importance of the domains was rated on a 1-9 Likert scale. A domain was considered for inclusion if, for both stakeholder groups, >= 70% of participants scored the domain as critical (7-9) and <= 15% scored it as not important (1-3) after 3 rounds.Results. A total of 132 (70%) patients and 135 (72%) experts completed at least 1 round. After 3 rounds, 7 domains (pain, physical function, stiffness, disease activity, mobility, overall functioning and health, peripheral manifestations) were selected for the symptom-modifying therapies setting. For the disease-modifying therapies setting, 6 domains (physical function, disease activity, mobility, structural damage, extramusculoskeletal manifestations, peripheral manifestations) were selected. All domains selected by experts were also selected by patients. Patients selected all offered domains except emotional function.Conclusion. This study provides the domains selected by patients and axSpA experts that should be considered for the core set for axSpA. Show less
Tanaka, Y.; Takeuchi, T.; Soen, S.; Yamanaka, H.; Yoneda, T.; Tanaka, S.; ... ; Heijde, D. van der 2021
Objective. To evaluate the safety and efficacy of long-term denosumab 60 mg every 6 months (Q6M) or every 3 months (Q3M) in patients with rheumatoid arthritis (RA). Methods. This 12-month,... Show moreObjective. To evaluate the safety and efficacy of long-term denosumab 60 mg every 6 months (Q6M) or every 3 months (Q3M) in patients with rheumatoid arthritis (RA). Methods. This 12-month, randomized, double-blind, placebo-controlled, multicenter, phase III trial with an open-label extension period from 12 to 36 months (DESIRABLE) enrolled Japanese patients with RA treated with placebo (P) for 12 months followed by either denosumab Q6M (P/Q6M) or denosumab Q3M (P/Q3M) for 24 months; denosumab Q6M for 36 months (Q6M/Q6M); or denosumab Q3M for 36 months (Q3M/Q3M). Efficacy was assessed by van der Heijde modified total Sharp score (mTSS), bone erosion score (BES), and joint space narrowing (JSN) score. Results. Long-term treatment better maintained mTSS and BES suppression in the P/Q3M and Q3M/ Q3M vs P/Q6M and Q6M/Q6M groups; changes from baseline in total mTSS (standard error) at 36 months were 2.8 (0.4) and 1.7 (0.3) vs 3.0 (0.4) and 2.4 (0.3), respectively, and corresponding changes in BES were 1.3 (0.2) and 0.4 (0.2) vs 1.4 (0.2) and 1.1 (0.2), respectively. No JSN effect was observed. Bone mineral density consistently increased in all groups after denosumab initiation, regardless of concomitant glucocorticoid administration. Serum C-terminal telopeptide of type I collagen decreased rapidly at 1 month postdenosumab administration (in both the initial 12-month [Q3M and Q6M groups] and long-term treatment [P/Q3M and P/Q6M groups] phases). Adverse event incidence leading to study drug discontinuation was similar across treatment groups. Conclusion. Denosumab treatment maintained inhibition of progression of joint destruction up to 36 months. Based on effects on BES progression, higher dosing frequency at an earlier treatment stage may be needed to optimize treatment. Denosumab was generally well tolerated. (ClinicalTrials.gov: NCT01973569). Show less
Groot, N.; Kardolus, A.; Bijl, M.; Dolhain, R.J.E.M.; Teng, Y.K.O.; Zirkzee, E.; ... ; Kamphuis, S. 2021
Objective. Long-term outcome data in adults with childhood-onset systemic lupus erythematosus (cSLE) are limited. Here, we report the effects of cSLE on education, vocation, and employment in a... Show moreObjective. Long-term outcome data in adults with childhood-onset systemic lupus erythematosus (cSLE) are limited. Here, we report the effects of cSLE on education, vocation, and employment in a large cohort of adults with cSLE.Methods. Patients were seen for a single study visit comprising a structured history and physical examination. Medical records were retrieved to supplement information obtained during the study visit. Education and employment status were assessed by questionnaires. I Iealth-related quality of life (HRQOL) was measured with the 36-Item Short Form Health Survey (SF-36).Results. One hundred six patients with cSLE (93% female, 73% White), with a median disease duration of 20 years, completed the visit and questionnaires. Almost all patients stated that cSLE had influenced their education, but the level of completed education was similar to the general Dutch population. Half of the patients had adjusted their vocational choice due to the disease. Still, 44% of patients who had finished education did not have a paid job. Of the employed patients, 61% worked part time. Disease damage was equally prevalent in patients with and without paid employment. A high percentage of patients (51%) were declared work disabled, due to disease damage. Patients who did not have paid employment were often work disabled. Both had a negative effect on HRQOL.Conclusion. The effect of cSLE on academic achievements and employment is substantial, despite patients adjusting their educational and vocational choices. To optimize participation in the community, ongoing support is necessary, not only to help patients find suitable education and vocations but also to offer guidance regarding potential adjustments during their career. Show less
Kiltz, U.; Wei, J.C.C.; Heijde, D. van der; Bosch, F. van den; Walsh, J.A.; Boonen, A.; ... ; Braun, J. 2021
Objective. This study evaluated the effect of ixekizumab (IXE) on self-reported functioning and health in patients with radiographic axial spondyloarthritis (r-axSpA) who were either biological... Show moreObjective. This study evaluated the effect of ixekizumab (IXE) on self-reported functioning and health in patients with radiographic axial spondyloarthritis (r-axSpA) who were either biological disease-modifying antirheumatic drug (bDMARD)-naive or failed at least 1 tumor necrosis factor inhibitor (TNFi).Methods. In 2 multicenter, randomized, double-blind, placebo-controlled, and active-controlled (bDMARD-naive only) trials, patients with r-axSpA were randomly assigned to receive 80 mg of IXE [every 2 weeks (Q2W) or every 4 weeks (Q4W)], placebo (PBO), or adalimumab (ADA; bDMARD-naive only). After 16 weeks, patients who received PBO or ADA were rerandomized to receive IXE (Q2W or Q4W) up to Week 52. Functioning and health were measured by the generic 36-item Short Form Health Survey (SF-36) and the disease-specific Assessment of Spondyloarthritis international Society Health Index (ASAS HI). Societal health utility was assessed by the 5-level EuroQol-5 Dimension (EQ-5D-5L).Results. At Week 16, both doses of IXE in bDMARD-naive and TNFi-experienced patients resulted in larger improvement in SF-36, ASAS HI, and EQ-5D-5L versus placcbo. For SF-36, the largest improvements were seen for the domains of bodily pain, physical function, and role physical. A larger proportion of patients reaching improvement in ASAS HI >= 3 as well as an achievement of ASAS HI good health status was reported in patients treated with IXE. Improvements were maintained through Week 52.Conclusion. IXE significantly improved functioning and health as assessed by both generic and disease-specific measures, as well as societal health utility values in patients with r-axSpA, as measured by SF-36, ASAS HI, and EQ-5D-5L at Week 16, and improvements were sustained through 52 weeks. Show less
Roe, Y.; Buchbinder, R.; Grotle, M.; Whittle, S.; Ramiro, S.; Huang, H.M.; ... ; Ostensjo, S. 2020
Objective. The objective of this paper is to assess the content and measurement constructs of the candidate instruments for the domains of "pain" and "physical function/activity" in the Outcome... Show moreObjective. The objective of this paper is to assess the content and measurement constructs of the candidate instruments for the domains of "pain" and "physical function/activity" in the Outcome Measures in Rheumatology (OMERACT) shoulder core set. The results of this International Classification of Functioning, Disability, and Health (ICF)-based analysis may inform further decisions on which instruments should ultimately be included in the core set.Methods. The materials for the analysis were the 13 candidate measurement instruments within pain and physical function/activity in the shoulder core domain set, which either passed or received amber ratings (meaning there were some issues with the instrument) in the OMERACT filtering process. The content of the candidate instruments was extracted and linked to the ICF using the refined linking rules. The linking rules enhance the comparability of instruments by providing a comprehensive overview of the content of the instruments, the context in which the measurements take place, the perspectives adopted, and the types of response options.Results. The ICF content analysis showed a large variation in content and measurement constructs in the candidate instruments for the shoulder core outcome measurement set.Conclusion. Two of 6 pain instruments include constructs other than pain. Within the physical function/activity domain, 2 candidate instruments matched the domain, 3 included additional content, and 2 included meaningful concepts in the response options, suggesting that they should be omitted as candidate instruments. The analyses show that the content in most existing instruments of shoulder pain and functioning extends across core set domains. Show less
Dakkak, Y.J.; Matthijssen, X.M.E.; Heijde, D. van der; Reijnierse, M.; Helm-van Mil, A.H.M. van der 2020
Objective. The Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS) is validated for hand MRI. Its reliability applied to metatarsophalangeal (MTP 1-5) joints is unknown and was studied... Show moreObjective. The Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS) is validated for hand MRI. Its reliability applied to metatarsophalangeal (MTP 1-5) joints is unknown and was studied in early arthritis and clinically suspect arthralgia.Methods. Patients underwent 1.5 Tesla MRI of MTP, metacarpophalangeal (MCP 2-5), and wrist joints. Two paired readers scored bone marrow edema (BME), synovitis, tenosynovitis, and erosions. Interreader reliability was assessed of 441 consecutive early arthritis patients at baseline, 215 by 2 readers, and the remaining 226 by 2 different readers. Two readers scored baseline MRI of 82 consecutive patients with clinically suspect arthralgia, and 40 randomly selected patients by 9 readers. Intrareader reliability was determined on a random set of 15 early arthritis patients, scored twice by 2 readers. For change scores, 30 early arthritis patients with baseline and 1-year followup MRI were scored by 2 readers. Intraclass correlation coefficients (ICC), Bland-Altman (BA) plots, and smallest detectable change (SDC) were determined. MRI data of MTP joints were compared to wrist and MCP joints.Results. Interreader ICC and mean scores in early arthritis were BME ICC 0.91-0.92 (mean 1.5 +/- SD 2.6), synovitis 0.90-0.92 (1.3 +/- 1.7), tenosynovitis 0.80-0.85 (1.1 +/- 1.8), and erosions 0.88-0.89 (0.7 +/- 1.0). In patients with clinically suspect arthralgia, ICC were comparable. Intrareader ICC for inflammatory MRI features were 0.84-0.98, for erosions 0.71 (reader 1), and 0.92 (reader 2). Change score ICC were = 0.90, except erosions (0.77). SDC were = 1.0. BA plots showed no systematic bias. Reliability scores of MTP joints were similar to MCP and wrist joints.Conclusion. Status and change MRI scores of BME, synovitis, tenosynovitis, and erosions of MTP joints can be assessed reliably by RAMRIS. Show less
Sepriano, A.; Ramiro, S.; FitzGerald, O.; Ostergaard, M.; Homik, J.; Heijde, D. van der; ... ; Maksymowych, W.P. 2020
Objective. Compelling evidence supports a treat-to-target (T2T) strategy for optimal outcomes in rheumatoid arthritis (RA). There is limited knowledge regarding the factors that impede... Show moreObjective. Compelling evidence supports a treat-to-target (T2T) strategy for optimal outcomes in rheumatoid arthritis (RA). There is limited knowledge regarding the factors that impede implementation of T2T, particularly in a setting where adherence to T2T is protocol-specified. We aimed to assess clinical factors that associate with failure to adhere to T2T.Methods. Patients with RA from 10 countries who were starting or changing conventional synthetic disease-modifying antirheumatic drugs and/or starting tumor necrosis factor inhibitors were followed for 2 years. Participating physicians were required per protocol to adhere to the T2T strategy. Factors influencing adherence to T2T low disease activity (T2T-LDA; 44-joint count Disease Activity Score <= 2.4) were analyzed in 2 types of binomial generalized estimating equations models: (1) including only baseline features (baseline model); and (2) modeling variables that inherently vary over time as such (longitudinal model).Results. A total of 571 patients were recruited and 439 (76.9%) completed 2-year followup. Failure of adherence to T2T-LDA was noted in 1765 visits (40.5%). In the baseline multivariable model, a high number of comorbidities (OR 1.10, 95% CI 1.02-1.19), smoking (OR 1.32, 95% CI 1.08-1.63) and high number of tender joints (OR 1.03, 95% CI 1.02-1.04) were independently associated with failure to implement T2T, while anticitrullinated protein antibody/rheumatoid factor positivity (OR 0.63, 95% CI 0.50-0.80) was a significant facilitator of T2T. Results were similar in the longitudinal model.Conclusion. Lack of adherence to T2T in the RA BIODAM cohort was evident in a substantial proportion despite being a protocol requirement, and this could be predicted by clinical features Show less
Maksymowych, W.P.; FitzGerald, O.; Ostergaard, M.; Homik, J.; Heijde, D. van der; Lambert, R.G.; ... ; Landewe, R. 2020
Objective. The Outcome Measures in Rheumatology Soluble Biomarker Working Group initiated an international, multicenter, prospective study, the Rheumatoid Arthritis (RA) BIODAM cohort, to generate... Show moreObjective. The Outcome Measures in Rheumatology Soluble Biomarker Working Group initiated an international, multicenter, prospective study, the Rheumatoid Arthritis (RA) BIODAM cohort, to generate resources for the clinical validation of candidate biomarkers predictive of radiographic progression. This first report describes the cohort, clinical outcomes, and radiographic findings.Methods. Patients with RA from 38 sites in 10 countries starting or changing conventional synthetic disease-modifying antirheumatic drugs and/or starting tumor necrosis factor inhibitors were followed for 2 years. Participating physicians were required to adhere to a treat-to-target strategy. Biosamples (serum, urine) were acquired every 3 months, radiography of hands and feet every 6 months, and ultrasound of hands and feet every 3 months in a subset. Primary endpoint was radiographic progression by the Sharp/van der Heijde score.Results. A total of 571 patients were recruited and 439 (76.9%) completed 2-year followup. At baseline, the majority was female (76%), mean age 55.7 years, and mean disease duration 6.5 years. Patients had a mean of 8.4 swollen and 13.6 tender joints, 44-joint count Disease Activity Score (DAS44) 3.8, 77.7% rheumatoid factor-positive or anticitrullinated protein antibody-positive. Percentage of patients in DAS and American College of Rheumatology remission at 2 years was 52.2% and 27.1%, respectively. Percentage of patients with radiographic progression (> 0.5) at 1 and 2 years was 38.2% and 59.9%, respectively.Conclusion. The RA BIODAM prospective study succeeded in generating an extensive list of clinical, imaging (2343 radiographs), and biosample (4638 sera) resources that will be made available to expedite the identification and validation of biomarkers for radiographic damage endpoints. Show less
Heijde, D. van der; Gladman, D.D.; Kishimoto, M.; Okada, M.; Rathmann, S.S.; Moriarty, S.R.; ... ; Mease, P.J. 2018
